Dissertations / Theses: 'Ventrale tegmentale Area'

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Jalabert, Marion. "Caractérisation des circuits neuronaux contrôlant l’activité des neurones dopaminergiques de l’aire tegmentale ventrale." Thesis, Bordeaux 2, 2011. http://www.theses.fr/2011BOR21824/document.

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Les neurones dopaminergiques (DA) de l’aire tegmentale ventrale (VTA) sont influencés par différents stimuli comme des récompenses naturelles et d’autres stimuli moins physiologiques tels que les drogues d’abus. Ces drogues agissent en détournant les mécanismes d’apprentissage qui sous-tendent normalement la motivation pour des renforçateurs naturels. Les neurones DA, en conditions physiologiques, sont subtilement régulés par une balance entre tonus GABA et glutamatergique. Ils sont soumis à de multiples sources inhibitrices dont le noyau accumbens, les interneurones locaux ou les neurones GABA de la queue de la VTA (tVTA). Le glutamate est également important dans leur modulation. Il contrôle leur activité en bursts, qui est le mode de décharge le plus efficace pour libérer de la dopamine et coder des informations associées à la récompense. Il permet des adaptations synaptiques à long terme qui se sont révélées importantes dans la prise de drogue. La connaissance des facteurs endogènes qui contrôlent l’excitabilité des cellules DA de la VTA est essentielle à la compréhension des processus physiologiques (recherche de plaisir…) mais aussi pathologiques (addiction…). L’objectif de mon travail a été de comprendre les circuits de régulation des neurones DA en conditions physiologiques et lors de l’exposition à la morphine. Dans un premier temps, nous avons étudié les mécanismes de régulation des neurones DA par la formation hippocampique ventrale incluant le subiculum ventral et l’aire CA1 ventrale (vSUB/CA1). Grâce à l’utilisation d’approches d’électrophysiologie in vivo chez le rat anesthésié, nous avons montré que le vSUB/CA1 exerce un contrôle excitateur glutamatergique des neurones DA. Nous avons mis en évidence que cette voie vSUB/CA1-VTA est polysynaptique, faisant intervenir le BNST comme relais. J’ai aussi pu confirmer le rôle fonctionnel de la tVTA en tant que nouvelle structure GABA modulant l’activité des neurones DA, renforçant ainsi l’idée d’une balance entre tonus GABA et glutamatergique régulant les neurones DA in vivo.La deuxième partie de ma thèse a consisté en l’étude des circuits neuronaux à l’origine des effets excitateurs de la morphine sur les neurones DA de la VTA in vivo. L’hypothèse actuelle est que la morphine excite les neurones DA par un mécanisme de désinhibition en inhibant les neurones GABA de la VTA. Grâce à l’utilisation d’approches multiples, nous avons proposé un nouveau circuit expliquant les effets de la morphine. Ces effets sont la conséquence d’une modification de la balance GABA/glutamate par la morphine. Elle se traduit par une diminution du tonus GABA et d’une augmentation du tonus glutamatergique. Enfin, nous avons pu démontrer qu’une seule exposition à la cocaïne augmente l’activité de base des neurones DA. Chez ces animaux, les effets excitateurs de la morphine sont potentialisés confirmant ainsi l’hypothèse que l’amplitude de l’activation des neurones DA par la morphine dépend de leur état d’excitabilité
Dopaminergic (DA) neurons of the ventral tegmental area (VTA) are influenced by several stimuli such as natural rewards or drugs of abuse. Drugs shunt learning mechanisms which underlie motivation for natural reinforcers. Under physiological conditions, DA neurons are regulated by a balance between GABA and glutamatergic inputs. They receive several inhibitory inputs especially from the nucleus accumbens, VTA local interneurons and GABA neurons of the tail of the VTA (tVTA). Glutamate is also important in modulating DA neuron activity. It controls their bursting activity which is the most efficient way to release dopamine and to encode reward-associated informations. It allows long term synaptic adaptations important for addiction. Knowing how these endogenous factors control VTA DA neuron excitability is essential to understand physiological (search for pleasure…) and pathological (drug addiction…) processes.In the first part of my thesis, we studied the regulation of the VTA by the hippocampal formation including the ventral subiculum and the ventral CA1 area (vSUB/CA1). Using electrophysiological approaches in anesthetized animal, we showed that the vSUB/CA1 controls VTA DA neurons and that this input is glutamatergic. We also demonstrated that the vSUB/CA1-VTA pathway is polysynaptic implicating the BNST as a relay. I also confirmed the inhibitory control of the VTA by tVTA, new GABA input to DA neurons. Thus, in vivo, DA neurons are regulated by a balance between GABA and glutamatergic inputs. The second part of my research consisted in studying the neuronal circuits underlying excitatory effects of morphine on VTA DA neurons in vivo. The actual hypothesis is that morphine excites DA neurons by a disinhibition mechanism inhibiting VTA GABA neurons. Using several approaches (electrophysiological approaches in anesthetized animal, tract-tracing methods), we proposed a new circuitry explaining morphine effects. These excitatory effects result from a modification of the balance between GABA and glutamatergic inputs with a decrease of the GABA tone and an increase of the glutamatergic tone. Finally, we demonstrated that an acute cocaine exposure increases DA neuron activity. In animals exposed to cocaine, morphine excitatory effects are potentiated. This last experiment confirms the hypothesis that the amplitude of morphine-induced activation of VTA DA neurons depends on their excitability state

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Faivre, Fanny. "La queue de l’aire tegmentale ventrale : définition anatomo-moléculaire, implication dans la réponse aux stimuli aversifs et influence sur la voie nigrostriée." Thesis, Strasbourg, 2018. http://www.theses.fr/2018STRAJ082.

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La queue de l’aire tegmentale ventrale (tVTA) est le principal contrôle inhibiteur des neurones dopaminergiques du mésencéphale. Cette structure, bien qu’aujourd’hui très étudiée, n’est cependant pas encore référencée dans les atlas stéréotaxiques. Anatomiquement, nous avons pu apporter une définition de référence de la tVTA, à travers son analyse neurochimique, stéréologique, hodologique et génomique. Fonctionnellement, nous avons montré son rôle dans la réponse à des expériences émotionnelles aversives et nous avons testé son influence sur les symptômes moteurs et non-moteurs de la maladie de Parkinson. Nous avons ainsi montré qu’une co-lésion de la tVTA dans un modèle murin de la maladie permet une amélioration des performances motrices, des seuils nociceptifs et des symptômes de type dépressifs. Ce travail a ainsi participé au progrès de nos connaissances sur la tVTA et ouvre de nouvelles pistes d’exploration quant à son implication fonctionnelle
The tail of the ventral tegmental area (tVTA) is the major brake of the midbrain dopamine neurons. This structure although studied, is not yet referenced in stereotaxic atlases. Anatomically, this work allowed to obtain a reference definition of the tVTA through its neurochemical, stereological, connectivity-based and genomic analyses. Functionally, we studied its role for the response of aversive stimuli and we tested its influence on motor and non-motor symptoms of Parkinson’s disease. We observed that a co-lesion of the tVTA in a rodent model of the disease induce motor, nociceptive and depressive-like symptoms improvements. This work has thus contributed to the progress of our knowledge on the tVTA and opens new explorative track for its functional implication

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Baudonnat, Mathieu. "Rôle des récompenses dans la sélection et l'utilisation de différentes formes de mémoire : interactions entre l'hippocampe et le striatum." Thesis, Bordeaux 1, 2011. http://www.theses.fr/2011BOR14392/document.

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Il existe différents types de mémoire chez l’homme et l’animal. Chez les mammifères, on distingue principalement une mémoire relationnelle/spatiale reposant sur l’hippocampe et le cortex préfrontal, et une mémoire procédurale/indicée dépendante du striatum. Lors de nouveaux apprentissages, ces systèmes interagissent de manière coopérative et/ou compétitive en fonction de la nature de la tâche. S’il est connu que les émotions négatives et le niveau d’entraînement modulent ces interactions, peu de travaux ont étudié le rôle des récompenses dans la sélection et l’utilisation de ces deux formes principales de mémoire. Nous avons utilisé deux versions du test de discrimination spatiale dans un labyrinthe en Y afin de d’évaluer la mémoire spatiale d’une part, et la mémoire procédurale d’autre part. Nos résultats montrent que la stimulation pharmacologique du système de récompense par auto-injection de morphine au niveau de l’aire tegmentale ventrale (ATV), perturbe de manière spécifique l’apprentissage spatial reposant sur le fonctionnement hippocampo-préfrontal Ce déficit spatial s’accompagne d’une forte réduction de l’activité du facteur de transcription CREB (cAMP Response Element Binding) au sein de ce réseau. Au contraire, l’apprentissage indicé est préservé et l’activation de CREB est potentialisée par l’utilisation d’une récompense pharmacologique (injections de morphine). Nous mettons en évidence que la suractivation de la voie PKA/CREB, dans le striatum dorsal, est la cause de l’interférence observée lors de la formation de la mémoire spatiale. De plus, la stimulation répétée du système de récompense par la drogue lors de l’acquisition d’une stratégie indicée entraîne une persistance de l’activité réverbérante de la voie PKA/CREB dans le striatum dorsal. Cette persistance peut être révélée par l’utilisation préférentielle d’une stratégie indicée dans une nouvelle tâche ambigüe, le test de compétition en piscine de Morris. L’ensemble de ce travail éclaire, grâce aux effets différentiels de récompenses sensorielles et pharmacologiques sur l’apprentissage, la compréhension des interactions dynamiques entre les systèmes de mémoire. De plus, il suggère que l’hyperassociativité persistante consécutive à l’usage de drogue est à l’origine de déficits de type déclaratifs qui pourraient jouer un rôle clé dans l’installation d’un comportement addictif
There are different forms of memory proceeded in human’s and animal’s brain. At least two major systems can be defined. A spatial/declarative form of memory relies on the hippocampus and prefrontal cortex, and secondly, a more rigid, procedural/cued type of memory supported by striatal circuitry. Learning requires cooperative and/or competitive interactions between memory systems, depending on the nature of the task. It is well established that negative emotions and training modulate these interactions. However, little is known about the role of rewards on the selection and formation of these forms of memory.Using two versions (spatial or cue) of a Y-maze discrimination task, we show that drug reward, but not food reward, disrupts spatial learning while sparing the cued task. The spatial memory deficit relies on an decrease of CREB (cAMP Response Element Binding) activity within the hippocampus and the prefrontal cortex. Inhibition of the PKA/CREB signalling pathway restored spatial learning, suggesting that striatal overactivation of this pathway is responsible for the spatial memory deficit. The cued learning strategy elicits a strong CREB activitiy within the dorsal striatum which is further increased by morphine injections. We propose that drug-induced activation of the DA reward system induces abnormal reverberating activity of the PKA/CREB signalling pathway within the dorsal striatum, eventually leading to a preferential use of a striatum-dependent strategy during a new ambiguous learning task, the water maze competition task.In conclusion, our results points to a key role of rewards in the modulation of learning systems. Furthermore, we provide evidence that drug-induced striatal hyperactivity may underlie the declarative memory deficit reported here. This mechanism could represent an important early step toward the development of addictive behaviors by promoting conditioning to the detriment more flexible forms of memory

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Vitay, Julien, and Fred H. Hamker. "Timing and expectation of reward: a neuro-computational model of the afferents to the ventral tegmental area." Universitätsbibliothek Chemnitz, 2014. http://nbn-resolving.de/urn:nbn:de:bsz:ch1-qucosa-147898.

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Neural activity in dopaminergic areas such as the ventral tegmental area is influenced by timing processes, in particular by the temporal expectation of rewards during Pavlovian conditioning. Receipt of a reward at the expected time allows to compute reward-prediction errors which can drive learning in motor or cognitive structures. Reciprocally, dopamine plays an important role in the timing of external events. Several models of the dopaminergic system exist, but the substrate of temporal learning is rather unclear. In this article, we propose a neuro-computational model of the afferent network to the ventral tegmental area, including the lateral hypothalamus, the pedunculopontine nucleus, the amygdala, the ventromedial prefrontal cortex, the ventral basal ganglia (including the nucleus accumbens and the ventral pallidum), as well as the lateral habenula and the rostromedial tegmental nucleus. Based on a plausible connectivity and realistic learning rules, this neuro-computational model reproduces several experimental observations, such as the progressive cancelation of dopaminergic bursts at reward delivery, the appearance of bursts at the onset of reward-predicting cues or the influence of reward magnitude on activity in the amygdala and ventral tegmental area. While associative learning occurs primarily in the amygdala, learning of the temporal relationship between the cue and the associated reward is implemented as a dopamine-modulated coincidence detection mechanism in the nucleus accumbens.

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Glangetas, Christelle. "The Bed Nucleus of the Stria Terminalis between Stress and Reward." Thesis, Bordeaux, 2014. http://www.theses.fr/2014BORD0419/document.

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L’objectif principal de mon projet de thèse a été d’identifier les mécanismes neuronaux adaptatifs se mettant en place au niveau des circuits de la récompense et des circuits activés en réponse à un stress aigu. Plus spécifiquement, nous avons étudié le rôle du noyau du lit de la strie terminale (BNST) au sein de ces deux circuits. Mon hypothèse est que le BNST appartient à un circuit de structures interconnectées dans lequel il intègre des informations contextuelles (hippocampe ventral) et des informations émotionnelles (cortex préfrontal médian) afin, d’une part, de réguler les niveaux d’anxiété innés ainsi que les réponses induites par les centres du stress suite à un épisode de stress aigu mais également, d’adapter l’activité des neurones dopaminergiques de l’aire tegmentale ventrale (VTA) en vue de motiver ou d’empêcher la reproduction d’un comportement associé à un stimulus récompensant ou aversif. Afin de tester cette hypothèse, nous avons mis en place et développé différents projets de recherche combinant des approches d’électrophysiologie in vivo, anatomiques et comportementales. Dans un premier temps, nous nous sommes intéressés au BNST en tant que structure clef participant à la régulation des centres de stress. Grâce à l’utilisation d’approches d’électrophysiologie in vivo chez la souris anesthésiée, nous avons montré qu’après l’exposition à un stress aigu, les neurones du BNST adaptent leur réponse suite à la stimulation du cortex préfrontal médian et passent d’une dépression à long terme (LTD) en situation contrôle à une potentialisation à long terme (LTP) après un stress aigu. Nous avons disséqué une partie des mécanismes permettant l’élaboration de ces plasticités grâce à l’utilisation de souris génétiquement modifiés pour le récepteur aux endocannabinoïdes de type 1 (CB1-R). Ainsi, nous avons trouvé que la LTD et la LTP mis en place dans le BNST sont médiées par le système endocannabinoïde via les récepteurs CB1. Ensuite, nous avons étudié le rôle du ventral subiculum (vSUB) dans la régulation des neurones du BNST ainsi que l’impact de l’activation de cette voie vSUB-BNST sur l’autre voie glutamatergique ILCx-BNST. Tout d’abord, nous avons montré par des approches électrophysiologiques et anatomiques, qu’un même neurone du BNST est capable d’intégrer des informations provenant à la fois du ventral subiculum et du cortex infralimbic (ILCx). Nous avons induit in vivo une LTP NMDA dépendante dans la voie vSUB-BNST suite à un protocole de stimulation haute fréquence dans le vSUB alors qu’en parallèle ce même protocole induit une LTD sur ces mêmes neurones dans la voie ILCx–BNST. Deplus, nous avons noté que ces adaptations plastiques se mettant en place dans le BNST suiteà une simple stimulation haute fréquence dans le vSUB permettent à long terme de diminuerles niveaux d’anxiété innés chez le rat. Enfin, nous avons mis en évidence que le BNST est un relai excitateur entre le vSUBet la VTA. Nous avons montré qu’une stimulation à haute fréquence dans le vSUBpotentialise in vivo l’activité des neurones dopaminergiques (DA) de la VTA. Or le vSUBne projette pas de manière directe sur les neurones DA de la VTA. Nous avons observé quece protocole de stimulation haute fréquence dans le vSUB induit dans un premier temps uneLTP NMDA dépendante dans les neurones du BNST projetant à la VTA qui est nécessairepour observer cette potentialisation des neurones DA. En dernier lieu, nous avons montréque cette potentialisation des neurones DA de la VTA augmente la réponse locomotrice à unchallenge avec de la cocaine.Ainsi, l’ensemble de ces projets nous ont permis de confirmer et de préciser lafonction majeure du BNST dans la régulation du stress et de l’anxiété ainsi que dans lecircuit de la motivation
The main goal of my PhD was to identify the adaptive neuronal mechanismsdeveloping in the reward circuit and in the circuit implicated in the regulation of stressresponses. More specifically, we have studied the function of the bed nucleus of the striaterminalis (BNST) in both circuits.My hypothesis was that, the BNST belongs to interconnected circuits in whichintegrates contextual (from ventral hippocampus) and emotional informations (from medialprefrontal cortex). Thus, the BNST diffuses these informations in order to regulate the basalinnate level of anxiety and stress centers responses induced after acute stress exposure, butalso to adapt the activity of dopaminergic neurons of the ventral tegmental area (VTA) thatcan promote or prevent a behavioral task associated with a rewarding or aversive stimulus.To test this hypothesis, we decided to develop several research projects usingelectrophysiological, anatomical and behavioral approaches.Firstly, we focused our interest on the stress circuit in which the BNST is a keystructure which participates in regulating the responses of stress centers after acute stressexposure. By using in vivo electrophysiology approach in anesthetized mice, we haveshown that after acute restraint stress, BNST neurons adapt their plastic responses inducedby the tetanic stimulation of the medial prefrontal cortex: switch from long term depression(LTD) under control condition to long term potentiation (LTP) after acute stress condition.Furthermore, we demonstrated that both LTD and LTP are endocannabinoid dependent byusing genetic modified mice for the type 1 endocannabinoid receptors and localpharmacological approach in the BNST.In a second step, we studied the function of the ventral subiculum (vSUB) in theregulation of BNST neurons and the impact of the vSUB-BNST pathway activation on theother glutamatergic ILCx-BNST pathway. In a first set of experiments, we showed that asame single BNST neuron could integrate informations from both vSUB and the infralimbiccortex. By using high frequency stimulation (HFS) protocols, we induced in vivo NMDAdependentLTP in the vSUB-BNST pathway whereas the same protocol led to LTD in thesame BNST neurons in the ILCx-BNST pathway. Moreover, we noted single application ofHFS protocol in the vSUB induced a long term decrease of the basal innate level of anxietyin rats.Lastly, we presented the BNST as a key excitatory relay between the vSUB and theVTA. Here, we have shown that in vivo HFS protocols in the vSUB potentiate the activity ofdopaminergic (DA) neurons of the VTA. However, the vSUB does not directly project to theVTA. We observed that a HFS protocol in the vSUB first induce NMDA-dependent LTP inBNST neurons that project to the VTA, which is necessary to promote the potentiation of7VTA DA neurons. In the last step, we demonstrated in vivo that the potentiation of VTA DAneurons increases the locomotor response to cocaine challenge.All together, these projects allow us to confirm and detail the major function of theBNST in the regulation of stress and anxiety and also in the motivational circuit

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Sheppard, Ashley B. "Role of the Ventral Tegmental Area and Ventral Tegmental Area Nicotinic Acetylcholine Receptors in the Incentive Amplifying Effect of Nicotine." Digital Commons @ East Tennessee State University, 2014. https://dc.etsu.edu/etd/2362.

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Nicotine has multiple behavioral effects as a result of its action in the central nervous system. Nicotine strengthens the behaviors that lead to nicotine administration (primary reinforcement), and this effect of nicotine depends on mesotelencephalic systems of the brain that are critical to goal directed behavior, reward, and reinforcement. Nicotine also serves as a ‘reinforcement enhancer’ – drug administration enhances behaviors that lead to other drug and nondrug reinforcers. Although the reinforcement enhancing effects of nicotine may promote tobacco use in the face of associated negative health outcomes, the neuroanatomical systems that mediate this effect of nicotine have never been described. The ventral tegmental area (VTA) is a nucleus that serves as a convergence point in the mesotelencephalic system, plays a substantial role in reinforcement by both drug and nondrug rewards and is rich in both presynaptic and postsynaptic nicotinic acetylcholine receptors (nAChRs). Therefore, these experiments were designed to determine the role of the VTA and nAChR subtypes in the reinforcement enhancing effect of nicotine. Transiently inhibiting the VTA with a gamma amino butyric acid (GABA) agonist cocktail (baclofen and muscimol) reduced both primary reinforcement by a visual stimulus and the reinforcement enhancing effect of nicotine, without producing nonspecific suppression of activity. Intra-VTA infusions of a high concentration of mecamylamine a nonselective nAChR antagonist, or methylycaconitine, an α7 nAChR antagonist, did not reduce the reinforcement enhancing effect of nicotine. Intra-VTA infusions of a low concentration of mecamylamine and dihydro-beta-erythroidine (DHβE), a selective antagonist of nAChRs containing the *β2 subunit, attenuated, but did not abolish, the reinforcement enhancing effect of nicotine. In follow-up tests replacing systemic nicotine injections with intra-VTA infusions (70mM, 105mM) resulted in complete substitution of the reinforcement enhancing effects – increases in operant responding were comparable to giving injections of systemic nicotine. These results suggest that *β2-subunit containing nAChRs in the VTA play a role in the reinforcement enhancing effect of nicotine. However, when nicotine is administered systemically these reinforcement enhancing effects may depend on the action of nicotine at nAChRs in multiple brain nuclei.

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Baimel, Corey. "Orexin modulation of ventral tegmental area dopamine neurons." Thesis, University of British Columbia, 2016. http://hdl.handle.net/2429/58211.

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Dopamine neurons in the ventral tegmental area (VTA) are critically involved in the expression of motivated behaviour. The activity of dopamine neurons is regulated by intrinsic conductances and by synaptic inputs, both of which are subject to neuromodulatory influences. This thesis explores how orexin signalling alters the synaptic regulation and the activity of VTA dopamine neurons. Chapter 1 describes a role for dopamine in motivated behaviour and highlights how drugs of abuse alter synaptic transmission in the mesocorticolimbic dopamine system to drive compulsive reward seeking. Moreover, it outlines how lateral hypothalamic orexin projections to the VTA alter synaptic transmission onto dopamine neurons to promote motivated behaviour. Chapter 2 examines how orexin signalling gates morphine-induced synaptic plasticity in the VTA. We demonstrate that inhibiting orexin receptor signalling in the VTA blocks morphine-induced increases and decreases in the strength of excitatory and inhibitory synaptic transmission respectively. Orexin neurons coexpress the inhibitory peptide dynorphin and the two are likely coreleased. In chapter 3 we demonstrate that orexin and dynorphin modulate the activity of dopamine neurons in a projection-target specific manner. Orexin preferentially increased the output of dopamine neurons that project to the lateral shell of the nucleus accumbens (NAc), while dynorphin was more effective at inhibiting the activity of dopamine neurons that project to the basolateral amygdala (BLA). Chapter 4 discusses the strength and weaknesses of these experiments and proposes future research to further enhance our understanding of orexin modulation of VTA dopamine neurons.
Medicine, Faculty of
Anesthesiology, Pharmacology and Therapeutics, Department of
Graduate

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Reisiger, Anne-Ruth. "Pathologie du système de récompense : effets à long terme d’une exposition chronique à la nicotine et au sucrose." Thesis, Bordeaux 1, 2013. http://www.theses.fr/2013BOR14870/document.

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La prise volontaire de nicotine augmente l'excitabilité de la voie ILCx-BNST, entraînant une hyperactivité des neurones DA de l’ATV. Dans une première partie, l'objectif était d’étudier les neuroadaptations de la voie ILCx-BNST induites par l'auto-administration intraveineuse (AAIV) de nicotine. Les récepteurs cannabinoides CB1 contrôlent les propriétés renforçantes de la nicotine. Par conséquent, nous avons examiné le rôle des récepteurs CB1 du BNST. Nous montrons que l'acquisition de l’AAIV de nicotine est associée à une facilitation persistante de l'induction d’une potentialisation à long terme (LTP) CB1-dépendantes des synapses ILCx-BNST. La stimulation électrique du ILCx favorise également la persistance du comportement de recherche de nicotine pendant les périodes où la drogue n'est pas disponible. En outre, en utilisant la pharmacologie intra-BNST, nous montrons que la stimulation des récepteurs CB1 du BNST au cours de l’acquisition de lAAIV augmente la sensibilité aux stimuli associés à la nicotine. L’idée qu’il existe un appétit incontrôlable pour les aliments palatables, en dépit des conséquences négatives. Dans une seconde partie, notre projet a porté sur le rôle des neurones dopaminergiques (DA) de l’ATV dans la perception d’un stimulus aversif chez l’animal exposé au sucrose. Nos résultats indiquent que le sucrose augmente l'activité spontanée des neurones DA de la VTA. En outre, si un choc électrique provoque une inhibition presque complète de l'activité de VTA neurones DA chez les rats témoins, le sucrose perturbe la signalisation d'un stimulus aversif, indépendamment de l’état calorique du rat
Learning mechanisms associated with active responding for nicotine enhanced the excitability of the ILCx-BNST pathway. The objective of this project was to better understand the involvement of the ILCx-BNST pathway in nicotine self-administration. Since the endocannabinoid system controls nicotine reinforcement and nicotine-induced synaptic modifications, we examined the role of CB1 receptors in the BNST. We showed that acquisition of nicotine IVSA was associated with a persistent facilitation of LTP induction at ILCx-BNST synapses. Behaviorally, electrical stimulation temporarily increased excessive responding to nicotine when nicotine was not available. Moreover, using intra-BNST pharmacology, we revealed that stimulation of BNST CB1 receptors enhanced sensitivity to nicotine-paired cue. In contrast, after a prolonged history of nicotine intake, it blocked drug-seeking in a reinstatement model of relapse. Drug addiction is partly due to the inability to stop using despite negative consequences. The hypothesis that palatable food induces similar uncontrolled consumption is becoming more widespread. As drug addiction is known to increases activity of VTA DA neurons, we aimed to examine whether exposure to sucrose would induce similar neuronal modifications and impair the capacity to respond to an aversive stimulus. We found that sucrose enhanced spontaneous activity of DA VTA neurons. In addition, while a footshock caused a nearly complete inhibition of activity of VTA DA neurons in control rats, sucrose disrupted signaling of an aversive stimulus. These modifications were independent from the caloric state of the rats

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Williams, Stephanie Bair. "Neuroimmune-Mediated Alcohol Effects on Ventral Tegmental Area Neurons." BYU ScholarsArchive, 2018. https://scholarsarchive.byu.edu/etd/7326.

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Dopamine (DA) transmission is a key player in the rewarding aspects of ethanol as well as ethanol dependence. The current dogma is that DA transmission is increased during ethanol via the inhibition of ventral tegmental area (VTA) GABA neurons and that excitation of VTA GABA neurons during withdrawal results in decreased DA transmission. Microglia, the major neuroimmune effector in the brain, may be a key mediator in this process by releasing cytokines following activation. We evaluated the effect of ethanol on cytokine concentrations in the VTA and NAc using a cytometric bead array, and found that low dose ethanol (1.0 g/kg) decreased interleukin (IL)-10 levels, but high dose ethanol increased IL-10 levels (4.0 g/kg). We also used standard cell-attached mode electrophysiological techniques to evaluate the effects of select cytokines on VTA neuron firing rate in vitro. We found no change in firing rate in response to IL-6, but an increase in firing rate in VTA DA neurons response to IL-10. Consistent with the changes in firing rate, optically-evoked IPSCs were also found to be decreased in response to IL-10. Ex vivo voltammetry and in vivo microdialysis were done to determine whether IL-10 can directly result in an increase in DA release. Although ex vivo voltammetry showed no change in DA release, IL-10 increased DA release in vivo. These findings suggest that the rewarding and/or addictive effects of ethanol are mediated by cytokines, specifically the anti-inflammatory cytokine IL-10.

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Taylor, Amanda Lee. "Elucidating the fear - maintaining properties of the Ventral Tegmental Area." Thesis, University of Canterbury. Psychology, 2008. http://hdl.handle.net/10092/2853.

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The ventral tegmental area (VTA) and its dopaminergic (DA) mesocorticolimbic projections are thought to be essential in the brain’s reward neurocircuitry. In humans and animal experimental subjects, mild electrical VTA stimulation increases dopamine levels and can induce euphoria. Paradoxically, aversive stimuli activate VTA neurons and forebrain DA activity, and excessive electrical stimulation of the VTA exaggerates fearfulness. Research suggests that experimental manipulation of either the amygdala or the VTA has similar effects on the acquisition and expression of Pavlovian conditioned fear. Recently it was demonstrated that electrical stimulation of the amygdala produced fear extinction deficits in rats. Fear extinction involves the progressive dissipation of conditioned fear responses by repeated non-reinforced exposure to a conditioned stimulus (CS). Maladaptive states of fear in fear-related anxiety disorders, such as post-traumatic stress disorders (PTSD) or specific phobias are thought to reflect fear extinction learning deficits. The primary purpose of the present study was to examine the effects of intra-VTA stimulation on fear extinction learning. Using fear-potentiated startle as a behavioural index of conditioned fear, it was found that 120 VTA stimulations paired or unpaired with non-reinforced CS presentations impaired the extinction of conditioned fear. This effect was not apparent in rats that received electrical stimulation of the substantia nigra (SN), suggesting that not all midbrain regions respond similarly. Electrical stimulation parameters did not have aversive affects because rats failed to show fear conditioning when electrical VTA stimulation was used as the unconditioned stimulus. Also, VTA stimulation did not alter conditioned fear expression in non-extinguished animals. Based on the results it is suggested that VTA activation disinhibited conditioned fear responding. Therefore, VTA neuronal excitation by aversive stimuli may play a role in fear-related anxiety disorders thought to reflect extinction learning deficits.

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Weed, Jared Mark. "Endocannabinoid-Dependent Long-Term Depression of Ventral Tegmental Area GABA Neurons." BYU ScholarsArchive, 2013. https://scholarsarchive.byu.edu/etd/4287.

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GABA neurons in the ventral tegmental area of the midbrain are important components in the brain's reward circuit. Long term changes in this circuit occur through the process of synaptic plasticity. It has been shown that high frequency stimulation, as well as treatment with endocannabinoids, can cause GABA neurons in the ventral tegmental area to undergo long term depression, a form of synaptic plasticity that decreases excitability of cells. The present study elaborates on the mechanism whereby high frequency stimulation can result in long term depression of ventral tegmental area GABA neurons. Using the whole cell patch clamp technique in acute brain slices, we recorded excitatory currents from ventral tegmental area GABA neurons in GAD-GFP expressing CD1 mice and observed how the excitatory currents changed in response to different treatments. We confirm that high frequency stimulation causes long term depression, and the cannabinoid type 1 receptor antagonist AM-251 blocks this effect. Long term depression is also elicited by treatment with the cannabinoid type 1 receptor agonist 2-arachidonylglycerol. It is inconclusive whether treatment with 2-arachidonylglycerol occludes further long term depression by high frequency stimulation. We also demonstrate that activation of group I metabotropic glutamate receptors by DHPG produces long term depression. These results support the model that at these excitatory synapses, high frequency stimulation causes the release of glutamate from presynaptic terminals, activating group I metabotropic glutamate receptors, causing production of 2-arachidonylglycerol. 2-arachidonylglycerol in turn acts on presynaptic cannabinoid type 1 receptors to decrease release of glutamate onto GABA neurons. This model can be tested by further research, which should include cannabinoid type 1 receptor knockout mice. This study provides more insight into how drugs of abuse such as tetrahydrocannabinol, the active component of marijuana that activate cannabinoid type I receptors, can corrupt the natural reward mechanisms of the brain.

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Friend, Lindsey Nicole. "Endocannabinoid-Mediated Synaptic Plasticity in the Ventral Tegmental Area and Hippocampus." BYU ScholarsArchive, 2016. https://scholarsarchive.byu.edu/etd/6596.

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Synaptic plasticity is the process whereby connections between neurons can be altered in an experience dependent manner. For example, drugs of abuse alter plasticity in the ventral tegmental area (VTA) of the midbrain. A large amount of research has been applied to uncovering the mechanism whereby synapses on the reward signaling dopamine cells is altered, however, less is known regarding the VTA inhibitory GABA neurons. Our objective was to examine the ability of GABA neurons to exhibit plasticity, and determine how drugs of abuse could influence it. Here we report a novel type of plasticity of excitatory neurotransmission onto VTA GABA cells. This plasticity is dependent on the metabotropic glutamate receptor 5, to signal for diacylglycerolipase alpha to make the endocannabinoid 2-arachadonoyl glycerol to signal via cannabinoid receptor 1 (CB1). Marijuana and cocaine are drugs of abuse that have been shown to alter the endocannabinoid system. Tetrahydrocannabinol is the active ingredient in marijuana, and is a known agonist of CB1, and cocaine is able to attenuate endocannabinoid signals. We tested the effects of these drugs on VTA GABA plasticity and found that it can be blocked by chronic injections of tetrahydrocannabinol, as well as acute and chronic injections of cocaine. If VTA GABA neurons are depressing excitatory inputs, that could lead to less inhibition onto VTA dopamine cells, and therefore, more reward signaling in the brain. This new type of plasticity could be an additional mechanism whereby cocaine and marijuana exert their rewarding and addictive effects. Another brain structure known to exhibit use-dependent plasticity is the hippocampus, which is involved in learning and memory. The stratum oriens is a layer of inhibitory interneurons in the hippocampus that is involved in feedback inhibition onto the principle excitatory cells in the stratum pyramidale. Our goal was to determine whether oriens interneurons were capable of producing an endocannabinoid signal, and if so, whether they could influence plasticity. We identified 2 major subtypes of oriens interneurons, oriens lacunosum-moleculare cells, and parvalbumin-positive basket cells, which are capable of receiving and producing an endocannabinoid signal. Furthermore, we demonstrated that one such endocannabinoid, anandamide, is responsible for signaling for synaptic plasticity. This plasticity is also dependent on CB1, and is unique in that there are few examples of CB1 signaling for potentiation rather than depression. Collectively, these experiments demonstrate two mechanisms of endocannabinoid mediated synaptic plasticity, which could influence reward signaling, addiction and memory.

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McLeod, Ross. "Exploring the heterogeneity of the ventral tegmental area in Parkinson’s disease." Thesis, Uppsala universitet, Institutionen för medicinsk biokemi och mikrobiologi, 2019. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-387352.

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Fullerton, Josephine L. "Examining cholinergic fuction in the ventral tegmental area and dorsal hippocampus." Thesis, University of Strathclyde, 2017. http://digitool.lib.strath.ac.uk:80/R/?func=dbin-jump-full&object_id=27929.

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Midbrain dopamine (DA) neurons project from the ventral tegmental area (VTA) to the prefrontal cortex (PFC) and ventral striatum (NAc and OT) forming a key part of the well-defined mesocorticolimbic system, as well as the hippocampal-VTA loop. The mesocorticolimbic system, at least partly, mediates the rewarding effects of drugs of abuse, such as nicotine. The VTA receives cholinergic projections from the pedunculopontine tegmental and laterodorsal tegmental nuclei (PPTg, LDTg). Previous studies have shown that selective bilateral cholinergic lesions of the posterior PPTg or LDTg can be achieved by directly infusing diphtheria-urotensin II toxin (Dtx-UII) into either region. This thesis aimed to selectively destroy the cholinergic input from both mesopontine nuclei to the posterior VTA (pVTA) by injection of Dtx-UII here. Unilateral or bilateral infusion of Dtx-UII into the pVTA did not destroy cholinergic terminals at any of the time points analysed. There was no evidence of neurodegeneration (as measured by Fluoro-jade C) present in the pVTA, PPTg or LDTg. A non-lesion approach was also adopted to better understand the actions of cholinergics in the pVTA. The effects of nicotine self-administered into the VTA or (as a point of contrast in the circuitry of the VTA) the dorsal hippocampus (dHPC) were assessed by measuring lever pressing and quantifying the expression of immediate early gene (IEG) c-fos as a marker of neural activation. Fos expression was quantified in the VTA and in structures on which VTA activity has effect – the shell and core of the NAc, the dorsal striatum and the dHPC. Fos was measured under two conditions: at the end of the very first exposure to nicotine and (in other groups) after repeated exposure. These results demonstrated that rats will lever press to directly administer nicotine into the VTA or dHPC, but that nicotine-induced Fos expression is not correlated with lever pressing. In addition, intra-VTA, but not intra-dHPC nicotine, activated all regions of interest. This demonstrates that intra-VTA nicotine mediates its effects through regions of the mesocorticolimbic system, but that intra-dHPC nicotine must mediate its effects through other brain regions and systems. These results raise questions about the nature of reward processing in the brain.

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Lin, Jingyang 1962. "The electrophysiological characterization of phencyclidine analogs on ventral tegmental area dopamine neurons." Thesis, The University of Arizona, 1990. http://hdl.handle.net/10150/277983.

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This study was designed to characterize the effects of PCP and PCP derivatives on dopamine systems using electrophysiological and behavioral methods. TCP, a high affinity PCP/NMDA receptor ligand only increased A10 firing while BTCP, a high affinity DA reuptake ligand only decreased activity. PCP with similar affinity for the NMDA and reuptake sites, produced a dose dependent bimodal change in the activity of A10 neurons. Lesions of the nucleus accumbens or treatment with picrotoxin, a GABA antagonist attenuated the BTCP and high dose PCP inhibitory effects thus supporting the existence of a GABAergic accumbal-VTA feedback pathway. Furthermore, BTCP and PCP produced significant increases in locomotor activity which were attenuated by accumbens lesions. The present data provide an explanation for PCP's bimodal effects and possibly for its psychotomimetic properties as well as abuse liability which may reside with its blockade of dopamine reuptake in the mesolimbic system.

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Clarke, Travis Jonathan. "Neuroimmune-Mediated Alcohol Effects on Ventral Tegmental Area Microglia and Infiltrating Leukocytes." BYU ScholarsArchive, 2018. https://scholarsarchive.byu.edu/etd/7566.

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Microglia are the primary immune cell in the central nervous system and are known as the “resident” macrophages in the central nervous system (CNS). While microglia are classically known as the immune cells of the CNS, their role has more recently been shown to extend far beyond immunity. The effects of ethanol on the brain are closely linked to neuroimmune responses mediated by microglia that are present in the healthy brain from the time of development. Though microglia have been classified as the “resident” immune cells of the CNS, new research suggests that other immune cells may be implicated in the immune response. Normally, the blood-brain barrier (BBB) prevents the infiltration of cells and foreign pathogens from crossing from the periphery into the CNS. However, peripheral monocytes are known to infiltrate the CNS in response to seizures, traumatic brain injury, infection, and multiple sclerosis. Whether or not these cells engraft and become microglia is still a topic of debate. The aim of this study was to determine the effect of acute ethanol on microglia activation and monocyte infiltration into the CNS. We hypothesized that acute EtOH would lead to an increase in neuroinflammation by activating “resident” microglia to an inflammatory polarization and induce the infiltration of macrophages across the BBB. Using the Macrophage FAS-Induced Apoptosis (MaFIA) mouse model (GFP+ on Csf1r promoter), fluorescent microscopy, and flow cytometry we assessed the presence and phenotype of microglia and infiltrating macrophages following 1, 2, and 4 g/kg ethanol at .5, 1, and 2 hours post-injection. By measuring volume/surface area of microglia in the VTA and NAc following EtOH, we found that EtOH caused microglia activation in these areas, and that the microglia are shifting toward an M1 polarization. However, some of our findings were counter to our hypothesis. We found that EtOH, decreases the number of infiltrating monocytes in the VTA and NAc. It is possible that other cells like T and B cells are recruited across the BBB. These findings suggest a neuroimmune connection for acute ethanol use and challenge the dogma that ethanol has exclusively central effects on DA neuronal activity and release. Further research is being performed to examine the implications of this effect, and what effects a conditional knockdown of monocytes has on ethanol intoxication and reward.

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Song, Minryung. "The Role of the Ventral Tegmental Area in the Extinction of Probabilistic Rewards." Thesis, The University of Arizona, 2011. http://hdl.handle.net/10150/188389.

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Because most of the events in the world are probabilistic and changing, the extinction of probabilistic events that no longer occur is important for survival. Here, we investigated the effect of reward probability on the rate of extinction using behavioral and pharmacological experiments in rats and temporal difference model simulations. Our experimental results suggested that ambiguity during extinction and the value of probabilistic reward are the two major causes that resulted in the inverted U-shaped relationship between the rate of extinction and reward probability. Using pharmacological activation and inactivation of midbrain dopamine neurons, we reasoned that ambiguity may not be signaled by dopamine neurons. By adding an ambiguity signal into an existing temporal difference model, we reproduced the inverted U-shape for the first time and supported our conclusion. Our study provides insights into the extinction of probabilistic rewards and gives a useful computational model for further investigation.

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Vishnubhotla, Bhavana. "The responses of ventral tegmental area neurons to appetitive and aversive conditioned cues." Diss., Search in ProQuest Dissertations & Theses. UC Only. Search in ProQuest Dissertations & Theses. UC Only, 2008. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3324585.

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Bull, Fiona A. "Targeting opioid receptor signal transduction to produce sustained analgesia." Thesis, University of Dundee, 2015. https://discovery.dundee.ac.uk/en/studentTheses/3e42e620-7115-4f45-9100-91c422fce812.

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Mu opioid receptors (MOPs) in the pain pathway contribute to morphine analgesia. Morphine also stimulates reward/reinforcement through disinhibition of dopaminergic (DA) neurones in the ventral tegmental area (VTA), an effect implicated in its abuse and dependence. We hope to develop approaches to achieve sustained analgesia without affecting reward by exploiting differential MOP signalling mechanisms in the pain and reward pathways. MOPs, delta opioid receptors (DOPs) and β-arrestin2 (BAR2) are all necessary components of the signalling complex in nociceptive neurones for morphine analgesic tolerance; c-Src (a tyrosine kinase), thought to couple to MOP receptors through BAR2 has also been implicated. To investigate opioid receptor signalling in response to morphine we used a variety of different techniques that included behavioural measures of nociception, reinforcement and locomotion and electrophysiological methods to study DRG neurones from the pain pathway and brain slices containing VTA neurones. This study in mice confirms that morphine administered subcutaneously (SC) causes analgesia, analgesic tolerance, and has psychomotor effects leading to enhanced locomotion and reinforcement. In VTA neurones morphine and the selective MOP receptor agonist DAMGO caused concentration-dependent inhibition of the frequency of IPSCs. All these actions of morphine were absent from MOP-/- mice. Morphine exhibited reduced potency as 1) an analgesic, 2) stimulator of locomotion, 3) a reinforcer in CPP and 4) an inhibitor of sIPSC frequency, when applied to MOP+/- mice or their VTA neurones. Morphine analgesic tolerance developed faster and to a greater extent in MOP+/- mice than in WT mice. DOP-/- mice exhibited morphine analgesia with less tolerance, as did BAR2-/- mice. BAR2-/- mice also exhibited reduced morphine locomotion and an increased sensitivity to morphine reinforcement. Morphine tolerance was absent from BAR2-/-//DOP-/- mice. The inhibition of sIPSC frequency by morphine was reduced in BAR2+/- and BAR2-/- VTA neurones. Dasatinib and PP2 (c-Src tyrosine kinase inhibitors) prevented the development of morphine tolerance in WT and MOP+/- mice and dasatinib caused its reversal in the latter. The drugs had no significant analgesic effect alone. Dasatinib did not affect morphine preference or locomotor activation. PP2 reduced morphine’s inhibition of sIPSC frequency. As c-Src inhibition does not appear to alter the psychomotor effects produced by morphine and it acts to reduce morphine analgesic tolerance. We believe that cSrc is an attractive target to prevent the development of morphine analgesic tolerance without affecting hedonic homeostasis.

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Allison, David Wilbanks. "Cocaine and Mefloquine-induced Acute Effects in Ventral Tegmental Area Dopamine and GABA Neurons." BYU ScholarsArchive, 2009. https://scholarsarchive.byu.edu/etd/2362.

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The aim of the two studies presented here was to evaluate the effects of cocaine and mefloquine (MFQ) on γ-aminobutyric acid (GABA) and dopamine (DA) neurons in the ventral tegmental area (VTA). Cocaine: In vivo, lower doses of intravenous cocaine (0.25-0.5 mg/kg), or methamphetamine (METH), enhanced VTA GABA neuron firing rate via D2/D5 receptor activation. Higher cocaine doses (1.0-2.0 mg/kg) inhibited their firing rate. Cocaine and lidocaine inhibited the firing rate and spike discharges induced by stimulation of the internal capsule (ICPSDs) at dose levels 0.25-2 mg/kg (IC50 1.2 mg/kg), but neither DA nor METH reduced ICPSDs. In VTA GABA neurons in vitro, cocaine reduced (IC50 13 µM) current-evoked spikes and sodium currents in a use-dependent manner. In VTA DA neurons, cocaine reduced IPSCs (IC50 13 µM), increased IPSC paired-pulse facilitation, and decreased sIPSC frequency, without affecting mIPSC frequency or amplitude. These findings suggest cocaine reduces activity-dependent GABA release on DA neurons in the VTA, and that cocaine's use-dependent blockade of VTA GABA neuron voltage-sensitive sodium channels (VSSCs) may synergize with its DAT inhibiting properties to enhance mesolimbic DA transmission implicated in cocaine reinforcement. Mefloquine: Mefloquine (MFQ) is an anti-malarial agent, Connexin-36 (Cx36) gap junction blocker, 5-HT3 antagonist, and calcium ionophore. Mounting evidence of a Cx36-mediated VTA GABA neuron syncytium suggests MFQ-related dysphoria may attribute to its gap junction blocking effects on VTA synaptic homeostasis. We observed that MFQ (25 µM) increased DA neuron spontaneous IPSC frequency 6 fold, and mIPSC 3 fold. Carbenoxolone (CBX, 100 µM) only increased sIPSC frequency 2 fold, and did not affect DA mIPSC frequency. Ondansetron did not mimic MFQ. Additionally, MFQ did not affect VTA DA evoked IPSC paired pulse ratio (PPR). However, Mefloquine did induce a 3.5 fold increase in bath-applied GABA current. Remarkably, MFQ did not affect VTA GABA neuron inhibition. At VTA DA neuron excitatory synapses MFQ increased sEPSC frequency in-part due to an increase in the AMPA/NMDA ratio. These finding suggest MFQ alters VTA synapses differentially depending on neuron and synapse type, and that these alterations appear to involve MFQ's gap junction blocking and calcium ionophore actions.

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Sandoval, Philip J. "Long-Term Depression of Excitatory Inputs to GABAergic Neurons in the Ventral Tegmental Area." BYU ScholarsArchive, 2012. https://scholarsarchive.byu.edu/etd/3911.

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Dopamine cells within the ventral tegmental area of the brain are involved in motivation and reward. Drugs of abuse target these dopamine cells altering their activity and plasticity resulting in addiction. While dopamine cell activity is primarily involved in addiction, the GABA neurons in the VTA have also been shown to have an indirect role. By decreasing the activity of the inhibitory GABA inputs onto dopamine neurons abusive drugs can indirectly increase dopamine cell activity resulting in addictive behaviors. However, although GABA neurons are important in the perception of reward, much less is known about how the excitatory inputs to these cells are regulated and possibly altered by drugs of abuse. Using transgenic mice expressing GFP attached to the GAD promoter, GABA cells were located and patched using whole cell voltage clamp and EPSCs were measured. High frequency stimulation induced LTD of the excitatory inputs to GABA neurons. The endocannabinoid analogue R- methanandamide also induced LTD at these excitatory synapses. These results suggest that endocannabinoids could potentially regulate the activity of GABA cells and as a result the activity of dopamine neurons. The endocannabinoid receptor involved is likely CB1, but not TRPV1 as only the CB1 antagonist AM-251 blocked this high frequency stimulus-induced LTD. Future research could then determine if the pathways involved in this LTD could potentially be altered by drugs of abuse contributing to addiction.

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Friend, Lauren. "Exploring dopamine function in the rat ventral tegmental area : the influence of persistent pain." Thesis, University College London (University of London), 2018. http://discovery.ucl.ac.uk/10053952/.

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This thesis describes an investigation into the pharmacological and neurobiological nature of one of the key neural populations in the interactions between pain- and reward-related information - the dopaminergic (DA) neurones of the ventral tegmental area (VTA). The aim of these experiments collectively was to increase understanding of the functioning of the VTA neurones in various pain-related contexts, in the hope that this information will act as a foundation upon which further developments in knowledge occur. Ultimately, it is hoped that such advances in understanding could lead to the development of effective therapeutics down the line. Through a series of five projects employing intra-VTA in vivo electrophysiology in the anaesthetised rat in combination with a variety of pharmacological and nociceptive manipulations, the work described in this thesis explored the activity of spontaneously firing VTA neurones. Initial experiments attempted to both electrophysiologically and pharmacologically identify the DA neurones amongst interspersed non-DA populations in vivo. From a series of results, it was concluded that there was likely significant heterogeneity amongst VTA DA and non-DA groups, resulting in a confusing picture of cell identity. Through adopting the pharmacological measure of response to systemic L-DOPA injection, recorded neurone populations were reliably split into two sub-populations with a size, response direction and dose dependency in line with DA and GABAergic identities, respectively. However, neurochemical identity was not confirmed, and the possibility of alternatives was considered throughout the thesis. Subsequent investigations moved on to test how the induction of persistent pain altered the activity of VTA neurones: first in a carrageenan-induced tonic inflammatory pain model, and secondly, in a spinal nerve ligationinduced chronic neuropathic pain model. Concurrently, the role of endogenous μ-opioid receptor (MOR) agonists in regulation of VTA neurone activity was unmasked though administration of the MOR antagonist, naloxone. It was found that the induction of a tonic inflammatory pain state caused changes in the firing rate and pattern of VTA neurones subpopulations. An effect of naloxone on neuronal firing rate was no longer apparent in the tonic inflammatory pain state, suggesting a down-regulation of tonic μ-opioid control. Unexpectedly, neurones recorded in naïve and neuropathic pain states showed very similar characteristics. It was suggested that this result may be underlined by longer-term reactions to the sustained increased nociceptive input. Several possible explanations for the above results are discussed, along with the functional implications in terms of a wider role for VTA dopamine neurones in the pain-processing system. Finally, it was noted that the current methodology possessed a few inherent limitations when it comes to translating these findings to an awake, freely moving state, and that that future efforts should attempt to address these.

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Nufer, Teresa Marie. "Variable Modulation of Inputs to GABA Cells in the Ventral Tegmental Area and Hippocampus." BYU ScholarsArchive, 2018. https://scholarsarchive.byu.edu/etd/7430.

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The ventral tegmental area (VTA) is an important component of the mesolimbic dopamine circuit and processes reward and motivational behaviors. In response to drug exposure, synaptic connections of this circuit can be rewired via synaptic plasticity—a phenomenon thought be responsible for the pathology of addiction. While much is known about dopamine neuron plasticity, less is known regarding plasticity exhibited by VTA GABA cells, specifically inhibitory inputs from outside the VTA. Expanding on the work of Bocklisch et al. (2013), we investigated the plasticity of inhibitory inputs to VTA GABA neurons. Using whole cell electrophysiology in GAD67 GFP mice, we observed that these VTA GABA cells can experience either long-term potentiation (LTP) or long-term depression (LTD) in response to a 5 Hz stimulus. While neither the LTP nor LTD appear to be mediated by the cannabinoid-1 receptor (CB1), the nitric oxide synthase (NOS) pathway, or the dopamine-2 (D2) receptor, the LTP is blocked by APV, an NMDA receptor antagonist, and the LTD is blocked by CGP 54626, an antagonist of the GABAB receptor. Additionally, Âµ-opioid and adenosine-1 receptors modulated plasticity at this synapse, but chronic morphine administration (10mg/kg) did not block the observed LTP or LTD. Furthermore, we used an optogenetic approach in VGAT-Cre mice to target inhibitory inputs from the lateral hypothalamus (LH) to the VTA. An optical stimulus (5 Hz) caused these inputs to depress, which has not been previously described and may be behaviorally important in reward processing. These novel findings increase our understanding of VTA neural circuitry, ultimately increasing our capacity to better comprehend and treat the pathology of addiction. Additionally, changes in synaptic strength in hippocampal CA1 pyramidal cells are thought to be responsible for the acquisition and retention of short-term memory. Feedforward stratum radiatum interneurons of many subtypes experience LTD, short-term depression (STD), or lack of plasticity, but it is not known whether plasticity correlates with specific interneuron subtypes. Using whole cell electrophysiology and qPCR, we characterized the plasticity expressed by hippocampal interneurons in correlation with their mRNA expression patterns to determine cell subtype. We also assessed the expression of endocannabinoid (eCB) biosynthetic enzymes as well as metabotropic glutamate receptor subunits known to mediate plasticity. Cells exhibiting LTD tended to express mRNA for at least one of the eCB biosynthetic enzymes and the metabotropic glutamate receptor subunit mGluR5. mGluR5 was not expressed by cells exhibiting STD or no plasticity. Cells that exhibited short-term depression tended to express mRNA for at least one of the eCB biosynthetic enzymes, but not mGluR5. This suggests that stratum radiatum interneuron plasticity can be predicted based on mGluR expression, and that these different types of plasticity may have some importance in hippocampal function.

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Hales, Kimberly. "Neuronal and Molecular Adaptations of GABA Neurons in the Ventral Tegmental Area to Chronic Alcohol." Diss., CLICK HERE for online access, 2007. http://contentdm.lib.byu.edu/ETD/image/etd2182.pdf.

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Sorrentino, Renee. "Projections of the ventral tegmental area: a PHA-L anterograde tracing study in the rat." Thesis, Boston University, 1994. https://hdl.handle.net/2144/27778.

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Boston University. University Professors Program Senior theses.
PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you.
2031-01-02

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Byrnes, John J. "Cyclic amp mechanisms in the ventral tegmental area : mediation of the behavioral effects of amphetamine /." The Ohio State University, 1996. http://rave.ohiolink.edu/etdc/view?acc_num=osu1487935573772511.

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Lima, Leandro Bueno. "Organização das projeções da área tegmental ventral para o estriado. Um estudo no rato com a técnica de rastreamento anterógrado da leucoaglutina do Phaseolus vulgaris." Universidade de São Paulo, 2010. http://www.teses.usp.br/teses/disponiveis/42/42137/tde-20052010-143551/.

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A área tegmental ventral (VTA) contém neurônios dopaminérgicos do grupamento A10 e envia projeções muito densas para o estriado ventral. Esta circuitaria está crucialmente envolvida em mecanismos de recompensa. Recentemente, a organização destas projeções foi reexaminada por Ikemoto S. (Brain Res. Rev., 56:27-78, 2007), em um estudo de rastreamento retrógrado minucioso, sendo proposto a subdivisão destas projeções em um sistema dopaminérgico mesoestriatal ventromedial que inerva a concha medial do accumbens e o tubérculo olfatório medial, e um sistema dopaminérgico mesoestriatal ventrolateral que inerva o cerne e a concha lateral do accumbens e o tubéculo olfatório lateral. Afim de complementar o conhecimento destas projeções, no presente estudo elas foram examinadas com a técnica anterógrada da leucoaglutinina do Phaseolus vulgaris. Nossos resultados indicam que há um extenso embricamento dos campos terminais estriatais inervados por diferentes setores/núcleos da VTA e reforçam a noção de que as eferências da VTA podem ser subdivididas em um sistema mesoestriatal ventromedial e um sistema mesoestriatal ventrolateral. Eles revelam ainda que as projeções da VTA para o estriado ventral têm uma organização topográfica médio-lateral mais complexa do que previamente reconhecido, a faixa médio-lateral do estriado ventral inervada depende de uma combinação da região médio-lateral e dorsoventral da VTA. Assim, as regiões mais ventrais e mediais da VTA (correspondendo ao núcleo interfascicular) inervam os distritos mais mediais do estriado ventral (a concha dorsomedial do accumbens e a extremidade medial do tubérculo olfatório), e as regiões mais dorsais e laterais da VTA (correspondendo à região dorsolateral do núcleo parabraquial pigmentoso) se projetam para os distritos mais laterais do estriado ventral (o cerne lateral e a concha lateral do accumbens, o caudado-putâmen ventral e o tubérculo olfatório lateral). Por outro lado, as projeções da VTA para o estriado ventral não possuem uma organização topográfica rostrocaudal. Outro fato a ser destacado é que a organização das projeções mesoestriatais da VTA lembra o padrão das projeções córticoestriatais, sendo observado no estriado, além de um campo terminal principal, pequenos focos isolados de marcação.
The ventral tegmental area (VTA) contains dopaminergic neurons of the A10 group and sends dense projections to the ventral striatum. This circuitry is critically involved in reward mechanisms. Recently, the organization of these projections was reexamined by Ikemoto S. (Brain Res. Rev., 56:27-78, 2007) in a detailed retrograde tracing study, being proposed that these projections can be subdivided into two main systems, a ventromedial mesostriatal dopaminergic system that innervates the medial shell of the accumbens and medial olfactory tubercle, and a ventrolateral mesostriatal dopaminergic system that targets the core and lateral shell of the accumbens and lateral olfactory tubercle. In order to complement these data, in the present study the VTA mesostriatal projections were examined with a sensitive anterograde tracing technique using the Phaseolus vulgaris leucoaglutinin. Our results indicate that there is an extensive overlap of terminal fields innervated by different sectors / nuclei of the VTA and reinforce the notion that VTA efferents can be subdivided into a ventromedial and a ventrolateral mesostriatal system. They also show that the VTA projections to the ventral striatum have a mediolateral topographical organization more complex than previously acknowledged. In fact, projections along the mediolateral dimension of the ventral striatum depends on a combination of the mediolateral and dorsoventral axis of the VTA. In other words, the most ventral and medial parts of the VTA (corresponding to the interfascicular nucleus) innervates the most medial districts of the ventral striatum (corresponding to the dorsomedial shell of the accumbens and medial tip of the olfactory tubercle), and the most dorsal and lateral parts of the VTA (corresponding to the dorsolateral region of the parabrachial pigmented nucleus) project to the most lateral districts of the ventral striatum (lateral core and lateral shell of the accumbens, ventral caudate-putamen and lateral olfactory tubercle). Moreover, VTA projections to the ventral striatum do not seem to have a rostrocaudal topographical organization. It is also of note that the organization of the VTA mesostriatal projections shares features with cortico-striatal projections, in the sense that both fiber systems have a main terminal field and also give rise to small, scattered isolated foci of terminal labeling.

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Liu, Yudan. "Dopaminergic neurons in the ventral tegmental area: role of L-type calcium channels in firing regulation /." Internet access available to MUN users only. Search for this title in:, 2009.

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Jones, Elizabeth Laura. "Neuromodulation of somatodendritic dopamine release in the ventral tegmental area by cholinergic and other local inputs." Thesis, University of Oxford, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.526478.

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Hernandez, Diana [Verfasser], and Uwe [Akademischer Betreuer] Ilg. "Limbic connections with the ventral tegmental area in the nonhuman primate / Diana Hernandez ; Betreuer: Uwe Ilg." Tübingen : Universitätsbibliothek Tübingen, 2017. http://d-nb.info/1199546704/34.

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Bushnik, Harris Tamara L. "Brain stimulation reward in the lateral preoptic area: An examination of its substrate and functional connectivity to the ventral tegmental area." Thesis, University of Ottawa (Canada), 1993. http://hdl.handle.net/10393/6935.

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In order to determine the nature of the hypothesized connection between the lateral preoptic and the ventral tegmental areas, two major experiments were conducted. The first major study consisted of an in-depth mapping of the substrate for self-stimulation in the lateral preoptic area using dorsoventrally moveable electrodes which permitted the testing and characterization of multiple stimulation sites in each subject. Self-stimulation was obtained throughout the lateral preoptic area and compartments 'a' and 'b' of the medial forebrain bundle; the pattern of positive sites was consistent with anatomical descriptions of the trajectory of the medial forebrain bundle. An examination of the period/current tradeoff functions generated at positive self-stimulation sites suggested that the substrate in the lateral preoptic area has a homogeneous distribution that is less dense than that found in the lateral hypothalamus. The next experiment investigated the existence of a direct anatomical connection between the lateral preoptic area and the ventral tegmental area reward neurons using the behavioural adaptation of the collision test. The collision test is a double pulse, two electrode technique based on the axonal conduction failure that occurs when two separate sites in the same axon bundle are electrically stimulated. In this study, nine rats with a total of forty-four pairs of sites were examined. In seven sites the double-pulse effectiveness curves were consistent with the characteristics of transynaptic collision. The unique shapes of collision curves predicted by the transynaptic collision model permit the direction of conduction to be inferred from the matching collision profiles; six of the seven curves were suggestive of a caudorostral direction of conduction, that is, ventral tegmental area to lateral preoptic area. These results do not support the hypothesis that the lateral preoptic area is the location of the cell bodies of origin for the descending reward pathway that courses between the lateral hypothalamus and ventral tegmental area. However, the absence of axonal collision effects or transynaptic collision profiles consistent with a rostrocaudal direction of conduction can not be interpreted to suggest that other patterns of connectivity between the reward neurons in the lateral preoptic and ventral tegmental areas do not exist. (Abstract shortened by UMI.)

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Bacon, Gregory. "The anatomical basis for 5-HT-dopamine interactions in the rat substantia nigra and ventral tegmental area." Thesis, University of Oxford, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.249483.

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Watanabe, Moe, Michiko Narita, Yusuke Hamada, Akira Yamashita, Hideki Tamura, Daigo Ikegami, Takashige Kondo, et al. "Activation of ventral tegmental area dopaminergic neurons reverses pathological allodynia resulting from nerve injury or bone cancer." SAGE PUBLICATIONS INC, 2018. http://hdl.handle.net/10150/627057.

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Chronic pain induced by nerve damage due to trauma or invasion of cancer to the bone elicits severe ongoing pain as well as hyperalgesia and allodynia likely reflecting adaptive changes within central circuits that amplify nociceptive signals. The present study explored the possible contribution of the mesolimbic dopaminergic circuit in promoting allodynia related to neuropathic and cancer pain. Mice with ligation of the sciatic nerve or treated with intrafemoral osteosarcoma cells showed allodynia to a thermal stimulus applied to the paw on the injured side. Patch clamp electrophysiology revealed that the intrinsic neuronal excitability of ventral tegmental area (VTA) dopamine neurons projecting to the nucleus accumbens (N.Acc.) was significantly reduced in those mice. We used tyrosine hydroxylase (TH)-cre mice that were microinjected with adeno-associated virus (AAV) to express channelrhodopsin-2 (ChR2) to allow optogenetic stimulation of VTA dopaminergic neurons in the VTA or in their N.Acc. terminals. Optogenetic activation of these cells produced a significant but transient anti-allodynic effect in nerve injured or tumor-bearing mice without increasing response thresholds to thermal stimulation in sham-operated animals. Suppressed activity of mesolimbic dopaminergic neurons is likely to contribute to decreased inhibition of N.Acc. output neurons and to neuropathic or cancer pain-induced allodynia suggesting strategies for modulation of pathological pain states.

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Legault, Mark. "Nucleus accumbens dopamine and investigatory behavior, modulation by the ventral subiculum of the hippocampus through the dopamine cell bodies of the ventral tegmental area." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape10/PQDD_0020/NQ43576.pdf.

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Taylor, Devin Hardy. "The Effects of Acute and Chronic Nicotine on GABA and Dopamine Neurons in the Midbrain Ventral Tegmental Area." BYU ScholarsArchive, 2011. https://scholarsarchive.byu.edu/etd/2951.

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Nicotine (NIC) abuse involves activation of midbrain dopamine (DA) neurons and NIC addiction involves neuroadaptive changes in the mesolimbic DA reward system. GABA neurons in the midbrain ventral tegmental area (VTA) express α4β2-containing nicotinic acetylcholine receptors (nAChRs), whose activation increases GABAergic input to DA neurons. However, this initial effect is decreased after chronic NIC treatment (as in the case of smokers) by inducing nAChR desensitization. Thus, GABA neuron inhibition results in increased DA release in limbic structures such as the nucleus accumbens. To support this hypothesis, we evaluated the effects of acute and chronic NIC on GAD-67 positive neurons in the VTA of GAD GFP mice using in vivo and in vitro electrophysiological methods. In in vivo studies in naïve mice, stimulation of the peduncopontine tegmental nucleus (PPT) activated VTA GABA neurons orthodromically and antidromically. Orthodromic activation of VTA GABA neuron spikes by PPT stimulation was blocked by the nAChR mecamylamine (1 mg/kg). Acute systemic NIC (0.15-0.5 mg/kg IV) had mixed overall effects on VTA GABA neuron firing rate, but in situ microelectrophoretic application of NIC produced a brisk and consistent enhancement (200-500 %) of VTA GABA neuron firing rate that showed no acute tolerance or sensitization with repeated, periodic current application. Local NIC activation was blocked by systemic administration of mecamylamine. Compared to 12 day chronic saline injections, chronic NIC injections (2 mg/kg IP/day) significantly increased VTA GABA neuron firing rate. In in vitro studies, compared to 12 day chronic saline injections, chronic NIC injections decreased DA neuron firing rate. In addition, chronic NIC increased DA neuron, but decreased GABA neuron GABA-mediated sIPSCs. These findings demonstrate that there is reciprocal innervation between the PPT and VTA and that cholinergic input from the PPT is excitatory on VTA GABA neurons. Moreover, VTA GABA neurons are excited by acute NIC and sensitize to chronic NIC, suggesting that α4β2 nAChR subunits on these neurons may play an important role in the adaptations to chronic NIC. Thus, quantitative molecular studies are ongoing to determine specific alterations in nAChRs on VTA GABA neurons to chronic NIC.

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Merrill, Collin Brutch. "Endocannabinoid Biosynthetic Enzyme mRNA: Patterns of Expression in Hippocampus and Ventral Tegmental Area and Effects on Synaptic Plasticity." BYU ScholarsArchive, 2014. https://scholarsarchive.byu.edu/etd/4400.

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Endocannabinoids (eCBs) are lipophilic signals that are produced by postsynaptic neurons in an activity-dependent manner, and signal in a retrograde fashion to modulate neurotransmitter release. As such, eCBs are highly involved in synaptic plasticity, a process that strengthens or weakens synapses. eCB-mediated synaptic plasticity is involved in many brain processes including learning, short-term memory, and adaptive reward, which are processed in the hippocampus and ventral tegmental area (VTA), respectively. However, the expression of eCB biosynthetic enzyme mRNA within hippocampal and VTA neurons, as well as the relationship between these mRNA species and the occurrence of synaptic plasticity, remains unclear. The goal of these studies was to demonstrate the expression pattern of eCB biosynthetic enzyme mRNA within hippocampal and VTA neurons, and to describe the relationship between synaptic plasticity and mRNA expression. Using whole-cell electrophysiology and real-time quantitative PCR, I tested hippocampal and VTA neurons for the presence of eCB biosynthetic enzyme mRNA and described the relationship between these enzymes and synaptic plasticity. The data presented herein demonstrate the importance of eCB signaling within the hippocampus and VTA and the expression patterns of eCB biosynthetic machinery within several neuron types. These data provide evidence that eCB signaling plays a critical role in learning, short-term memory, and adaptive reward.

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Macedo, Giovana Camila de [UNIFESP]. "Participação do sistema da orexina na sensibilização comportamental ao efeito estimulante do etanol em camundongos machos." Universidade Federal de São Paulo (UNIFESP), 2011. http://repositorio.unifesp.br/handle/11600/9914.

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Made available in DSpace on 2015-07-22T20:50:34Z (GMT). No. of bitstreams: 0 Previous issue date: 2011-03-30. Added 1 bitstream(s) on 2015-08-11T03:26:11Z : No. of bitstreams: 1 Publico-12803.pdf: 1327527 bytes, checksum: 4fb071f9df6c6a7299fea37a3cbfb20a (MD5)
As orexinas são dois neuropeptídeos, orexina-A e orexina-B, derivados do mesmo gene precursor (pré-pro-orexina), produzidos em alguns milhares de neurônios localizados na área perifornicial do Hipotálamo lateral. Apesar de ter uma produção restrita ao hipotálamo, os neurônios orexinérgicos projetam-se amplamente para todo o cérebro regulando uma série de funções endócrinas e homeostáticas. Evidências recentes, no entanto, mostram o envolvimento do sistema da orexina no circuito de recompensa. Neste estudo avaliamos o envolvimento do sistema da orexina na sensibilização comportamental induzida por etanol. No experimento 1 foi utilizado o modelo de sensibilização comportamental e os animais do grupo salina, agudo (uma administração de EtOH) e crônico (7 administrações de EtOH) foram tratados durante 14 dias para verificar o desenvolvimento de sensibilização comportamental; após o término do tratamento os animais foram perfundidos e a imunorreatividade de duplas marcações para orexina e c-Fos foi avaliada pela técnica de imunohistoquímica. No experimento 2 foi utilizado o modelo de sensibilização comportamental para verificar se o antagonista de receptor do tipo 1 da orexina, SB 334867, bloqueia esse fenômeno. No primeiro experimento não houve diferença estatística entre os grupos salina, agudo e crônico quanto à ORX+c-Fos-IR; porém os animais tratados cronicamente com EtOH apresentaram uma tendência de aumento da dupla marcação de neurônios orexinérgicos indicando que o desenvolvimento da sensibilização comportamental produz ativação desses neurônios; além disso, os animais tratados cronicamente com etanol desenvolveram a sensibilização comportamental. No segundo experimento, o SB 334867 bloqueou a expressão deste fenômeno, indicando que o sistema orexinérgico parece influenciar de maneira importante o processo de sensibilização comportamental, já que a administração sistêmica do SB334867 bloqueou a expressão da sensibilização comportamental aos efeitos estimulantes do etanol em camundongos machos.
Orexins are two neuropeptides, orexin-A and orexin-B, derived from the same precursor gene (pre-pro-orexin) produced by a few thousand neurons located in the perifornical area of the lateral hypothalamus. Despite having a restricted production, orexinergic neurons project widely to brain structures that regulate a number of endocrine and homeostatic functions. Recent evidence suggests the involvement of the orexin system in the reward circuit. We evaluated the role of this system in ethanol-induced behavioral sensitization. In Experiment 1 was used the behavioral sensitization model (development), in which animals were chronically treated for 14 days with saline, acute ethanol after saline treatment or with ethanol (seven administration) to induce behavioral sensitization; at the end of the treatment animals were perfused and immunohistochemistry technique was used to determine double staining for orexin and c-Fos (ORX+c-Fos-IR). In Experiment 2 behavioral sensitization was induced and SB 334867, an orexin-1 receptor antagonist, was used to examine whether it could block the expression of this phenomenon. The results of Experiment 1 showed no statistical difference among the groups (saline, acute and chronic) as to ORX+c-Fos-IR, although animals chronically treated with EtOH exhibited an trend to more double staining of orexin neurons indicating that this treatment regimen activates this neuropeptide system. In the second experiment, SB 334867 blocked the expression of this phenomenon. The orexin system seems to influence the process of behavioral sensitization, since systemic administration of SB 334867 blocked the expression of this phenomenon induced by a stimulant dose of ethanol in male mice.
TEDE
BV UNIFESP: Teses e dissertações

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Konji, Sandra. "Gestational and Postnatal Exposure to a Contaminant Mixture: Effects on Estrogen Receptor Protein Expression In the Postpartum Maternal Brain." Thesis, Université d'Ottawa / University of Ottawa, 2019. http://hdl.handle.net/10393/38792.

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Maternal behaviours are those that increase offspring survival. Estrogens affect maternal behaviour by activating Estrogen Receptors (ER) in the brain. Maternal brain plasticity was explored by characterizing the effects of exposure to a mixture of environmental pollutants on number of ERs. Following exposure to the toxicants during pregnancy and lactation, brains of female rats were collected, sectioned at 30 μm and immunohistochemistry for ERα performed. Immuno-positive cells in the mPOA, VTA and NAc were counted. A two way ANOVA revealed no main effect of Treatment on the number of immunopositive cells for all three brain regions. However, a significant difference between the High and Low Doses with the high dose reducing the number of ERα+ cells in the mPOA and VTA. Our work showcases the importance of studying the effects of multiple chemical co-exposures on the mother's brain, as maternal brain changes impact maternal behaviour consequently affecting offspring neurodevelopment.

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39

Spencer, P. M. "A study of projections from the substantia nigra and the ventral tegmental area to the hippocampus of the rat." Thesis, University of Southampton, 1986. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.373979.

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40

Powers, Kyle. "Extracellular signal-regulated kinase (ERK) signaling in the brain-ventral tegmental area and its regulation of mood in rat." Tallahassee, Fla. : Florida State University, 2008. http://purl.fcla.edu/fsu/lib/digcoll/undergraduate/honors-theses/341821.

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Thesis (Honors paper)--Florida State University, 2008.
Advisor: Dr. Quine, Florida State University, College of Arts and Sciences, Dept. of Biomedical Mathematics. Includes bibliographical references.

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41

Druhan, Jonathan Peter. "Pharmacological assessment of the relationship between cue properties and rewarding effects of electrical stimulation of the ventral tegmental area." Thesis, University of British Columbia, 1985. http://hdl.handle.net/2429/25382.

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The present series of experiments was designed to assess the utility of a discrimination procedure for measuring the affective properties of rewarding brain-stimulation. If the rewarding and discriminative stimulus properties of electrical brain stimulation were related, they may share a common substrate and be affected similarly by the same pharmacological manipulations. In Experiment 1, a discrimination procedure was developed to measure the cue properties of EBS delivered to the ventral tegmental area (VTA). Rats with VTA electrodes were trained to obtain food pellets by making a discriminated operant response on one of two levers following pulses of high intensity stimulation, or on the alternate lever after low intensity pulses. Following training, the rats were given tests in which generalized responding to intermediate intensities was measured. These tests were repeated either with conditions kept constant, or with the absolute intensities of the cues delivered within a sesion increased or decreased relative to baseline. The tests with higher or lower intensity ranges were intended to mimic the conditions that might prevail if the perceived intensities of the EBS were modified by drugs. The results of this experiment indicated that generalization gradients remained stable across three tests with conditions kept constant. When higher or lower current ranges were delivered, the discriminated responses were appropriately biased towards one lever or the other, resulting in lateral shifts in the generalization gradients. These results verified that the discrimination procedure provided a stable measure of the EBS stimulus properties, and that this measure was sensitive to changes in the intensities of the cues. In Experiment 2, tests for EBS generalization and self-stimulation (ICSS) were given after injections of vehicle, d-amphetamine (1.0 mg/kg and 2.0 mg/kg) and haloperidol (.075 mg/kg and .10 mg/kg). The results indicated that these doses of amphetamine and haloperidol did not affect the EBS generalization. However, during ICSS sessions, 2.0 mg/kg amphetamine decreased threshold and increased rates for ICSS whereas .10 mg/kg haloperidol resulted in an increase in threshold. These results suggest a dissociation of the stimulus properties of EBS from the DA reward substrate. In Experiment 3, the rats were tested for generalization after injections of physostigmine (.25 mg/kg and .50 mg/kg), scopolamine (.10 mg/kg and .25 mg/kg) and vehicle. Only the high dose of physostigmine (.50 mg/kg) produced significant differences in responding in this experiment. After injection of this drug, lower intensity stimuli elicited responding on the lever appropriate for the high current intensity, indicating a possible augmentation of the stimulus property of a fixed intensity of brain stimulation. The results of this study indicate that the cue properties of VTA brain-stimulation are dissociable from EBS reward related to the activation of DA neurons. However, evidence is provided which suggests that cholinergic neurons may be involved in the mediation of the EBS cues. In as much as cholinergic neurons are also involved in the rewarding effects of VTA brain-stimulation, these results may indicate a relationship between the cue properties of VTA EBS and an acetylcholine reward system.
Arts, Faculty of
Psychology, Department of
Graduate

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Caetano, Kátia Alessandra de Souza. "Envolvimento de mecanismos dopaminérgicos na expressão do medo condicionado contextual em ratos." Universidade de São Paulo, 2012. http://www.teses.usp.br/teses/disponiveis/59/59134/tde-14052012-182651/.

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É reconhecido que as experiências que geram reações de medo são praticamente indeléveis do encéfalo dos organismos e que condicionamentos aversivos suscitam inúmeras respostas defensivas, como o congelamento, sendo esta resposta um indicador de medo em roedores. Vários trabalhos têm apontado para a relação entre alterações na transmissão dopaminérgica e os estados aversivos. Entretanto, observam-se resultados conflitantes com a utilização de drogas dopaminérgicas em diferentes modelos animais de ansiedade. Assim, investigações devem ainda ser realizadas objetivando avaliar a funcionalidade da modulação dopaminérgica nos estados emocionais aversivos. O objetivo do presente estudo foi avaliar o envolvimento de mecanismos dopaminérgicos na expressão do medo condicionado ao contexto. Inicialmente foram avaliados os efeitos de agonistas (SKF 38393 e quimpirole) e antagonistas (SCH 23390 e sulpirida) de receptores D1 e D2 administrados sistemicamente sobre a expressão do medo condicionado contextual, sendo mensurado o tempo de congelamento dos animais. A atividade motora foi avaliada com o teste do campo aberto. Os resultados indicam que os receptores da família D2, e não D1, estão envolvidos na expressão do medo condicionado contextual, uma vez que a administração de quimpirole e sulpirida, mas não de SCH 23390 e SKF 38393, levou a uma diminuição do congelamento condicionado ao contexto. Não houve alterações na atividade motora dos animais. Com base nestes resultados foi levantada a hipótese de que a capacidade da sulpirida e do quimpirole em diminuir o medo condicionado poderia ocorrer devido a uma ação em receptores pós-sinápticos de estruturas do sistema mesocorticolímbico e em autoreceptores da área tegmental ventral (ATV), respectivamente, levando ao efeito comum de diminuição da atividade dopaminérgica. A fim de testar esta hipótese, foram realizadas microinjeções de quimpirole na ATV. Os resultados obtidos mostram uma diminuição da expressão do congelamento condicionado e que os efeitos obtidos com a administração sistêmica desse agonista de receptores D2 provavelmente devem-se a sua ação na ATV. Portanto, a ATV parece atuar na modulação das respostas de medo condicionado e a ativação desta estrutura deve ser importante para a recuperação da aprendizagem aversiva ocorrida no dia do condicionamento.
It is well established that experiences that generate fear reactions are practically unforgettable and that aversive conditioning raises several defensive responses such as freezing, which is an index of fear in rodents. Several studies have pointed to the existence of a relationship between changes in dopaminergic neurotransmission and aversive states. However, there are conflicting results in the literature with the use of dopaminergic drugs in different animal models of anxiety. Thus, further investigations should be conducted to evaluate the importance of dopaminergic modulation of aversive states. The aim of the present study was to evaluate the involvement of dopaminergic neurotransmission in the expression of contextual conditioned fear in rats. Initially, we evaluated the effects of intraperitoneal injections of D1 and D2 receptors agonists (SKF 38393 and quinpirole) and antagonists (SCH 23390 and sulpiride) in the expression of contextual conditioned fear by measuring the time of freezing response of the animals. The motor activity was evaluated in the open field test. The results indicate that the D2 receptors, but not D1 receptors, are involved in the expression of contextual conditioned fear, since administration of quinpirole and sulpiride, but not SCH 23390 and SKF 38393, decreased conditioned freezing to the context. There were no changes in motor activity of animals. Based on these results it was hypothesized that quinpirole and sulpiride probably acted on presynaptic and postsynaptic D2 receptors, respectively, leading to a decrease of dopaminergic neurotransmission in both cases. To test this hypothesis, microinjections of quinpirole were performed into the ventral tegmental area (VTA). The results show a decrease in the expression of conditioned freezing, indicating that the effects obtained with the intraperitoneal administration of the dopamine D2 receptor agonist is probably due to its action in the VTA. Therefore, dopaminergic mechanisms in the VTA seem to be important in the modulation of conditioned fear responses and activation of this structure appears to take place during the fear memory following the context aversive conditioning.

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Wang, Junshi, Ryan M. Bastle, Caroline E. Bass, Ronald P. Hammer, Janet L. Neisewander, and Ella M. Nikulina. "Overexpression of BDNF in the ventral tegmental area enhances binge cocaine self-administration in rats exposed to repeated social defeat." PERGAMON-ELSEVIER SCIENCE LTD, 2016. http://hdl.handle.net/10150/621303.

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Stress is a major risk factor for substance abuse. Intermittent social defeat stress increases drug self-administration (SA) and elevates brain-derived neurotrophic factor (BDNF) expression in the ventral tegmental area (VTA) in rats. Intra-VTA BDNF overexpression enhances social defeat stress-induced cross-sensitization to psychostimulants and induces nucleus accumbens (NAc) ΔFosB expression. Therefore, increased VTA BDNF may mimic or augment the development of drug abuse-related behavior following social stress. To test this hypothesis, adeno-associated virus (AAV) was infused into the VTA to overexpress either GFP alone (control) or GFP + BDNF. Rats were then either handled or exposed to intermittent social defeat stress before beginning cocaine SA training. The SA acquisition and maintenance phases were followed by testing on a progressive ratio (PR) schedule of cocaine reinforcement, and then during a 12-h access "binge" cocaine SA session. BDNF and ΔFosB were quantified postmortem in regions of the mesocorticolimbic circuitry using immunohistochemistry. Social defeat stress increased cocaine intake on a PR schedule, regardless of virus treatment. While stress alone increased intake during the 12-h binge session, socially-defeated rats that received VTA BDNF overexpression exhibited even greater cocaine intake compared to the GFP-stressed group. However, VTA BDNF overexpression alone did not alter binge intake. BDNF expression in the VTA was also positively correlated with total cocaine intake during binge session. VTA BDNF overexpression increased ΔFosB expression in the NAc, but not in the dorsal striatum. Here we demonstrate that VTA BDNF overexpression increases long-access cocaine intake, but only under stressful conditions. Therefore, enhanced VTA-BDNF expression may be a facilitator for stress-induced increases in drug abuse-related behavior specifically under conditions that capture compulsive-like drug intake.

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Cage, Mary Pauline. "Molecular characterization of mesocorticolimbic brain regions in DBA/2J mice sensitized to the locomotor activating effects of ethanol /." Abstract, 24-page preview and downloadable full-text (PDF format) available to VCU users at:, 2005. http://wwwlib.umi.com/cr/vcu/fullcit?p3196511.

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45

Sandoval, Karin. "An assessment of nicotine's effects on behavioral and in vivo electrophysiological responses of ventral tegmental area dopamine neurons in the mouse." Diss., The University of Arizona, 2004. http://hdl.handle.net/10150/280646.

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This dissertation represents some of the first work to investigate how acute and chronic nicotine treatment affects the in vivo electrophysiological responses of mouse ventral tegmental area (VTA) dopamine neurons, behavior, and the involvement of nicotinic acetylcholine receptors (nAChRs). We found that when mice were given an initial dose of 8μg/kg intravenous nicotine and the dose increased incrementally (16μg/kg, 32μg/kg, 64μg/kg, 128μg/kg); nicotine had no effect on VTA dopamine neuronal firing, even when the individual dose reached 256 μg/kg nicotine. However, if a higher initial dose of acute nicotine (0.1mg/kg IV doses) was administered, a dose self-administered by mice (Stolerman et al, 1999), nicotine inhibited VTA dopamine neuronal firing, with the inhibitory effect desensitizing with subsequent doses of nicotine. The inhibitory effect of acute nicotine on VTA dopamine neuronal firing and locomotion was blocked by the non-specific nAChR antagonist mecamylamine, demonstrating that the locomotor and in vivo electrophysiological responses to acute nicotine are mediated through nAChRs. Furthermore, α4*β2* nAChRs were found to mediate the inhibitory effect of acute nicotine with respect to locomotion and in vivo electrophysiological responses of VTA dopamine neurons, as nicotine's depressant effects were blocked in mice pretreated with dihydro-beta-erythroidine (DHβE). The α7 nAChRs appear to play no role in the inhibitory effects of acute nicotine on locomotion as methyllycaconitine (doses up to 10mg/kg), had no effect on nicotine-induced hypolocomotion. Chronic nicotine treatment for 10 days resulted in electrophysiological (in vivo) and behavioral tolerance to the effects of nicotine in mice. In mice chronically treated with nicotine, the VTA dopamine neuronal response to nicotine was significantly reduced. Nicotine's depressant effects on body temperature and locomotion were also significantly reduced after 10 days of nicotine treatment. Furthermore, the ICR mouse strain was found to be nicotine-sensitive, as nicotine inhibited locomotor activity in a manner more similar to the DBA/2 strain, a standard nicotine-sensitive strain of mouse as compared to the C3H/HeJ strain, a standard nicotine-resistant strain. The ICR mouse was also found to be spontaneously more active than the DBA/2 and C3H/HeJ strain.

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Linderholm, Klas. "Kynurenic acid in psychiatric disorders studies on the mechanisms of action /." Stockholm, 2010. http://diss.kib.ki.se/2010/978-91-7409-818-1/.

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Petzel, Anja [Verfasser]. "The mammalian lateral habenular complex - projection and back projection to the ventral tegmental area, the center of the reward system / Anja Petzel." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2018. http://d-nb.info/1153769670/34.

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48

Linsenbardt, David Nathaniel. "Agonism of the endocannabinoid system modulates binge-like alcohol intake in male C57BL/6J mice involvement of the posterior ventral tegmental area /." Diss., Online access via UMI:, 2008.

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49

Druhan, Jonathan Peter. "An assessment of the effects of psychoactive drugs and electrical stimulatin of the ventral tegmental area on the stimulus properties of amphetamine." Thesis, University of British Columbia, 1989. http://hdl.handle.net/2429/29091.

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The discriminative stimulus properties of amphetamine are thought to result from the facilitatory actions of this drug on dopamine neurotransmission within the nucleus accumbens. As such actions within the nucleus accumbens also are hypothesized to be responsible for amphetamine's rewarding effects, the stimulus properties of amphetamine may be related to the hedonic effects of the drug. If these conclusions are correct, then tests for generalization with the stimulus properties of amphetamine might be useful either to determine the dopaminergic actions of drugs, or to screen newly developed compounds for their abuse potential. In the present thesis rats were trained to discriminate 1.0 mg/kg amphetamine from saline, and then tested for stimulus generalization to a range of amphetamine doses (0.0, 0.25, 0.50 and 1.0 mg/kg) injected either alone or in combination with either cocaine, apomorphine, haloperidol, nicotine, morphine, midazolam, ethanol or electrical stimulation of the ventral tegmental area (VTA). Comparisons were then made between the amphetamine stimulus generalization functions obtained in the presence and absence of the test stimuli, to determine whether the functions were altered in a manner consistent with the known dopaminergic actions or hedonic effects of the drugs and VTA stimulation. It was predicted that test stimuli that could enhance dopamine neurotransmission or produce positive hedonic effects might augment the stimulus properties of amphetamine and elevate stimulus generalization functions relative to a control curve. Conversely, test stimuli that inhibited dopamine neurotransmission or reduced positive affect might interfere with the amphetamine stimuli and lower the generalization functions. The results indicated that amphetamine stimulus generalization functions were altered in a manner that generally reflected the known actions of each test stimulus on dopamine neurotransmission. Thus, the generalization functions were elevated by stimuli that enhanced dopamine neurotransmission (cocaine, a dose of apomorphine affecting post-synaptic dopamine receptor sites, nicotine and VTA stimulation) and lowered by stimuli that interfered with dopamine neurotransmission (haloperidol, midazolam, and a dose of apomorphine that acts preferentially at presynaptic dopamine autoreceptors). Ethanol, which has not been found to consistently affect dopamine neurotransmission, did not generalize with the stimulus properties of amphetamine. Only morphine was found to affect amphetamine stimulus generalization functions (a lowering) in a manner that was inconsistent with the drug's facilitatory actions on dopamine neurotransmission. The amphetamine stimulus generalization functions were not affected in a manner consistent with the hedonic actions of each test stimulus. Certain drugs that could produce positive hedonic effects (morphine, midazolam and ethanol) failed to elevate the generalization functions. In fact, the functions were elevated only by stimuli that appear to produce most of their rewarding effects by enhancing mesoaccumbens dopamine neurotransmission (cocaine, apomorphine, nicotine, and VTA stimulation). Two additional experiments suggested that this property could have been responsible for the ability of VTA stimulation to elevate amphetamine stimulus generalization functions. In one experiment, the ability of the VTA stimulation to substitute for the stimulus properties of amphetamine was found to be correlated positively with its rewarding efficacy measured during ICSS tests. A subsequent experiment indicated that dopamine neurons could indeed mediate discriminative stimuli produced by VTA stimulation, as the brain stimulation cues were augmented by amphetamine and attenuated by the dopamine receptor antagonist, haloperidol. Together, the findings of this thesis indicated that amphetamine stimulus generalization paradigms might be useful for detecting the dopaminergic actions of certain psychoactive drugs. However, such procedures may not detect the abuse potential of all compounds. This latter result indicates that certain drugs of abuse do not produce amphetamine-like stimulus properties, and that this may be due to differences in the neural mechanisms that mediate their positive hedonic effects.
Arts, Faculty of
Psychology, Department of
Graduate

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Oliveira, Amanda Ribeiro de. "Envolvimento de receptores dopaminérgicos da área tegmental ventral e do complexo basolateral da amígdala na aquisição e na expressão do medo condicionado." Universidade de São Paulo, 2010. http://www.teses.usp.br/teses/disponiveis/59/59134/tde-18022010-093027/.

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OLIVEIRA, A.R. Envolvimento de receptores dopaminérgicos da área tegmental ventral e do complexo basolateral da amígdala na aquisição e na expressão do medo condicionado. 2010. 93 f. Tese (Doutorado) Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo. O condicionamento Pavloviano é um dos paradigmas mais utilizados para estudar as bases biológicas das emoções, assim como da aprendizagem e memória. A dopamina (DA) é um dos principais neurotransmissores envolvidos na mediação de estados de medo e ansiedade. Um conjunto crescente de evidências dá suporte à hipótese de que a ativação da via mesocorticolímbica, proveniente de neurônios dopaminérgicos da área tegmental ventral (ATV), é particularmente sensível à estimulação aversiva. Entre as regiões inervadas por esta via, o complexo basolateral da amígdala (BLA) é um componente essencial dos circuitos neurais do medo condicionado. Assim, o presente estudo explorou o envolvimento de mecanismos DA da ATV e do BLA, através do uso de agonistas e antagonistas de receptores DA, na aquisição e expressão do medo condicionado à luz. Não houve efeito das drogas DA no sobressalto potencializado pelo medo (SPM), quando injetadas na ATV antes do condicionamento, indicando que os receptores DA da ATV não participam da aquisição do medo condicionado à luz. Ao contrário, quando injetado na ATV antes do teste, quimpirole (agonista D2) reduziu o SPM, enquanto as demais drogas não tiveram efeito. A administração de SCH 23390 (antagonista D1) no BLA não produziu efeitos no SPM, indicando que os receptores D1 do BLA não parecem envolvidos na expressão do SPM. Já a administração de sulpirida (antagonista D2) no BLA inibiu o SPM produzido pela luz. Além disso, a expressão do medo condicionado foi associada a um aumento do congelamento e dos níveis extracelulares de DA no BLA, ambos inibidos com a administração de quimpirole na ATV. A capacidade do quimpirole em diminuir o SPM e o congelamento condicionado parece ser resultado de sua ação em auto-receptores D2 da ATV. A ativação desses receptores diminui os níveis de dopamina em áreas que recebem terminações da via mesocorticolímbica. Os resultados com a sulpirida realçam a importância dos receptores D2 do BLA na expressão do medo condicionado Pavloviano.
OLIVEIRA, A.R. Involvement of dopaminergic receptors of ventral tegmental area and basolateral amygdala in the acquisition and expression of conditioned fear. 2010. 93 p. Thesis (Doctoral) Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo. The Pavlovian fear conditioning is one of the most used paradigms to study the biological basis of emotion, as well as of learning and memory. Dopamine (DA) is one of the most important neurotransmitters involved in mechanisms underlying states of fear and anxiety. A growing body of evidence supports the hypothesis that excitation of the mesocorticolimbic pathway, originating from DA neurons in the ventral tegmental area (VTA), is particularly sensitive to fear-arousing stimuli. Among the forebrain regions innervated by this pathway, the basolateral amygdala (BLA) is an essential component of the neural circuitry of conditioned fear. The present study explored the involvement of VTA and BLA DA receptors, using DA agonists and antagonists, in the acquisition and expression of conditioned fear to a light conditioned stimulus (CS). None of the drugs used produced significant effects on fear-potentiated startle (FPS) when injected in VTA before conditioning, indicating that VTA DA receptors are not involved in the acquisition of conditioned fear to a light-CS. In contrast, when injected before the test session, intra-VTA quinpirole (D2 agonist) significantly reduced FPS, whereas the other drugs had no effect. Intra-BLA SCH 23390 (D1 antagonist) did not produce significant effects on FPS, indicating that BLA D1 receptors do not appear to be involved in the expression of FPS. On the other hand, intra-BLA sulpiride (D2 antagonist) inhibited FPS produced by light-CS previously paired with footshocks. Also, conditioned fear was associated with increased freezing and DA levels in the BLA, both inhibited by intra-VTA quinpirole. Quinpirole\'s ability to decrease FPS and conditioned freezing may be the result of an action on VTA D2 presynaptic autoreceptors. The activation of those receptors decreases dopamine levels in terminal fields of the mesocorticolimbic pathway. Sulpirides results stress the importance of BLA D2 receptors in the fear-activating effects of the Pavlovian conditioning.

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