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1
Kirouac, G. J., and J. Ciriello. "Cardiovascular afferent inputs to ventral tegmental area." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 272, no. 6 (June 1, 1997): R1998—R2003. http://dx.doi.org/10.1152/ajpregu.1997.272.6.r1998.
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Extracellular single-unit recording experiments were done in alpha-chloralose-anesthetized, paralyzed, and artificially ventilated rats to investigate the effect of selective activation of arterial baroreceptors and stimulation of cardiovascular depressor sites in the nucleus of the solitary tract (NTS) on the discharge rate of neurons in the ventral tegmental area (VTA). Electrical stimulation of the aortic depressor nerve (ADN), which is known to carry aortic baroreceptor afferent fibers only, excited 12 of 21 (mean onset latency 42.4 +/- 8.8 ms) and inhibited 2 of 21 (mean onset latency 42.5 +/- 6.5 ms) single units in the VTA. The discharge rate of VTA units was also altered during the reflex activation of arterial baroreceptors by the acute rise in arterial pressure (AP) to systemic injections of phenylephrine (10 micrograms/kg i.v.): 12 of 44 units were excited and 15 of 44 were inhibited. Units that responded to either ADN stimulation or the reflex activation of the baroreflex also responded to stimulation of depressor sites in the NTS. An additional 12 units that were found in barodenervated controls to be responsive to NTS stimulation were nonresponsive to selective activation of arterial baroreceptors. These data indicate that cardiovascular afferent inputs modulate the activity of neurons in the VTA and suggest that changes in systemic AP may exert an effect on the activity of neurons involved in mesolimbic and mesocortical function.
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Andino, Lourdes M., Daniel J. Ryder, Alexandra Shapiro, Michael K. Matheny, Yi Zhang, Melanie K. Judge, K. Y. Cheng, Nihal Tümer, and Philip J. Scarpace. "POMC overexpression in the ventral tegmental area ameliorates dietary obesity." Journal of Endocrinology 210, no. 2 (May 12, 2011): 199–207. http://dx.doi.org/10.1530/joe-10-0418.
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The activation of proopiomelanocortin (POMC) neurons in different regions of the brain, including the arcuate nucleus of the hypothalamus (ARC) and the nucleus of the solitary tract curtails feeding and attenuates body weight. In this study, we compared the effects of delivery of a recombinant adeno-associated viral (rAAV) construct encoding POMC to the ARC with delivery to the ventral tegmental area (VTA). F344×Brown Norway rats were high-fat (HF) fed for 14 days after which self-complementary rAAV constructs expressing either green fluorescent protein or the POMC gene were injected using coordinates targeting either the VTA or the ARC. Corresponding increased POMC levels were found at the predicted injection sites and subsequent α-melanocyte-stimulating hormone levels were observed. Food intake and body weight were measured for 4 months. Although caloric intake was unaltered by POMC overexpression, weight gain was tempered with POMC overexpression in either the VTA or the ARC compared with controls. There were parallel decreases in adipose tissue reserves. In addition, levels of oxygen consumption and brown adipose tissue uncoupling protein 1 were significantly elevated with POMC treatment in the VTA. Interestingly, tyrosine hydroxylase levels were increased in both the ARC and VTA with POMC overexpression in either the ARC or the VTA. In conclusion, these data indicate a role for POMC overexpression within the VTA reward center to combat HF-induced obesity.
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Kalivas, P. W., and R. Richardson-Carlson. "Endogenous enkephalin modulation of dopamine neurons in ventral tegmental area." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 251, no. 2 (August 1, 1986): R243—R249. http://dx.doi.org/10.1152/ajpregu.1986.251.2.r243.
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Many lines of evidence support the possibility that the opioid pentapeptides Met- and Leu-enkephalin can modulate dopamine neurons in the ventral tegmental area (VTA). Thus microinjection of enkephalin analogues into the VTA of rats produces a dopamine-dependent increase in spontaneous motor activity and an increase in dopamine metabolism in certain mesolimbic dopamine terminal fields, such as the nucleus accumbens. To determine if these effects can be produced by endogenous enkephalins, an enkephalinase A inhibitor, thiorphan, was microinjected into the VTA to inhibit enkephalin metabolism. Thiorphan produced a dose-dependent (0.3-3.33 micrograms) increase in spontaneous motor activity that was blocked by pretreatment with the opioid antagonist naloxone (2.0 mg/kg ip) or the dopamine antagonist haloperidol (0.1 mg/kg ip). Thiorphan injection into the VTA increased dopamine metabolism in the nucleus accumbens, prefrontal cortex, and septum but not in the striatum. In all brain regions the increase in dopamine metabolism was blocked by pretreatment with naloxone. These data demonstrate that endogenous enkephalin in the VTA can increase the activity of A10 dopamine neurons, supporting a physiological role for enkephalin in mesolimbic and mesocortical dopamine-mediated behaviors.
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Hung, Lin W., Sophie Neuner, Jai S. Polepalli, Kevin T. Beier, Matthew Wright, Jessica J. Walsh, Eastman M. Lewis, et al. "Gating of social reward by oxytocin in the ventral tegmental area." Science 357, no. 6358 (September 28, 2017): 1406–11. http://dx.doi.org/10.1126/science.aan4994.
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The reward generated by social interactions is critical for promoting prosocial behaviors. Here we present evidence that oxytocin (OXT) release in the ventral tegmental area (VTA), a key node of the brain’s reward circuitry, is necessary to elicit social reward. During social interactions, activity in paraventricular nucleus (PVN) OXT neurons increased. Direct activation of these neurons in the PVN or their terminals in the VTA enhanced prosocial behaviors. Conversely, inhibition of PVN OXT axon terminals in the VTA decreased social interactions. OXT increased excitatory drive onto reward-specific VTA dopamine (DA) neurons. These results demonstrate that OXT promotes prosocial behavior through direct effects on VTA DA neurons, thus providing mechanistic insight into how social interactions can generate rewarding experiences.
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Simmons, DeNard V., Alyssa K. Petko, and Carlos A. Paladini. "Differential expression of long-term potentiation among identified inhibitory inputs to dopamine neurons." Journal of Neurophysiology 118, no. 4 (October 1, 2017): 1998–2008. http://dx.doi.org/10.1152/jn.00270.2017.
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The in vivo firing pattern of ventral tegmental area (VTA) dopamine neurons is controlled by GABA afferents originating primarily from the nucleus accumbens (NAc), rostromedial tegmental nucleus (RMTg), and local GABA neurons within the VTA. Although different forms of plasticity have been observed from GABA inputs to VTA dopamine neurons, one dependent on cyclic GMP synthesis and the other on adenylyl cyclase activation, it is unknown whether plasticity is differentially expressed in each. Using an optogenetic strategy, we show that identified inhibitory postsynaptic currents (IPSCs) from local VTA GABA neurons and NAc afferents exhibit a cyclic GMP-dependent long-term potentiation (LTP) that is capable of inhibiting the firing activity of dopamine neurons. However, this form of LTP was not induced from RMTg afferents. Only an adenylyl cyclase-mediated increase in IPSCs was exhibited by all three inputs. Thus discrete plasticity mechanisms recruit overlapping but different subsets of GABA inputs to VTA dopamine neurons. NEW & NOTEWORTHY We describe a mapping of plasticity expression, mediated by different mechanisms, among three distinct GABA afferents to ventral tegmental area (VTA) dopamine neurons: the rostromedial tegmental nucleus, the nucleus accumbens, and the local GABA neurons within the VTA known to synapse on VTA dopamine neurons. This work is the first demonstration that discrete plasticity mechanisms recruit overlapping but different subsets of GABA inputs to VTA dopamine neurons.
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Lepack, Ashley E., Craig T. Werner, Andrew F. Stewart, Sasha L. Fulton, Ping Zhong, Lorna A. Farrelly, Alexander C. W. Smith, et al. "Dopaminylation of histone H3 in ventral tegmental area regulates cocaine seeking." Science 368, no. 6487 (April 9, 2020): 197–201. http://dx.doi.org/10.1126/science.aaw8806.
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Vulnerability to relapse during periods of attempted abstinence from cocaine use is hypothesized to result from the rewiring of brain reward circuitries, particularly ventral tegmental area (VTA) dopamine neurons. How cocaine exposures act on midbrain dopamine neurons to precipitate addiction-relevant changes in gene expression is unclear. We found that histone H3 glutamine 5 dopaminylation (H3Q5dop) plays a critical role in cocaine-induced transcriptional plasticity in the midbrain. Rats undergoing withdrawal from cocaine showed an accumulation of H3Q5dop in the VTA. By reducing H3Q5dop in the VTA during withdrawal, we reversed cocaine-mediated gene expression changes, attenuated dopamine release in the nucleus accumbens, and reduced cocaine-seeking behavior. These findings establish a neurotransmission-independent role for nuclear dopamine in relapse-related transcriptional plasticity in the VTA.
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Chen, Li, and Daniel J. Lodge. "The lateral mesopontine tegmentum regulates both tonic and phasic activity of VTA dopamine neurons." Journal of Neurophysiology 110, no. 10 (November 15, 2013): 2287–94. http://dx.doi.org/10.1152/jn.00307.2013.
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Anatomic studies have demonstrated that the mesolimbic dopamine system receives a substantial afferent input from a variety of regions ranging from the prefrontal cortex through to the brain stem. However, how these afferents regulate dopamine neuron activity is still largely unknown. The mesopontine tegmentum provides a significant input to ventral tegmental area (VTA) dopamine neurons, and it has been demonstrated that discrete subdivisions within this region differentially alter dopamine neuron activity. Thus the laterodorsal tegmental nucleus provides a tonic input essential for maintaining burst firing of dopamine neurons, whereas the pedunculopontine tegmental (PPTg) nucleus regulates a transition from single-spike firing to burst firing. In contrast, the recently identified rostromedial tegmental nucleus provides an inhibitory input to the VTA and decreases spontaneous dopamine neuron activity. Here, we demonstrate that an area adjacent to the PPTg regulates both population activity as well as burst firing of VTA dopamine neurons. Specifically, N-methyl-d-aspartic acid (NMDA) activation of the lateral mesopontine tegmentum produces an increase in the number of spontaneously active dopamine neurons and an increase in the average percentage of burst firing of dopamine neurons. This increase in neuronal activity was correlated with extracellular dopamine efflux in the nucleus accumbens, as measured by in vivo microdialysis. Taken together, we provide further evidence that the mesopontine tegmentum regulates discrete dopamine neuron activity states that are relevant for the understanding of dopamine system function in both normal and disease states.
8
Koyama, Susumu, and Sarah B. Appel. "Characterization of M-Current in Ventral Tegmental Area Dopamine Neurons." Journal of Neurophysiology 96, no. 2 (August 2006): 535–43. http://dx.doi.org/10.1152/jn.00574.2005.
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M-current ( IM) is a voltage-gated potassium current (KCNQ type) that affects neuronal excitability and is modulated by some drugs of abuse. Ventral tegmental area (VTA) dopamine (DA) neurons are important for the reinforcing effects of drugs of abuse. Therefore we studied IM in acutely dissociated rat DA VTA neurons with nystatin-perforated patch recording. The standard deactivation protocol was used to measure IM during voltage-clamp recording with hyperpolarizing voltage steps to −65 mV (in 10-mV increments) from a holding potential of −25 mV. IM amplitude was voltage dependent and maximal current amplitude was detected at −45 mV. The deactivation time constant of IM was voltage dependent and became shorter at more negative voltages. The IM/KCNQ antagonist XE991 (0.3–30 μM) caused a concentration-dependent reduction in IM amplitude with an IC50 of 0.71 μM. Tetraethylammonium (TEA, 0.3–10 mM) caused a concentration-dependent inhibition of IM with an IC50 of 1.56 mM. In current-clamp recordings, all DA VTA neurons were spontaneously active. Analysis of evoked action potential shape indicated that XE991 (1–10 μM) reduced the fast and slow components of the spike afterhyperpolarization (AHP) without affecting the middle component of the AHP. Action potential amplitude, duration, and threshold were not affected by XE991. In addition, 10 μM XE991 significantly shortened the interspike intervals in evoked spike trains. In conclusion, IM is active near threshold in DA VTA neurons, is blocked by XE991 (10 μM) and TEA (10 mM), may contribute to the shape of the AHP, and may decrease excitability of these neurons.
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Li, Wei, William M. Doyon, and John A. Dani. "Quantitative unit classification of ventral tegmental area neurons in vivo." Journal of Neurophysiology 107, no. 10 (May 15, 2012): 2808–20. http://dx.doi.org/10.1152/jn.00575.2011.
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Neurons in the ventral tegmental area (VTA) synthesize several major neurotransmitters, including dopamine (DA), GABA, and glutamate. To classify VTA single-unit neural activity from freely moving rats, we used hierarchical agglomerative clustering and probability distributions as quantitative methods. After many parameters were examined, a firing rate of 10 Hz emerged as a transition frequency between clusters of low-firing and high-firing neurons. To form a subgroup identified as high-firing neurons with GABAergic characteristics, the high-firing classification was sorted by spike duration. To form a subgroup identified as putative DA neurons, the low-firing classification was sorted by DA D2-type receptor pharmacological responses to quinpirole and eticlopride. Putative DA neurons were inhibited by the D2-type receptor agonist quinpirole and returned to near-baseline firing rates or higher following the D2-type receptor antagonist eticlopride. Other unit types showed different responses to these D2-type receptor drugs. A multidimensional comparison of neural properties indicated that these subgroups often clustered independently of each other with minimal overlap. Firing pattern variability reliably distinguished putative DA neurons from other unit types. A combination of phasic burst properties and a low skew in the interspike interval distribution produced a neural population that was comparable to the one sorted by D2 pharmacology. These findings provide a quantitative statistical approach for the classification of VTA neurons in unanesthetized animals.
10
Brodie, M. S., and E. B. Bunney. "Serotonin potentiates dopamine inhibition of ventral tegmental area neurons in vitro." Journal of Neurophysiology 76, no. 3 (September 1, 1996): 2077–82. http://dx.doi.org/10.1152/jn.1996.76.3.2077.
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1. The ventral tegmental area (VTA) has been implicated in both the rewarding effects of drugs of abuse and the etiology of schizophrenia. We report here that serotonin (5-HT) potentiates the inhibitory effect of dopamine on dopaminergic VTA neurons. Dopamine (0.5-10 microM) inhibited the spontaneous firing of putative dopamine-containing neurons of the VTA. 5-HT (5-10 microM) itself did not significantly alter the spontaneous firing rate; however, in the presence of 5-HT, the inhibitory potency of dopamine was significantly increased. 2. The inhibitory potency of the dopamine agonist quinpirole was also increased by 5-HT. 3. 5-HT-induced potentiation was also produced by the selective 5-HT2 agonist (+/-)-2,5-dimethoxy-4-iodoamphetamine, and was reversed by the selective 5-HT2 antagonist ketanserin. 4. This novel action of 5-HT on dopaminergic neurons has important implications for the development of drugs to treat schizophrenia, and for the identification of agents that will be useful in treating drug abuse disorders like alcoholism.
11
Kirouac, Gilbert J., and John Ciriello. "Cardiovascular depressor responses to stimulation of substantia nigra and ventral tegmental area." American Journal of Physiology-Heart and Circulatory Physiology 273, no. 6 (December 1, 1997): H2549—H2557. http://dx.doi.org/10.1152/ajpheart.1997.273.6.h2549.
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Experiments were done in α-chloralose-anesthetized, paralyzed, and artificially ventilated rats to investigate the effect ofl-glutamate (Glu) stimulation of the substantia nigra (SN) and ventral tegmental area (VTA) on arterial pressure (AP) and heart rate (HR). Glu stimulation of the SN pars compacta (SNC) elicited decreases in both mean AP (MAP; −18.9 ± 1.3 mmHg; n = 52) and HR (−26.1 ± 1.6 beats/min; n = 46) at 81% of the sites stimulated. On the other hand, stimulation of the SN pars lateralis or pars reticulata did not elicit cardiovascular responses. Stimulation of the adjacent VTA region elicited similar decreases in MAP (−18.0 ± 2.6 mmHg; n = 20) and HR (−25.4 ± 3.8 beats/min; n = 17) at ∼74% of the sites stimulated. Intravenous administration of the dopamine D2-receptor antagonist raclopride significantly attenuated both the MAP (70%) and the HR (54%) responses elicited by stimulation of the transitional region where the SNC merges with the lateral VTA (SNC-VTA region). Intravenous administration of the muscarinic receptor blocker atropine methyl bromide had no effect on the magnitude of the MAP and HR responses to stimulation of the SNC-VTA region, whereas administration of the nicotinic receptor blocker hexamethonium bromide significantly attenuated both the depressor and the bradycardic responses. These data suggest that dopaminergic neurons in the SNC-VTA region activate a central pathway that exerts cardiovascular depressor effects that are mediated by the inhibition of sympathetic vasoconstrictor fibers to the vasculature and cardioacceleratory fibers to the heart.
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Keath, J. Russel, Michael P. Iacoviello, Lindy E. Barrett, Huibert D. Mansvelder, and Daniel S. McGehee. "Differential Modulation by Nicotine of Substantia Nigra Versus Ventral Tegmental Area Dopamine Neurons." Journal of Neurophysiology 98, no. 6 (December 2007): 3388–96. http://dx.doi.org/10.1152/jn.00760.2007.
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Midbrain dopamine (DA) neurons are found in two nuclei, the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA). The SNc dopaminergic projections to the dorsal striatum are involved in voluntary movement and habit learning, whereas the VTA projections to the ventral striatum contribute to reward and motivation. Nicotine induces profound DA release from VTA dopamine neurons but substantially less from the SNc. Nicotinic acetylcholine receptor (nAChR) expression differs between these nuclei, but it is unknown whether there are differences in nAChR expression on the afferent projections to these nuclei. Here we have compared the nicotinic modulation of excitatory and inhibitory synaptic inputs to VTA and SNc dopamine neurons. Although nicotine enhances both the excitatory and inhibitory drive to SNc DA cells with response magnitudes similar to those seen in the VTA, the prevalence of these responses in SNc is much lower. We also found that a mixture of nAChR subtypes underlies the synaptic modulation in SNc, further distinguishing this nucleus from the VTA, where α7 nAChRs enhance glutamate inputs and non-α7 receptors enhance GABA inputs. Finally, we compared the nicotine sensitivity of DA neurons in these two nuclei and found larger response magnitudes in VTA relative to SNc. Thus the observed differences in nicotine-induced DA release from VTA and SNc are likely due to differences in nAChR expression on the afferent inputs as well as on the DA neurons themselves. This may explain why nicotine has a greater effect on behaviors associated with the VTA than the SNc.
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Roseberry, Aaron G. "Acute fasting increases somatodendritic dopamine release in the ventral tegmental area." Journal of Neurophysiology 114, no. 2 (August 2015): 1072–82. http://dx.doi.org/10.1152/jn.01008.2014.
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Fasting and food restriction alter the activity of the mesolimbic dopamine system to affect multiple reward-related behaviors. Food restriction decreases baseline dopamine levels in efferent target sites and enhances dopamine release in response to rewards such as food and drugs. In addition to releasing dopamine from axon terminals, dopamine neurons in the ventral tegmental area (VTA) also release dopamine from their soma and dendrites, and this somatodendritic dopamine release acts as an autoinhibitory signal to inhibit neighboring VTA dopamine neurons. It is unknown whether acute fasting also affects dopamine release, including the local inhibitory somatodendritic dopamine release in the VTA. In these studies, I have tested whether fasting affects the inhibitory somatodendritic dopamine release within the VTA by examining whether an acute 24-h fast affects the inhibitory postsynaptic current mediated by evoked somatodendritic dopamine release (D2R IPSC). Fasting increased the contribution of the first action potential to the overall D2R IPSC and increased the ratio of repeated D2R IPSCs evoked at short intervals. Fasting also reduced the effect of forskolin on the D2R IPSC and led to a significantly bigger decrease in the D2R IPSC in low extracellular calcium. Finally, fasting resulted in an increase in the D2R IPSCs when a more physiologically relevant train of D2R IPSCs was used. Taken together, these results indicate that fasting caused a change in the properties of somatodendritic dopamine release, possibly by increasing dopamine release, and that this increased release can be sustained under conditions where dopamine neurons are highly active.
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Mooney, Kenneth E., Akira Inokuchi, James B. Snow, and Charles P. Kimmelman. "Projections from the Ventral Tegmental Area to the Olfactory Tubercle in the Rat." Otolaryngology–Head and Neck Surgery 96, no. 2 (February 1987): 151–57. http://dx.doi.org/10.1177/019459988709600207.
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The projection between the ventral tegmental area (VTA) and the olfactory tubercle (OT) was examined electrophysiologically in the rat. Stimulation of the olfactory bulb (OB) determined if the OT neurons were olfactory-related. Ipsilateral VTA stimulation produced a change in neuronal activity in 77% of the neurons tested, with 41% being inhibited, 24% excited, and 12% had mixed response. Contralateral VTA stimulation produced changes in only 38%. Intravenous administration of haloperidol was used in examination of the role of dopamine in this neural connection. The results suggest that the VTA-induced inhibitory response on OT neurons is mediated by dopamine, whereas excitatory responses are not. The VTA inhibitory influence projects primarily to olfactory-related neurons, since 60% of olfactory-related OT neurons were inhibited—as compared to 34% of non-olfactory-related neurons. This study documents electrophysiologically the VTA-OT connection and suggests that the dopaminergic input may modulate olfactory information projected to the OT from the OB. It also supports the concept that the OT acts as an integration center in central olfactory processing.
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Solt, Ken, Christa J. Van Dort, Jessica J. Chemali, Norman E. Taylor, Jonathan D. Kenny, and Emery N. Brown. "Electrical Stimulation of the Ventral Tegmental Area Induces Reanimation from General Anesthesia." Anesthesiology 121, no. 2 (August 1, 2014): 311–19. http://dx.doi.org/10.1097/aln.0000000000000117.
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Abstract Background: Methylphenidate or a D1 dopamine receptor agonist induces reanimation (active emergence) from general anesthesia. The authors tested whether electrical stimulation of dopaminergic nuclei also induces reanimation from general anesthesia. Methods: In adult rats, a bipolar insulated stainless steel electrode was placed in the ventral tegmental area (VTA, n = 5) or substantia nigra (n = 5). After a minimum 7-day recovery period, the isoflurane dose sufficient to maintain loss of righting was established. Electrical stimulation was initiated and increased in intensity every 3 min to a maximum of 120 µA. If stimulation restored the righting reflex, an additional experiment was performed at least 3 days later during continuous propofol anesthesia. Histological analysis was conducted to identify the location of the electrode tip. In separate experiments, stimulation was performed in the prone position during general anesthesia with isoflurane or propofol, and the electroencephalogram was recorded. Results: To maintain loss of righting, the dose of isoflurane was 0.9% ± 0.1 vol%, and the target plasma dose of propofol was 4.4 ± 1.1 µg/ml (mean ± SD). In all rats with VTA electrodes, electrical stimulation induced a graded arousal response including righting that increased with current intensity. VTA stimulation induced a shift in electroencephalogram peak power from δ (<4 Hz) to θ (4–8 Hz). In all rats with substantia nigra electrodes, stimulation did not elicit an arousal response or significant electroencephalogram changes. Conclusions: Electrical stimulation of the VTA, but not the substantia nigra, induces reanimation during general anesthesia with isoflurane or propofol. These results are consistent with the hypothesis that dopamine release by VTA neurons, but not substantia nigra neurons, induces reanimation from general anesthesia.
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Koyama, Susumu, and Sarah B. Appel. "A-type K+ Current of Dopamine and GABA Neurons in the Ventral Tegmental Area." Journal of Neurophysiology 96, no. 2 (August 2006): 544–54. http://dx.doi.org/10.1152/jn.01318.2005.
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A-type K+ current ( IA) is a rapidly inactivating voltage-dependent potassium current which can regulate the frequency of action potential (AP) generation. Increased firing frequency of ventral tegmental area (VTA) neurons is associated with the reinforcing effects of some drugs of abuse like nicotine and ethanol. In the present study, we classified dopamine (DA) and GABA VTA neurons, and investigated IA properties and the physiological role of IA in these neurons using conventional whole cell current- and voltage-clamp recording. DA VTA neurons had a mean firing frequency of 3.5 Hz with a long AP duration. GABA VTA neurons had a mean firing frequency of 16.7 Hz with a short AP duration. For IA properties, the voltage-dependence of steady-state IA activation and inactivation was similar in DA and GABA VTA neurons. IA inactivation was significantly faster and became faster at positive voltages in GABA neurons than DA neurons. Recovery from inactivation was significantly faster in DA neurons than GABA neurons. IA current density at full recovery was significantly larger in DA neurons than GABA neurons. In DA and GABA VTA neurons, latency to the first AP after the recovery from membrane hyperpolarization (repolarization latency) was measured. Longer repolarization latency was accompanied by larger IA current density in DA VTA neurons, compared with GABA VTA neurons. We suggest that IA contributes more to the regulation of AP generation in DA VTA neurons than in GABA VTA neurons.
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Margolis, Elyssa B., Gregory O. Hjelmstad, Antonello Bonci, and Howard L. Fields. "Both Kappa and Mu Opioid Agonists Inhibit Glutamatergic Input to Ventral Tegmental Area Neurons." Journal of Neurophysiology 93, no. 6 (June 2005): 3086–93. http://dx.doi.org/10.1152/jn.00855.2004.
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The ventral tegmental area (VTA) plays a critical role in motivation and reinforcement. Kappa and μ opioid receptor (KOP-R and MOP-R) agonists microinjected into the VTA produce powerful and largely opposing motivational actions. Glutamate transmission within the VTA contributes to these motivational effects. Therefore information about opioid control of glutamate release onto VTA neurons is important. To address this issue, we performed whole cell patch-clamp recordings in VTA slices and measured excitatory postsynaptic currents (EPSCs). There are several classes of neuron in the VTA: principal, secondary, and tertiary. The KOP-R agonist ( trans)-3,4-dichloro- N-methyl- N-[2-(1-pyrrolidinyl)-cyclohexyl] benzeneacetamide methane-sulfonate hydrate (U69593; 1 μM) produced a small reduction in EPSC amplitude in principal neurons (14%) and a significantly larger inhibition in secondary (47%) and tertiary (33%) neurons. The MOP-R agonist [d-Ala2, N-Me-Phe4, Gly-ol5]-enkephalin (DAMGO; 3 μM) inhibited glutamate release in principal (42%), secondary (45%), and tertiary neurons (35%). Unlike principal and tertiary neurons, in secondary neurons, the magnitude of the U69593 EPSC inhibition was positively correlated with that produced by DAMGO. Finally, DAMGO did not occlude the U69593 effect in principal neurons, suggesting that some glutamatergic terminals are independently controlled by KOP and MOP receptor activation. These findings show that MOP-R and KOP-R agonists regulate excitatory input onto each VTA cell type.
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Gale, Samuel D., and David J. Perkel. "Physiological Properties of Zebra Finch Ventral Tegmental Area and Substantia Nigra Pars Compacta Neurons." Journal of Neurophysiology 96, no. 5 (November 2006): 2295–306. http://dx.doi.org/10.1152/jn.01040.2005.
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The neurotransmitter dopamine plays important roles in motor control, learning, and motivation in mammals and probably other animals as well. The strong dopaminergic projection to striatal regions and more moderate dopaminergic projections to other regions of the telencephalon predominantly arise from midbrain dopaminergic neurons in the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA). Homologous dopaminergic cell groups in songbirds project anatomically in a manner that may allow dopamine to influence song learning or song production. The electrophysiological properties of SNc and VTA neurons have not previously been studied in birds. Here we used whole cell recordings in brain slices in combination with tyrosine-hydroxylase immunolabeling as a marker of dopaminergic neurons to determine electrophysiological and pharmacological properties of dopaminergic and nondopaminergic neurons in the zebra finch SNc and VTA. Our results show that zebra finch dopaminergic neurons possess physiological properties very similar to those of mammalian dopaminergic neurons, including broad action potentials, calcium- and apamin-sensitive membrane-potential oscillations underlying pacemaker firing, powerful spike-frequency adaptation, and autoinhibition via D2 dopamine receptors. Moreover, the zebra finch SNc and VTA also contain nondopaminergic neurons with similarities (fast-firing, inhibition by the μ-opioid receptor agonist [d-Ala2, N-Me-Phe4, Gly-ol5]-enkephalin (DAMGO)) and differences (strong h-current that contributes to spontaneous firing) compared with GABAergic neurons in the mammalian SNc and VTA. Our results provide insight into the intrinsic membrane properties that regulate the activity of dopaminergic neurons in songbirds and add to strong evidence for anatomical, physiological, and functional similarities between the dopaminergic systems of mammals and birds.
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Terrill, Sarah J., Kellie M. Hyde, Kristen E. Kay, Hayden E. Greene, Calyn B. Maske, Amanda E. Knierim, Jon F. Davis, and Diana L. Williams. "Ventral tegmental area orexin 1 receptors promote palatable food intake and oppose postingestive negative feedback." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 311, no. 3 (September 1, 2016): R592—R599. http://dx.doi.org/10.1152/ajpregu.00097.2016.
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Hypothalamic orexin neurons project to numerous brain areas, including the ventral tegmental area (VTA), which is involved in motivation and food-seeking behavior. Here we address how exogenously administered orexin-A and endogenous orexin 1 receptor (OX1R) activation in the VTA affects feeding behavior. We hypothesized that orexin-A and OX1R antagonist SB334867 delivered to the VTA, at doses that were subthreshold for effect when injected into the ventricle, would affect intake of palatable foods in multiple test situations. We first used a hedonic feeding model in which satiated rats selectively consume a high-fat diet (HFD). Intra-VTA orexin-A stimulated additional consumption of chow and increased HFD intake in this model. In ad libitum-fed rats given daily 30-min test sessions, intra-VTA orexin-A also increased intake of HFD and 0.1 M sucrose. Further analysis of licking patterns revealed that that VTA orexin-A increased meal size and licking burst size only toward the end of the meal. Consistent with this finding, a subthreshold dose of VTA orexin-A prevented intake suppression induced by gastrointestinal nutrient infusion. Surprisingly, intra-VTA orexin-A had no effect on operant responding for sucrose pellets on a progressive ratio schedule of reinforcement. A role for endogenous VTA OX1R stimulation is supported by our finding that bilateral VTA injection of the selective OX1R antagonist SB334867 suppressed 0.1 M sucrose intake. Together, our data suggest that OX1R activity in the VTA facilitates food intake, potentially by counteracting postingestive negative feedback that would normally suppress feeding later in a meal.
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Ballard, Ian C., Kelly Hennigan, and Samuel M. McClure. "Mere Exposure: Preference Change for Novel Drinks Reflected in Human Ventral Tegmental Area." Journal of Cognitive Neuroscience 29, no. 5 (May 2017): 793–804. http://dx.doi.org/10.1162/jocn_a_01098.
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Preferences for novel stimuli tend to develop slowly over many exposures. Psychological accounts of this effect suggest that it depends on changes in the brain's valuation system. Participants consumed a novel fluid daily for 10 days and underwent fMRI on the first and last days. We hypothesized that changes in activation in areas associated with the dopamine system would accompany changes in preference. The change in activation in the ventral tegmental area (VTA) between sessions scaled with preference change. Furthermore, a network comprising the sensory thalamus, posterior insula, and ventrolateral striatum showed differential connectivity with the VTA that correlated with individual changes in preference. Our results suggest that the VTA is centrally involved in both assigning value to sensory stimuli and influencing downstream regions to translate these value signals into subjective preference. These results have important implications for models of dopaminergic function and behavioral addiction.
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Taylor, Norman E., Christa J. Van Dort, Jonathan D. Kenny, JunZhu Pei, Jennifer A. Guidera, Ksenia Y. Vlasov, Justin T. Lee, Edward S. Boyden, Emery N. Brown, and Ken Solt. "Optogenetic activation of dopamine neurons in the ventral tegmental area induces reanimation from general anesthesia." Proceedings of the National Academy of Sciences 113, no. 45 (October 24, 2016): 12826–31. http://dx.doi.org/10.1073/pnas.1614340113.
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Dopamine (DA) promotes wakefulness, and DA transporter inhibitors such as dextroamphetamine and methylphenidate are effective for increasing arousal and inducing reanimation, or active emergence from general anesthesia. DA neurons in the ventral tegmental area (VTA) are involved in reward processing, motivation, emotion, reinforcement, and cognition, but their role in regulating wakefulness is less clear. The current study was performed to test the hypothesis that selective optogenetic activation of VTA DA neurons is sufficient to induce arousal from an unconscious, anesthetized state. Floxed-inverse (FLEX)-Channelrhodopsin2 (ChR2) expression was targeted to VTA DA neurons in DA transporter (DAT)-cre mice (ChR2+ group; n = 6). Optical VTA stimulation in ChR2+ mice during continuous, steady-state general anesthesia (CSSGA) with isoflurane produced behavioral and EEG evidence of arousal and restored the righting reflex in 6/6 mice. Pretreatment with the D1 receptor antagonist SCH-23390 before optical VTA stimulation inhibited the arousal responses and restoration of righting in 6/6 ChR2+ mice. In control DAT-cre mice, the VTA was targeted with a viral vector lacking the ChR2 gene (ChR2− group; n = 5). VTA optical stimulation in ChR2− mice did not restore righting or produce EEG changes during isoflurane CSSGA in 5/5 mice. These results provide compelling evidence that selective stimulation of VTA DA neurons is sufficient to induce the transition from an anesthetized, unconscious state to an awake state, suggesting critical involvement in behavioral arousal.
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Saebi Rad, Farzaneh, Abbas Haghparast, and Afsaneh Eliassi. "Ventral Tegmental Area Microinjected-SKF38393 Increases Regular Chow Intake in 18 Hours Food-Deprived Rats." Basic and Clinical Neuroscience Journal 11, no. 6 (November 1, 2020): 773–80. http://dx.doi.org/10.32598/bcn.11.6.2226.1.
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Introduction: Ventral Tegmental Area (VTA) dopamine neurons play an important role in reward mechanisms of food intake, and VTA dopamine receptors exist on the terminal of glutamatergic and GABAergic neurons and regulate Gamma-Aminobutyric Acid (GABA) and glutamate release. To our knowledge, no evidence indicates any role for VTA D1 dopamine receptors in regular chow intake. Methods: In this paper, different dose of SKF38393, a D1 receptor agonist, was microinjected in VTA of 18-h food deprived-conscious rats and food intake was measured. Results: Our results revealed that VTAmicroinjected SKF383993 increased regular chow intake in a dose-dependent manner. The SKF3833 stimulatory effect persisted over 2 h post-injection. The results showed that the SKF38393, at doses less than 5 μg, did not affect locomotor activities. Conclusion: VTA D1-like and/or serotonergic receptors may be involved in regulatory pathways. the current study suggests that VTA D1-like and/or serotonergic receptors not only affects food reward but is also involved in regulatory mechanisms of regular feeding.
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Kirouac, Gilbert J., and Quentin J. Pittman. "A projection from the ventral tegmental area to the periaqueductal gray involved in cardiovascular regulation." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 278, no. 6 (June 1, 2000): R1643—R1650. http://dx.doi.org/10.1152/ajpregu.2000.278.6.r1643.
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Experiments were done in α-chloralose-anesthetized rats to determine a pathway mediating the cardiovascular depressor responses elicited from stimulation of the ventral tegmental area (VTA). The magnitude of the depressor responses elicited by glutamate stimulation (0.1 M/30 nl) of the VTA was examined after neuronal block produced by microinjections of lidocaine into ascending fiber bundles leaving the VTA to innervate the forebrain and thalamus. Bilateral microinjections of 1 μl of 4% lidocaine in the medial forebrain bundle ( n = 6) and in the periventricular fibers of the midbrain ( n = 5) did not attenuate the depressor response from stimulation of the VTA. Experiments were done using the anterograde tracer biotinylated dextran amine to identify descending projections from the VTA to cardiovascular centers in the brain stem. Examination of the nucleus of the solitary tract, ventrolateral medulla, and A5 catecholaminergic cell group revealed few or no fibers or terminals. Occasional fibers and some terminals were observed in the nucleus of raphe magnus, parabrachial nucleus, and locus ceruleus. A very dense bilateral projection was found to the ventrolateral periaqueductal gray (PAGvl) and dorsal raphe nucleus adjacent to the PAGvl. Bilateral injections of 4% lidocaine ( n = 4) or 10 mM cobalt chloride ( n = 5) into the PAGvl region attenuated the depressor responses elicited by stimulation of the VTA by ∼50%. These experiments indicate that the depressor responses elicited from activation of the VTA are mediated in part by a pathway to a cardiovascular depressor area located in the PAGvl.
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Mietlicki-Baase, Elizabeth G., Diana R. Olivos, Brianne A. Jeffrey, and Matthew R. Hayes. "Cooperative interaction between leptin and amylin signaling in the ventral tegmental area for the control of food intake." American Journal of Physiology-Endocrinology and Metabolism 308, no. 12 (June 15, 2015): E1116—E1122. http://dx.doi.org/10.1152/ajpendo.00087.2015.
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Peripheral coadministration of amylin and leptin produces enhanced suppression of food intake and body weight, but the central nuclei mediating these effects remain unclear. Because each of these peptides controls feeding via actions at the ventral tegmental area (VTA), we tested the hypothesis that the VTA is a site of action for the cooperative effects of leptin and amylin on energy balance control. First, we show that intra-VTA injection of amylin and leptin at doses of each peptide that are effective in reducing food intake and body weight when administered separately produces an enhanced suppression of feeding when administered in combination. We also demonstrate that subthreshold doses of both amylin and leptin cause significant hypophagia and body weight loss when coadministered into the VTA. Additionally, we provide evidence that VTA amylin receptor blockade significantly attenuates the ability of intra-VTA leptin to reduce feeding and body weight gain. Together, these data provide the first evidence that the VTA mediates the interaction of amylin and leptin to cooperatively promote negative energy balance.
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Cragg, S. J., M. E. Rice, and S. A. Greenfield. "Heterogeneity of Electrically Evoked Dopamine Release and Reuptake in Substantia Nigra, Ventral Tegmental Area, and Striatum." Journal of Neurophysiology 77, no. 2 (February 1, 1997): 863–73. http://dx.doi.org/10.1152/jn.1997.77.2.863.
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Cragg, S. J., M. E. Rice, and S. A. Greenfield. Heterogeneity of electrically evoked dopamine release and reuptake in substantia nigra, ventral tegmental area, and striatum. J. Neurophysiol. 77: 863–873, 1997. Somatodendritic dopamine (DA) released in substantia nigra pars compacta (SNc) and the ventral tegmental area (VTA) may mediate extrasynaptic neuronal signaling. The concentration of extracellular DA ([DA]o) attained during somatodendritic activation will be governed by the density of release sites and properties of DA uptake. We evaluated these factors in SNc, VTA, and dorsal striatum with carbon-fiber microelectrodes and fast-scan cyclic voltammetry to monitor [DA]o during local electrical stimulation (10 Hz, 5 s) in guinea pig brain slices. Stimulated DA efflux was site specific, with significantly higher [DA]o in caudal (0.48 ± 0.03 μM, mean ± SE) than rostral SNc (0.16 ± 0.01 μM), averaged over their mediolateral extents, and higher [DA]o in VTA (0.74 ± 0.07 μM) than in medial (0.43 ± 0.04 μM) or lateral SNc (0.29 ± 0.05 μM), averaged rostrocaudally. Throughout SNc, evoked [DA]o correlated positively ( r = 0.91) with the density of tyrosine-hydroxylase-immunoreactive cells. Modulation of evoked [DA]o by uptake was also site specific. The selective DA uptake inhibitor GBR 12909 significantly increased evoked [DA]o in caudal SNc (to 185 ± 27%) and striatum (408 ± 24%), but had no effect in rostral SNc or VTA. Conversely, the norepinephrine (NE) uptake inhibitor desipramine did not alter stimulated [DA]o in caudal SNc or striatum, but caused significant enhancement in rostral SNc (196 ± 17%) and VTA (126 ± 12%). Paroxetine, a selective 5-hydroxytryptamine uptake inhibitor, had little effect in any region tested. Site-specific sensitivity to desipramine mandated evaluation of dopamine-β-hydroxylase immunoreactivity (DβH-ir) in midbrain. The density of filaments positive for DβH-ir was greater in rostral SNc and VTA than in caudal SNc, suggesting DA clearance via the NE transporter in these regions. Importantly, DβH-ir was most dense in sections rostral to SNc where no catecholamine signal was detected and no enhancement was observed with desipramine, indicating a lack of NE contribution to evoked release in any region examined. Taken together, these data confirmed that evoked somatodendritic [DA]o depends on DA cell density and on local uptake properties. Uptake was less efficient in SNc and VTA than in striatum. Moreover, enhancement of stimulated [DA]o by GBR 12909 demonstrated that evoked release from dendrites is not via reversal of the DA transporter. Lastly, the heterogeneous patterns of DA uptake within SNc and VTA were consistent with the pattern of degeneration in Parkinson's disease: less vulnerable DA cells, e.g., those in VTA, have less DA uptake than the more vulnerable cells of caudal SNc.
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Luu, Percy, and Robert C. Malenka. "Spike Timing-Dependent Long-Term Potentiation in Ventral Tegmental Area Dopamine Cells Requires PKC." Journal of Neurophysiology 100, no. 1 (July 2008): 533–38. http://dx.doi.org/10.1152/jn.01384.2007.
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Long-term potentiation (LTP) of excitatory synapses on ventral tegmental area (VTA) dopamine (DA) cells is thought to play an important role in mediating some of the behavioral effects of drugs of abuse yet little is known about its underlying mechanisms. We find that spike timing-dependent LTP (STD LTP) in VTA DA cells is absent in slices prepared from mice previously administered cocaine, suggesting that cocaine-induced LTP and STD LTP share underlying mechanisms. This form of STD LTP is dependent on NMDA receptor (NMDAR) activation and a rise in postsynaptic calcium but surprisingly was not affected by an inhibitor of calcium/calmodulin-dependent protein kinase II (CaMKII). It was blocked by antagonists of conventional isoforms of PKC, whereas activation of protein kinase C (PKC) using a phorbol ester enhanced synaptic strength. These results suggest that NMDAR-mediated activation of PKC, but not CaMKII, is a critical trigger for LTP in VTA DA cells.
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Trutti, Anne C., Laura Fontanesi, Martijn J. Mulder, Pierre-Louis Bazin, Bernhard Hommel, and Birte U. Forstmann. "A probabilistic atlas of the human ventral tegmental area (VTA) based on 7 Tesla MRI data." Brain Structure and Function 226, no. 4 (February 12, 2021): 1155–67. http://dx.doi.org/10.1007/s00429-021-02231-w.
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AbstractFunctional magnetic resonance imaging (fMRI) BOLD signal is commonly localized by using neuroanatomical atlases, which can also serve for region of interest analyses. Yet, the available MRI atlases have serious limitations when it comes to imaging subcortical structures: only 7% of the 455 subcortical nuclei are captured by current atlases. This highlights the general difficulty in mapping smaller nuclei deep in the brain, which can be addressed using ultra-high field 7 Tesla (T) MRI. The ventral tegmental area (VTA) is a subcortical structure that plays a pivotal role in reward processing, learning and memory. Despite the significant interest in this nucleus in cognitive neuroscience, there are currently no available, anatomically precise VTA atlases derived from 7 T MRI data that cover the full region of the VTA. Here, we first provide a protocol for multimodal VTA imaging and delineation. We then provide a data description of a probabilistic VTA atlas based on in vivo 7 T MRI data.
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Morton, Gregory J., James E. Blevins, Francis Kim, Miles Matsen, and Dianne P. Figlewicz. "The action of leptin in the ventral tegmental area to decrease food intake is dependent on Jak-2 signaling." American Journal of Physiology-Endocrinology and Metabolism 297, no. 1 (July 2009): E202—E210. http://dx.doi.org/10.1152/ajpendo.90865.2008.
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Recent evidence suggests that leptin reduces food intake via actions in the brain circuitry of food reward, such as the ventral tegmental area (VTA), as leptin receptors are present in the VTA, and leptin injection in the VTA reduces food intake. In the hypothalamus, leptin-induced anorexia requires signaling via Janus kinase-signal transducer and activator of transcription (Jak-STAT), insulin receptor substrate (IRS)-phosphatidylinositol 3-kinase (PI 3-kinase), and mammalian target of rapamycin (mTOR). In this study, we determined whether leptin activates each of these signal transduction pathways in the VTA and whether these signaling pathways are required for VTA-leptin induced anorexia. Here, we show that pSTAT3-Tyr705, a marker of leptin activation, was induced in a midbrain region containing the VTA and substantia nigra following either intracerebroventricular leptin or direct administration of leptin to the VTA, but these interventions failed to increase levels of either pAKT-Ser473 or phospho-p70S6K-Thr389, markers of IRS-PI 3-kinase and mTOR signaling, respectively. Moreover, the effect of intra-VTA leptin administration to reduce 4- and 20-h food intake and 20-h body weight was blocked by an inhibitor of Jak-2, at a dose that had no effect on food intake or body weight by itself, but not by local inhibition of either PI 3-kinase (LY-294002) or mTOR (rapamycin) in this timeframe. Taken together, these data support the hypothesis that leptin signaling in the VTA is involved in the regulation of energy balance, but, in contrast to the leptin signaling in the hypothalamus, these effects are mediated predominantly via Jak-2 signaling rather than via the IRS-PI 3-kinase or mTOR signaling pathway.
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MacNiven, Kelly H., Josiah K. Leong, and Brian Knutson. "Medial forebrain bundle structure is linked to human impulsivity." Science Advances 6, no. 38 (September 2020): eaba4788. http://dx.doi.org/10.1126/sciadv.aba4788.
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Comparative research indicates that projections from midbrain dopamine nuclei [including the ventral tegmental area (VTA)] to the ventral striatum [including the nucleus accumbens (NAcc)] critically support motivated behavior. Using diffusion-weighted imaging and probabilistic tractography in humans, we characterized the trajectory and structure of two tracts connecting the VTA and NAcc, as well as others connecting the substantia nigra and dorsal striatum. Decreased structural coherence of an inferior VTA–NAcc tract was primarily and replicably associated with increased trait impulsivity and also distinguished individuals with a stimulant use disorder from healthy controls. These findings suggest that decreased coherence of the inferior VTA–NAcc tract is associated with increased impulsivity in humans and identify a previously uncharacterized structural target for diagnosing disorders marked by impulsivity.
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Valdés, José L., Bruce L. McNaughton, and Jean-Marc Fellous. "Offline reactivation of experience-dependent neuronal firing patterns in the rat ventral tegmental area." Journal of Neurophysiology 114, no. 2 (August 2015): 1183–95. http://dx.doi.org/10.1152/jn.00758.2014.
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In a rest period immediately after a task, neurons in the hippocampus, neocortex, and striatum exhibit spatiotemporal correlation patterns resembling those observed during the task. This reactivation has been proposed as a neurophysiological substrate for memory consolidation. We provide new evidence that rodent ventral tegmental area (VTA) neurons are selective for different types of food stimuli and that stimulus-sensitive neurons strongly reactivate during the rest period following a task that involved those stimuli. Reactivation occurred primarily during slow wave sleep and during quiet awakeness. In these experiments, VTA reactivation patterns were uncompressed and occurred at the firing rate level, rather than on a spike-to-spike basis. Mildly aversive stimuli were reactivated more often than positive ones. The VTA is a pivotal structure involved in the perception and prediction of reward and stimulus salience and is a key neuromodulatory system involved in synaptic plasticity. These results suggest new ways in which dopaminergic signals could contribute to the biophysical mechanisms of selective, system-wide, memory consolidation, and reconsolidation during sleep.
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Kimmey, Blake A., Alexey Ostroumov, and John A. Dani. "5-HT2Areceptor activation normalizes stress-induced dysregulation of GABAergic signaling in the ventral tegmental area." Proceedings of the National Academy of Sciences 116, no. 52 (December 5, 2019): 27028–34. http://dx.doi.org/10.1073/pnas.1911446116.
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Stress is known to alter GABAergic signaling in the ventral tegmental area (VTA), and this inhibitory plasticity is associated with increased alcohol self-administration. In humans, serotonin 2A receptor (5-HT2AR) agonists can treat stress- and alcohol-related disorders, but the neural substrates are ill-defined. Thus, we reasoned that 5-HT2AR pharmacotherapies may ameliorate the stress-induced dysregulated inhibitory VTA circuitry that contributes to subsequent alcohol abuse. We found that acute stress exposure in mice compromised GABA-mediated inhibition of VTA GABA neurons corresponding with increased ethanol-induced GABAergic transmission. This stress-induced inhibitory plasticity was reversible by applying the 5-HT2AR agonist TCB-2 ex vivo via functional enhancement of the potassium-chloride cotransporter KCC2. The signaling pathway linking 5-HT2AR activation and normalization of KCC2 function was dependent on protein kinase C signaling and phosphorylation of KCC2 at serine 940 (S940), as mutation of S940 to alanine prevented restoration of chloride transport function by TCB-2. Through positive modulation of KCC2, TCB-2 also reduced elevated ethanol-induced GABAergic signaling after stress exposure that has previously been linked to increased ethanol consumption. Collectively, these findings provide mechanistic insights into the therapeutic action of 5-HT2AR agonists at the neuronal and circuit levels of brain reward circuitry.
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Good, Cameron H., and Carl R. Lupica. "Properties of distinct ventral tegmental area synapses activated via pedunculopontine or ventral tegmental area stimulationin vitro." Journal of Physiology 587, no. 6 (March 13, 2009): 1233–47. http://dx.doi.org/10.1113/jphysiol.2008.164194.
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Koyama, Susumu, Yoshio Kanemitsu, and Forrest F. Weight. "Spontaneous Activity and Properties of Two Types of Principal Neurons From the Ventral Tegmental Area of Rat." Journal of Neurophysiology 93, no. 6 (June 2005): 3282–93. http://dx.doi.org/10.1152/jn.00776.2004.
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We investigated the spontaneous activity and properties of freshly isolated ventral tegmental area (VTA) principal neurons by whole cell recording and single-cell RT-PCR. The VTA principal neurons, which were tyrosine hydroxylase-positive and glutamic acid decarboxylase (GAD67)-negative, exhibited low firing frequency and a long action potential (AP) duration. The VTA principal neurons exhibited a calretinin-positive and parvalbumin-negative Ca2+-binding protein mRNA expression pattern. The VTA principal neurons were classified into two subpopulations based on their firing frequency coefficient of variation (CV) at room temperature (21–23°C): irregular-type neurons with a large CV and tonic-type neurons with a small CV. These two firing patterns were also recorded at the temperature of 34°C and in nystatin-perforated patch recording. In VTA principal neurons, the AP afterhyperpolarization (AHP) amplitude contributed to the firing regularity and AHP decay slope contributed to the firing frequency. The AHP amplitude in the irregular-type VTA principal neurons was smaller than that in the tonic-type VTA principal neurons. There was no significant difference in the AHP decay slope between the two-types of VTA principal neurons. Apamin-sensitive small-conductance Ca2+-activated K+ (SK) channels contributed to the AHP and the regular firing of the tonic-type neurons but contributed little to the AHP and firing of the irregular-type neurons. In voltage-clamp tail-current analysis, in both conventional and nystatin-perforated whole cell recording, the apamin-sensitive AHP current density of the tonic-type neurons was significantly larger than that of the irregular-type neurons. We suggest that apamin-sensitive SK current contributes to intrinsic firing differences between the two subpopulations of VTA principal neurons.
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Koyama, Susumu, Mark S. Brodie, and Sarah B. Appel. "Ethanol Inhibition of M-Current and Ethanol-Induced Direct Excitation of Ventral Tegmental Area Dopamine Neurons." Journal of Neurophysiology 97, no. 3 (March 2007): 1977–85. http://dx.doi.org/10.1152/jn.00270.2006.
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Ethanol-induced excitation of ventral tegmental area dopamine (DA VTA) neurons is thought to be critical for the reinforcing effects of ethanol. Although ligand-gated ion channels are known to be the targets of ethanol, ethanol modulation of voltage-dependent ion channels of central neurons has not been well studied. We have demonstrated that ethanol excites DA VTA neurons by the reduction of sustained K+ currents and recently reported that M-current ( IM) regulates action potential generation through fast and slow afterhyperpolarization phases. In the present study we thus examined whether ethanol inhibition of IM contributes to the excitation of DA VTA neurons using nystatin-perforated patch current- and voltage-clamp recordings. Ethanol (20–120 mM) reduced IM in a concentration-dependent manner and increased the spontaneous firing frequency of DA VTA neurons. Ethanol-induced increase in spontaneous firing frequency correlated positively with ethanol inhibition of IM with a slope value of 1.3. Specific IM inhibition by XE991 (0.3–10 μM) increased spontaneous firing frequency which correlated positively with IM inhibition with a slope value of 0.5. In the presence of 10 μM XE991, a concentration that produced maximal inhibition of IM, ethanol still increased the spontaneous firing frequency of DA VTA neurons in a concentration-dependent manner. Thus we conclude that, although ethanol causes inhibition of IM and this results in some increase in the firing frequency of DA VTA neurons, another effect of ethanol is primarily responsible for the ethanol-induced increase in firing rate in these neurons.
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Murris, Sjoerd R., John T. Arsenault, and Wim Vanduffel. "Frequency- and State-Dependent Network Effects of Electrical Stimulation Targeting the Ventral Tegmental Area in Macaques." Cerebral Cortex 30, no. 8 (April 9, 2020): 4281–96. http://dx.doi.org/10.1093/cercor/bhaa007.
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Abstract The ventral tegmental area (VTA) is a midbrain structure at the heart of the dopaminergic system underlying adaptive behavior. Endogenous firing rates of dopamine cells in the VTA vary from fast phasic bursts to slow tonic activity. Artificial perturbations of the VTA, through electrical or optogenetic stimulation methods, generate different and sometimes even contrasting behavioral outcomes depending on stimulation parameters such as frequency, amplitude, and pulse width. Here, we investigate the global functional effects of electrical stimulation frequency (10, 20, 50, and 100 Hz) of the VTA in rhesus monkeys. We stimulated 2 animals with chronic electrodes, either awake or anesthetized, while concurrently acquiring whole-brain functional magnetic resonance imaging (fMRI) signals. In the awake state, activity as a function of stimulation frequency followed an inverted U-shape in many cortical and subcortical structures, with highest activity observed at 20 and 50 Hz and lower activity at 10 and 100 Hz. Under anesthesia, the hemodynamic responses in connected brain areas were slightly positive at 10 Hz stimulation, but decreased linearly as a function of higher stimulation frequencies. A speculative explanation for the remarkable frequency dependence of stimulation-induced fMRI activity is that the VTA makes use of different frequency channels to communicate with different postsynaptic sites.
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Yan, Rongzhen, Tianyu Wang, and Qiang Zhou. "Elevated dopamine signaling from ventral tegmental area to prefrontal cortical parvalbumin neurons drives conditioned inhibition." Proceedings of the National Academy of Sciences 116, no. 26 (June 10, 2019): 13077–86. http://dx.doi.org/10.1073/pnas.1901902116.
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Conditioned inhibition is an important process to suppress learned responses for optimal adaptation, but its underlying biological mechanism is poorly understood. Here we used safety learning (SL)/fear discrimination after fear conditioning as a conditioned inhibition model because it demonstrates the essential properties of summation and retardation. Activity of the dorsomedial prefrontal cortex (dmPFC) parvalbumin (PV) neurons bidirectionally regulates spiking levels of dmPFC excitatory neurons and fear states. Responses to safety cues are increased in dopaminergic (DA) neurons in the ventral tegmental area (VTA) and in PV neurons in dmPFC after SL. Plasticity in the VTA is implicated, since SL requires activation ofN-methyl-d-aspartate receptors. Furthermore, in a posttraumatic stress disorder model, impaired SL is associated with impaired potentiation of VTA DA neuron activity. Our results demonstrate a DA-dependent learning process that targets prefrontal inhibitory neurons for suppression of learned responses, and have implications for the pathogenesis and treatment of various psychiatric diseases.
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Heshmati, Mitra. "Cocaine-Induced LTP in the Ventral Tegmental Area: New Insights Into Mechanism and Time Course Illuminate the Cellular Substrates of Addiction." Journal of Neurophysiology 101, no. 6 (June 2009): 2735–37. http://dx.doi.org/10.1152/jn.00127.2009.
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Previous work has shown that a single dose of cocaine can produce long-term potentiation (LTP) of the glutamatergic synapses received by dopamine neurons in the ventral tegmental area (VTA). This and other plastic changes in the brain's reward circuitry have been suggested to underlie addiction. A recent study has provided new insights into cocaine-induced LTP, showing that it begins 3–5 h after exposure, requires activation of a dopamine D5/NMDA receptor cascade, and can be evoked by cocaine application directly to the VTA.
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MARCO, N., M. CADOR, L. STINUS, MOAL M. LE, and G. SIMONNET. "INTERACTIONS BETWEEN GLUTAMATE, GABA AND NEUROPEPTIDE FF IN THE VENTRAL TEGMENTAL AREA (VTA)." Behavioural Pharmacology 6, no. 5 (August 1995): 625. http://dx.doi.org/10.1097/00008877-199508000-00056.
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Mervosh, Nicholas L., Rashaun Wilson, Navin Rauniyar, Rebecca S. Hofford, Munir Gunes Kutlu, Erin S. Calipari, TuKiet T. Lam, and Drew D. Kiraly. "Granulocyte-Colony-Stimulating Factor Alters the Proteomic Landscape of the Ventral Tegmental Area." Proteomes 6, no. 4 (September 23, 2018): 35. http://dx.doi.org/10.3390/proteomes6040035.
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Cocaine addiction is characterized by aberrant plasticity of the mesolimbic dopamine circuit, leading to dysregulation of motivation to seek and take drug. Despite the significant toll that cocaine use disorder exacts on society, there are currently no available pharmacotherapies. We have recently identified granulocyte-colony stimulating factor (G-CSF) as a soluble cytokine that alters the behavioral response to cocaine and which increases dopamine release from the ventral tegmental area (VTA). Despite these known effects on behavior and neurophysiology, the molecular mechanisms by which G-CSF affects brain function are unclear. In this study mice were treated with repeated injections of G-CSF, cocaine or a combination and changes in protein expression in the VTA were examined using an unbiased proteomics approach. Repeated G-CSF treatment resulted in alterations in multiple signaling pathways related to synaptic plasticity and neuronal morphology. While the treatment groups had marked overlap in their effect, injections of cocaine and the combination of cocaine and G-CSF lead to distinct patterns of significantly regulated proteins. These experiments provide valuable information as to the molecular pathways that G-CSF activates in an important limbic brain region and will help to guide further characterization of G-CSF function and evaluation as a possible translational target.
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Karim, Tahseen J., Cruz Reyes-Vazquez, and Nachum Dafny. "Comparison of the VTA and LC response to methylphenidate: a concomitant behavioral and neuronal study of adolescent male rats." Journal of Neurophysiology 118, no. 3 (September 1, 2017): 1501–14. http://dx.doi.org/10.1152/jn.00145.2017.
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Methylphenidate (MPD), also known as Ritalin, is a psychostimulant used to treat attention deficit hyperactivity disorder. However, it is increasingly being misused by normal adolescents for recreation and academic advantage. Therefore, it is important to elucidate the behavioral and neurophysiological effects of MPD in normal subjects. MPD inhibits the reuptake of catecholamines, mainly found in the ventral tegmental area (VTA) and locus coeruleus (LC). The VTA and LC normally mediate attention, motivation, and drug reward behaviors. Selective neuronal connections between the VTA and LC have been identified implicating regular interaction between the structures. The objective of this study was to compare the neuronal responses of the VTA and LC to MPD in normal adolescent rats. Animals were implanted with permanent electrodes in the VTA and LC, and neuronal units were recorded following acute and repetitive (chronic) saline or 0.6, 2.5, or 10.0 mg/kg MPD exposure. Animals displayed either behavioral sensitization or tolerance to all three doses of MPD. Acute MPD exposure elicited excitation in the majority of all VTA and LC units. Chronic MPD exposure elicited a further increase in VTA and LC neuronal activity in animals exhibiting behavioral sensitization and an attenuation in VTA and LC neuronal activity in animals exhibiting behavioral tolerance, demonstrating neurophysiological sensitization and tolerance, respectively. The similar pattern in VTA and LC unit activity suggests that the two structures are linked in their response to MPD. These results may help determine the exact mechanism of action of MPD, resulting in optimized treatment of patients. NEW & NOTEWORTHY The same dose of 0.6, 2.5, and 10 mg/kg methylphenidate (MPD) elicits either behavioral sensitization or tolerance in adolescent rats. There is a direct correlation between the ventral tegmental area (VTA) and locus coeruleus (LC) neuronal response to chronic MPD exposure. Both the VTA and LC are involved in the behavioral and neurophysiological effects of chronic MPD.
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Stuhrman, Katherine, and Aaron G. Roseberry. "Neurotensin inhibits both dopamine- and GABA-mediated inhibition of ventral tegmental area dopamine neurons." Journal of Neurophysiology 114, no. 3 (September 2015): 1734–45. http://dx.doi.org/10.1152/jn.00279.2015.
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Dopamine is an essential neurotransmitter that plays an important role in a number of different physiological processes and disorders. There is substantial evidence that the neuropeptide neurotensin interacts with the mesolimbic dopamine system and can regulate dopamine neuron activity. In these studies we have used whole cell patch-clamp electrophysiology in brain slices from mice to examine how neurotensin regulates dopamine neuron activity by examining the effect of neurotensin on the inhibitory postsynaptic current generated by somatodendritic dopamine release (D2R IPSC) in ventral tegmental area (VTA) dopamine neurons. Neurotensin inhibited the D2R IPSC and activated an inward current in VTA dopamine neurons that appeared to be at least partially mediated by activation of a transient receptor potential C-type channel. Neither the inward current nor the inhibition of the D2R IPSC was affected by blocking PKC or calcium release from intracellular stores, and the inhibition of the D2R IPSC was greater with neurotensin compared with activation of other Gq-coupled receptors. Interestingly, the effects of neurotensin were not specific to D2R signaling as neurotensin also inhibited GABAB inhibitory postsynaptic currents in VTA dopamine neurons. Finally, the effects of neurotensin were significantly larger when intracellular Ca2+ was strongly buffered, suggesting that reduced intracellular calcium facilitates these effects. Overall these results suggest that neurotensin may inhibit the D2R and GABAB IPSCs downstream of receptor activation, potentially through regulation of G protein-coupled inwardly rectifying potassium channels. These studies provide an important advance in our understanding of dopamine neuron activity and how it is controlled by neurotensin.
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Ye, Jiang Hong, Liang Tao, Li Zhu, Kres̆imir Krnjević, and Joseph J. McArdle. "Ethanol Inhibition of Glycine-Activated Responses in Neurons of Ventral Tegmental Area of Neonatal Rats." Journal of Neurophysiology 86, no. 5 (November 1, 2001): 2426–34. http://dx.doi.org/10.1152/jn.2001.86.5.2426.
Full textAbstract:
The brain is particularly sensitive to alcohol during the period of its rapid growth. To better understand the mechanism(s) involved, we studied ethanol effects on glycine-activated responses of ventral tegmental area (VTA) neurons isolated from the newborn rat, using whole cell and gramicidin perforated patch-clamp techniques. Previously we reported that 0.1–40 mM ethanol enhances glycine-induced responses of 35% of VTA neurons ( Ye et al. 2001 ). We now direct our attention to the inhibitory effects of ethanol observed in 45% (312 of 694) of neonatal VTA neurons. Under current-clamp conditions, 1 mM ethanol had no effect on the membrane potential of these cells, but it decreased glycine-induced membrane depolarization and the frequency of spontaneous action potentials. Under voltage-clamp conditions, 0.1–10 mM ethanol did not elicit a current but depressed the glycine-induced currents. The ethanol-induced inhibition of glycine current was independent of membrane potential (between −60 and +60 mV). Likewise, ethanol did not alter the reversal potential of the glycine-activated currents. Ethanol-mediated inhibition of glycine current depended on the glycine concentration. While ethanol strongly depressed currents activated by 30 μM glycine, it had no appreciable effect on maximal currents activated by 1 mM glycine. In the presence of ethanol (1 mM), the EC50 for glycine increased from 32 ± 5 to 60 ± 3 μM. Thus ethanol may decrease the agonist affinity of glycine receptors. A kinetic analysis indicated that ethanol shortens the time constant of glycine current deactivation but has no effect on activation. In conclusion, by altering VTA neuronal function, ethanol-induced changes in glycine receptors may contribute to neurobehavioral manifestations of the fetal alcohol syndrome.
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Nakamoto, Tomoko, Kanji Matsukawa, Nan Liang, Rie Wakasugi, L. Britt Wilson, and Jouji Horiuchi. "Coactivation of renal sympathetic neurons and somatic motor neurons by chemical stimulation of the midbrain ventral tegmental area." Journal of Applied Physiology 110, no. 5 (May 2011): 1342–53. http://dx.doi.org/10.1152/japplphysiol.01233.2010.
Full textAbstract:
We examined whether neurons in the midbrain ventral tegmental area (VTA) play a role in generating central command responsible for autonomic control of the cardiovascular system in anesthetized rats and unanesthetized, decerebrated rats with muscle paralysis. Small volumes (60 nl) of an N-methyl-d-aspartate receptor agonist (l-homocysteic acid) and a GABAergic receptor antagonist (bicuculline) were injected into the VTA and substantia nigra (SN). In anesthetized rats, l-homocysteic acid into the VTA induced short-lasting increases in renal sympathetic nerve activity (RSNA; 66 ± 21%), mean arterial pressure (MAP; 5 ± 2 mmHg), and heart rate (HR; 7 ± 2 beats/min), whereas bicuculline into the VTA produced long-lasting increases in RSNA (130 ± 45%), MAP (26 ± 2 mmHg), and HR (66 ± 6 beats/min). Bicuculline into the VTA increased blood flow and vascular conductance of the hindlimb triceps surae muscle, suggesting skeletal muscle vasodilatation. However, neither drug injected into the SN affected all variables. Renal sympathetic nerve and cardiovascular responses to chemical stimulation of the VTA were not essentially affected by decerebration at the premammillary-precollicular level, indicating that the ascending projection to the forebrain from the VTA was not responsible for evoking the sympathetic and cardiovascular responses. Furthermore, bicuculline into the VTA in decerebrate rats produced long-lasting rhythmic bursts of RSNA and tibial motor nerve discharge, which occurred in good synchrony. It is likely that the activation of neurons in the VTA is capable of eliciting synchronized stimulation of the renal sympathetic and tibial motor nerves without any muscular feedback signal.
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Hritcu, Lucian, and Toshitaka Nabeshima. "Kainic acid lesion-induced spatial memory deficits of rats." Open Life Sciences 4, no. 2 (June 1, 2009): 179–85. http://dx.doi.org/10.2478/s11535-009-0001-9.
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AbstractThe effects of lesioning the ventral tegmental area (VTA) or substantia nigra (SN) neurons by means of bilateral stereotaxic microinjections of kainic acid (KA) (0.4 mM) were investigated to clarify the role of the VTA and the SN neurons in learning and memory processes. The present study demonstrates that KA in the SN and the VTA lesioned rats significantly decreased spontaneous alternation in Y-maze task, working memory and reference memory in radial 8 arm-maze task, suggesting effects on spatial memory performance. Our findings provide further support for the role of the VTA and the SN neurons in processing and storage of information.
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Patterson, Christa M., Jenny-Marie T. Wong, Gina M. Leinninger, Margaret B. Allison, Omar S. Mabrouk, Chelsea L. Kasper, Ian E. Gonzalez, et al. "Ventral Tegmental Area Neurotensin Signaling Links the Lateral Hypothalamus to Locomotor Activity and Striatal Dopamine Efflux in Male Mice." Endocrinology 156, no. 5 (March 3, 2015): 1692–700. http://dx.doi.org/10.1210/en.2014-1986.
Full textAbstract:
Projections from the lateral hypothalamic area (LHA) innervate components of the mesolimbic dopamine (MLDA) system, including the ventral tegmental area (VTA) and nucleus accumbens (NAc), to modulate motivation appropriately for physiologic state. Neurotensin (NT)-containing LHA neurons respond to multiple homeostatic challenges and project to the VTA, suggesting that these neurons could link such signals to MLDA function. Indeed, we found that pharmacogenetic activation of LHA NT neurons promoted prolonged DA-dependent locomotor activity and NAc DA efflux, suggesting the importance of VTA neurotransmitter release by LHA NT neurons for the control of MLDA function. Using a microdialysis-mass spectrometry technique that we developed to detect endogenous NT in extracellular fluid in the mouse brain, we found that activation of LHA NT cells acutely increased the extracellular concentration of NT (a known activator of VTA DA cells) in the VTA. In contrast to the prolonged elevation of extracellular NAc DA, however, VTA NT concentrations rapidly returned to baseline. Intra-VTA infusion of NT receptor antagonist abrogated the ability of LHA NT cells to increase extracellular DA in the NAc, demonstrating that VTA NT promotes NAc DA release. Thus, transient LHA-derived NT release in the VTA couples LHA signaling to prolonged changes in DA efflux and MLDA function.
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McDaid, John, Maureen A. McElvain, and Mark S. Brodie. "Ethanol Effects on Dopaminergic Ventral Tegmental Area Neurons During Block of Ih: Involvement of Barium-Sensitive Potassium Currents." Journal of Neurophysiology 100, no. 3 (September 2008): 1202–10. http://dx.doi.org/10.1152/jn.00994.2007.
Full textAbstract:
The dopaminergic neurons of the ventral tegmental area (DA VTA neurons) are important for the rewarding and reinforcing properties of drugs of abuse, including ethanol. Ethanol increases the firing frequency of DA VTA neurons from rats and mice. Because of a recent report on block of ethanol excitation in mouse DA VTA neurons with ZD7288, a selective blocker of the hyperpolarization-activated cationic current Ih, we examined the effect of ZD7288 on ethanol excitation in DA VTA neurons from C57Bl/6J and DBA/2J mice and Fisher 344 rats. Ethanol (80 mM) caused only increases in firing rate in mouse DA VTA neurons in the absence of ZD7288, but in the presence of ZD7288 (30 μM), ethanol produced a more transient excitation followed by a decrease of firing. This same biphasic phenomenon was observed in DA VTA neurons from rats in the presence of ZD7288 only at very high ethanol concentrations (160–240 mM) but not at lower pharmacologically relevant concentrations. The longer latency ethanol-induced inhibition was not observed in DA VTA neurons from mice or rats in the presence of barium (100 μM), which blocks G protein–linked potassium channels (GIRKs) and other inwardly rectifying potassium channels. Ethanol may have a direct effect to increase an inhibitory potassium conductance, but this effect of ethanol can only decrease the firing rate if Ih is blocked.
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Brizuela, Mariana, Steven J. Swoap, James Ang, William W. Blessing, and Youichirou Ootsuka. "Neurons in ventral tegmental area tonically inhibit sympathetic outflow to brown adipose tissue: possible mediation of thermogenic signals from lateral habenula." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 316, no. 1 (January 1, 2019): R6—R12. http://dx.doi.org/10.1152/ajpregu.00256.2018.
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The lateral habenula (LHb), a nucleus involved in the response to salient, especially adverse, environmental events, is implicated in brown adipose tissue (BAT) thermogenesis caused by these events. LHb-elicited thermogenesis involves a neural pathway to the lower brain stem sympathetic control center in the medullary raphé. There are no direct connections from the LHb to the medullary raphé. LHb-mediated behavioral responses involve inhibitory control over the dopamine neurons in the ventral tegmental area (VTA), mediated via an excitatory drive from the LHb to GABAergic neurons in the tail of the VTA. We hypothesized that inhibition of the VTA is also involved in LHb-mediated BAT thermogenesis. To test this hypothesis, inhibition of neurons in the VTA with muscimol increased BAT sympathetic nerve discharge by 22.0 ± 9.2 dBμV ( n = 24, P < 0.0001) and BAT temperature by 1.2 ± 0.1°C ( P < 0.001). This response was abolished by inhibition of the medullary raphé neurons with muscimol. BAT thermogenesis initiated with focal injections of bicuculline in the LHb was reversed by subsequent blockade of GABAA receptors in the VTA with bicuculline. These results suggest that, at least in anesthetized rats, neurons in the VTA tonically inhibit BAT thermogenesis via a link, presently unknown, to the medullary raphé. Removal of this VTA-initiated inhibition is an important mechanism whereby LHb neurons activate BAT thermogenesis.
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Zubair, Muhammad, Sjoerd R. Murris, Kaoru Isa, Hirotaka Onoe, Yoshinori Koshimizu, Kenta Kobayashi, Wim Vanduffel, and Tadashi Isa. "Divergent Whole Brain Projections from the Ventral Midbrain in Macaques." Cerebral Cortex 31, no. 6 (February 9, 2021): 2913–31. http://dx.doi.org/10.1093/cercor/bhaa399.
Full textAbstract:
ABSTRACT To understand the connectome of the axonal arborizations of dopaminergic midbrain neurons, we investigated the anterograde spread of highly sensitive viral tracers injected into the ventral tegmental area (VTA) and adjacent areas in 3 macaques. In 2 monkeys, injections were centered on the lateral VTA with some spread into the substantia nigra, while in one animal the injection targeted the medial VTA with partial spread into the ventro-medial thalamus. Double-labeling with antibodies against transduced fluorescent proteins (FPs) and tyrosine hydroxylase indicated that substantial portions of transduced midbrain neurons were dopaminergic. Interestingly, cortical terminals were found either homogeneously in molecular layer I, or more heterogeneously, sometimes forming patches, in the deeper laminae II–VI. In the animals with injections in lateral VTA, terminals were most dense in somatomotor cortex and the striatum. In contrast, when the medial VTA was transduced, dense terminals were found in dorsal prefrontal and temporal cortices, while projections to striatum were sparse. In all monkeys, orbitofrontal and occipito-parietal cortex received strong and weak innervation, respectively. Thus, the dopaminergic ventral midbrain sends heterogeneous projections throughout the brain. Furthermore, our results suggest the existence of subgroups in meso-dopaminergic neurons depending on their location in the primate ventral midbrain.
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Butts, Kelly A., and Anthony G. Phillips. "Glucocorticoid receptors in the prefrontal cortex regulate dopamine efflux to stress via descending glutamatergic feedback to the ventral tegmental area." International Journal of Neuropsychopharmacology 16, no. 8 (September 1, 2013): 1799–807. http://dx.doi.org/10.1017/s1461145713000187.
Full textAbstract:
Abstract Enhanced dopamine (DA) efflux in the medial prefrontal cortex (mPFC) is a well-documented response to acute stress. We have previously shown that glucocorticoid receptors in the mPFC regulate stress-evoked DA efflux but the underlying mechanism is unknown. DA neurons in the ventral tegmental area (VTA) receive excitatory input from and send reciprocal projections to the mPFC. We hypothesize that blockade of prefrontal glucocorticoid receptors can reduce activity of descending glutamatergic input to the VTA, thereby attenuating stress-evoked DA efflux in the mPFC. Using in vivo microdialysis, we demonstrate that acute tail-pinch stress leads to a significant increase in glutamate efflux in the VTA. Blockade of prefrontal glucocorticoid receptors with the selective antagonist CORT 108297 attenuates stress-evoked glutamate efflux in the VTA together with DA efflux in the mPFC. Furthermore, blockade of ionotrophic glutamate receptors in the VTA attenuates stress-evoked DA efflux in the mPFC. We also examine the possible role of glucocorticoid-induced synthesis and release of endocannabinoids acting presynaptically via cannabinoid CB1 receptors to inhibit GABA release onto prefrontal pyramidal cells, thus enhancing descending glutamatergic input to the VTA leading to an increase in mPFC DA efflux during stress. However, administration of the cannabinoid CB1 receptor antagonist into the mPFC does not attenuate stress-evoked DA efflux in the mPFC. Taken together, our data indicate that glucocorticoids act locally within the mPFC to modulate mesocortical DA efflux by potentiation of glutamatergic drive onto DA neurons in the VTA.
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West, Katherine Stuhrman, and Aaron G. Roseberry. "Neuropeptide-Y alters VTA dopamine neuron activity through both pre- and postsynaptic mechanisms." Journal of Neurophysiology 118, no. 1 (July 1, 2017): 625–33. http://dx.doi.org/10.1152/jn.00879.2016.
Full textAbstract:
The mesocorticolimbic dopamine system, the brain’s reward system, regulates many different behaviors including food intake, food reward, and feeding-related behaviors, and there is increasing evidence that hypothalamic feeding-related neuropeptides alter dopamine neuron activity to affect feeding. For example, neuropeptide-Y (NPY), a strong orexigenic hypothalamic neuropeptide, increases motivation for food when injected into the ventral tegmental area (VTA). How NPY affects the activity of VTA dopamine neurons to regulate feeding behavior is unknown, however. In these studies we have used whole cell patch-clamp electrophysiology in acute brain slices from mice to examine how NPY affects VTA dopamine neuron activity. NPY activated an outward current that exhibited characteristics of a G protein-coupled inwardly rectifying potassium channel current in ~60% of dopamine neurons tested. In addition to its direct effects on VTA dopamine neurons, NPY also decreased the amplitude and increased paired-pulse ratios of evoked excitatory postsynaptic currents in a subset of dopamine neurons, suggesting that NPY decreases glutamatergic transmission through a presynaptic mechanism. Interestingly, NPY also strongly inhibited evoked inhibitory postsynaptic currents onto dopamine neurons by a presynaptic mechanism. Overall these studies demonstrate that NPY utilizes multiple mechanisms to affect VTA dopamine neuron activity, and they provide an important advancement in our understanding of how NPY acts in the VTA to control feeding behavior. NEW & NOTEWORTHY Neuropeptide-Y (NPY) has been shown to act on mesolimbic dopamine circuits to increase motivated behaviors toward food, but it is unclear exactly how NPY causes these responses. Here, we demonstrate that NPY directly inhibited a subset of ventral tegmental area (VTA) dopamine neurons through the activation of G protein-coupled inwardly rectifying potassium currents, and it inhibited both excitatory postsynaptic currents and inhibitory postsynaptic currents onto subsets of dopamine neurons through a presynaptic mechanism. Thus NPY uses multiple mechanisms to dynamically control VTA dopamine neuron activity.