Academic literature on the topic 'Dopaminergic reward pathway'

AbstractDopamine regulates reward-related behavior through the mesolimbic dopaminergic pathway. Stress affects dopamine levels and dopaminergic neuronal activity in the mesolimbic dopamine system. Changes in mesolimbic dopaminergic neurotransmission are important for coping with stress, as they allow adaption to behavioral responses to various environmental stimuli. Upon stress exposure, modulation of the dopaminergic reward system is necessary for monitoring and selecting the optimal process for coping with stressful situations. Aversive stressful events may negatively regulate the dopaminergic reward system, perturbing reward sensitivity, which is closely associated with chronic stress-induced depression. The mesolimbic dopamine system is excited not only by reward but also by aversive stressful stimuli, which adds further intriguing complexity to the relationship between stress and the reward system. This review focuses on lines of evidence related to how stress, especially chronic stress, affects the mesolimbic dopamine system, and discusses the role of the dopaminergic reward system in chronic stress-induced depression.

Pain involves both sensory and affective dimensions. The amygdala is a key player in linking nociceptive stimuli to negative emotional behaviors or affective states. Relief of pain is rewarding and activates brain reward circuits. Whether the reward circuit from the ventral tegmental area (VTA) to the central amygdala (CeA) is involved in pain relief remains unexplored. Using a model of experimental postsurgical pain, we found that pain relief elicited conditioned place preference (CPP), activated CeA-projecting dopaminergic cells in the VTA, and decreased dopaminergic D2 receptor expression in the CeA. Activation of the VTA–CeA neural pathway using optogenetic approaches relieved incisional pain. Administration of a D2 receptor agonist reversed the pain relief elicited by light-induced activation of the VTA-CeA pathway. These findings indicate that the VTA-CeA circuit is involved in pain relief in mice via dopamine receptor D2 in the CeA.

Abstract Probabilistic reward learning reflects the ability to adapt choices based on probabilistic feedback. The dopaminergically innervated corticostriatal circuit in the brain plays an important role in supporting successful probabilistic reward learning. Several components of the corticostriatal circuit deteriorate with age, as it does probabilistic reward learning. We showed previously that D1 receptor availability in NAcc predicts the strength of anticipatory value signaling in vmPFC, a neural correlate of probabilistic learning that is attenuated in older participants and predicts probabilistic reward learning performance. We investigated how white matter integrity in the pathway between nucleus accumbens (NAcc) and ventromedial prefrontal cortex (vmPFC) relates to the strength of anticipatory value signaling in vmPFC in younger and older participants. We found that in a sample of 22 old and 23 young participants, fractional anisotropy in the pathway between NAcc and vmPFC predicted the strength of value signaling in vmPFC independently from D1 receptor availability in NAcc. These findings provide tentative evidence that integrity in the dopaminergic and white matter pathways of corticostriatal circuitry supports the expression of value signaling in vmPFC which supports reward learning, however, the limited sample size calls for independent replication. These and future findings could add to the improved understanding of how corticostriatal integrity contributes to reward learning ability.

Midbrain dopamine neurons are an essential component of the basal ganglia circuitry, playing key roles in the control of fine movement and reward. Recently, it has been demonstrated that γ-aminobutyric acid (GABA), the chief inhibitory neurotransmitter, is co-released by dopamine neurons. Here, we show that GABA co-release in dopamine neurons does not use the conventional GABA-synthesizing enzymes, glutamate decarboxylases GAD65 and GAD67. Our experiments reveal an evolutionarily conserved GABA synthesis pathway mediated by aldehyde dehydrogenase 1a1 (ALDH1a1). Moreover, GABA co-release is modulated by ethanol (EtOH) at concentrations seen in blood alcohol after binge drinking, and diminished ALDH1a1 leads to enhanced alcohol consumption and preference. These findings provide insights into the functional role of GABA co-release in midbrain dopamine neurons, which may be essential for reward-based behavior and addiction.

As the incidence of obesity continues to rise, clinicians and researchers alike are seeking explanations for why some people become obese while others do not. While caloric intake and physical activity most certainly play a role, some individuals continue to gain weight despite careful attention to these factors. Increasing evidence suggests that genetics may play a role, with one potential explanation being genetic variability in genes within the neurotransmitter dopamine pathway. This variability can lead to a disordered experience with the rewarding properties of food. This review of literature examines the extant knowledge about the relationship between obesity and the dopaminergic reward pathways in the brain, with particularly strong evidence provided from neuroimaging and neurogenetic data. Pubmed, Google Scholar, and Cumulative Index to Nursing and Allied Health Literature searches were conducted with the search terms dopamine, obesity, weight gain, food addiction, brain regions relevant to the mesocortical and mesolimbic (reward) pathways, and relevant dopaminergic genes and receptors. These terms returned over 200 articles. Other than a few sentinel articles, articles were published between 1993 and 2013. These data suggest a conceptual model for obesity that emphasizes dopaminergic genetic contributions as well as more traditional risk factors for obesity, such as demographics (age, race, and gender), physical activity, diet, and medications. A greater understanding of variables contributing to weight gain and obesity is imperative for effective clinical treatment.

The neural mechanisms conferring reduced motivation, as observed in depressed individuals, is poorly understood. Here, we examine in rodents if reduced motivation to exert effort is controlled by transmission from the lateral habenula (LHb), a nucleus overactive in depressed-like states, to the rostromedial tegmental nucleus (RMTg), a nucleus that inhibits dopaminergic neurons. In an aversive test wherein immobility indicates loss of effort, LHb→RMTg transmission increased during transitions into immobility, driving LHb→RMTg increased immobility, and inhibiting LHb→RMTg produced the opposite effects. In an appetitive test, driving LHb→RMTg reduced the effort exerted to receive a reward, without affecting the reward’s hedonic property. Notably, LHb→RMTg stimulation only affected specific aspects of these motor tasks, did not affect all motor tasks, and promoted avoidance, indicating that LHb→RMTg activity does not generally reduce movement but appears to carry a negative valence that reduces effort. These results indicate that LHb→RMTg activity controls the motivation to exert effort and may contribute to the reduced motivation in depression.

Major depressive disorder is a leading cause of disability and suicide worldwide. Consecutive rounds of conventional interventions are ineffective in a significant sub-group of patients whose disorder is classified as treatment-resistant depression. Significant progress in managing this severe form of depression has been achieved through the use of deep brain stimulation of the medial forebrain bundle (MFB). The beneficial effect of such stimulation appears strong, safe, and enduring. The proposed neural substrate for this promising clinical finding includes midbrain dopamine neurons and a subset of their cortical afferents. Here, we aim to broaden the discussion of the candidate circuitry by exploring potential implications of a new “convergence” model of brain reward circuitry in rodents. We chart the evolution of the new model from its predecessors, which held that midbrain dopamine neurons constituted an obligatory stage of the final common path for reward seeking. In contrast, the new model includes a directly activated, non-dopaminergic pathway whose output ultimately converges with that of the dopaminergic neurons. On the basis of the new model and the relative ineffectiveness of dopamine agonists in the treatment of depression, we ask whether non-dopaminergic circuitry may contribute to the clinical efficacy of deep brain stimulation of the MFB.

Projeto de Pós-Graduação/Dissertação apresentado à Universidade Fernando Pessoa como parte dos requisitos para obtenção do grau de Mestre em Ciências Farmacêuticas
Os neurotransmissores e neuromoduladores, são moléculas do sistema nervoso que desempenham um papel fundamental na comunicação intercelular. Quando estimulados os neurónios libertam estas moléculas que posteriormente vão atuar em recetores pré e/ou pós-sinápticos, desencadeando uma resposta biológica. A comunicação intercelular no sistema nervoso central exige um controlo rigoroso da duração e intensidade da ação de um neurotransmissor num determinado alvo. Os neurotransmissores podem ser excitatórios ou inibitórios dependendo do recetor que é ativado. As drogas de abuso, como o álcool, as metanfetaminas, a cocaína, a heroína, o LDS e a cannabis, influenciam a comunicação entre as células nervosas ao alterar a forma como os neurotransmissores transmitem sinais (informação) de neurónio para neurónio. As drogas possuem diversas ações psicotrópicas que vão desde a supressão de sensações negativas à potenciação de emoções positivas. Além disso, estão associadas a diferentes graus de toxidade, bem como a efeitos adversos graves, a nível mental e físico, e dependência. Grande parte da ação das drogas de abuso deve-se a alterações na transmissão sináptica. Neurotransmitters and neuromodulators are molecules that are part of the nervous system and play a fundamental role in the intercellular communication. When stimulated, the neurons release these molecules that will then act on pre or post-synaptic receptors, triggering a biological response. The intercellular communication in the central nervous system requires a rigorous control on the duration an intensity of a neurotransmitter action on a determined target. Neurotransmitters may be excitatory or inhibitory depending on the receptor that is activated. Drug abuse, such as alcohol, methamphetamines, cocaine, heroin, LSD and cannabis influence the communication between nervous cells by altering the way neurotransmitters transmit signals (information) between neurons. Drugs have different psychotropic actions, from the suppression of negative sensations to the potentiation of positive emotions. Besides, they are associated to different levels of toxicity as well as to severe adverse physical and mental effects and dependency. A major part of the abuse drugs action is due to alterations in the synaptic transmission.

博士
國立陽明大學
藥理學研究所
94
Abstract Background: Emerging evidence indicates that the prefrontal cortex (PFC) is involved in associative learning, as well as in conducting visuomotor conditional tasks and cue-response association. Dopamine (DA) is implicated to be involved in the formation of associations between salient contextual stimuli and reinforcing experience. Repeated exposures to psychostimulants, e.g., methamphetamine (MA), produce behavioral sensitization and neuroadaptations that are conceptualized to play an important role in the development of drug addiction. Some second-generation of antipsychotics are reported to have therapeutic benefits in the drug-related behavior of patients with psychosis. Objectives: Profiles of prefrontal DA outflow in conscious rats were assessed in three perspectives: (1) under contextual stimuli reminiscent with previous MA exposure, (2) under acute administration of antipsychotic medication, atypicals (aripiprazole, APZ, a partial D2 agonist) vs. typicals (haloperidol, HAL, a potent D2 antagonist), and (3) with a MA (a CNS psychostimulant) challenge in rats having received prior sensitizing regimen of MA. Methods: Experiment I. One group of rats received MA (1 mg/kg) or saline injection (each for 6 sessions) to pair with chambers of distinct contexts on alternative days to achieve drug-place conditioning. A second group of rats received in advance a sensitizing regimen with MA (1 mg/kg, every other day for 6 sessions) followed by drug withdrawal of 7 days period for behavioral sensitization, this group of rats then undertook the same drug-place conditioning protocol. And conditioned place preference (CPP) test was performed for these two groups of rats to mesure their conditioned drug reward response. DA outflows in the mPFC were analyzed on the next day following the CPP test via microdialysis study as animals exposed to the MA or saline-paired context chamber, respectively. Experiment II. Separate groups of rats received the same MA sensitizing protocol as in Exp. I. On the 7th-9th drug withdrawal day, acute administration of either APZ (0.3 mg/kg), HAL (0.1 mg/kg), or (Experiment III) MA challenge (1 mg/kg) was given and DA efflux in the mPFC was assessed via microdialysis and HPLC for determination of DA level, respectively. Aditional groups of saline pretreatment for control were allocated in both experiments II and III. Results: A conditioned increase of prefrontal DA efflux was observed in rats without sensitizing pretreatment, when occupying the MA-paired chamber. The rats with prior sensitizing regimens demonstrated a higher place preference response than those without MA pretreatment or saline control, however, they demonstrated attenuated conditioned dopamine efflux, while remaining in MA-paired context. In antipsychotic study, APZ slightly but significantly increased prefrontal DA output in the MA-pretreated rats, compared to the saline-pretreated group. There was no difference in the levels of DA between the MA and saline pretreated groups after receiving acute HAL. In addition, administration of APZ did not produce significant differences in the total prefrontal DA profile between MA and saline pretreated rats, though differences in the initial period post drug injection were observed. The MA-induced DA increase was higher in the rats that had prior MA sensitizing regimen, compared to those had saline pretreatment. Conclusions: The enhanced drug reward behavior and augmented prefrontal DA output upon exposure to context reminiscent of previous drug experience imply there being a disinhibited or arousal state of the mPFC in the subjects that completed drug-place conditioning protocol but without prior MA pretreatment. Further, the demonstration of even more significantly robust drug reward behavior and the attenuated responsiveness of mesocortical dopamine transmission in rats prior sensitized to MA may represent a reciprocal enhancement of activity in those brain areas which together are involved in strengthening of the learned response to drug-related contextual stimuli. And this model is suggested to mimic a dysregulated prefrontal function that may be responsible for compulsive drug seeking in methamphetamine abusers. The enhanced DA efflux as induced by APZ, but not by HAL, in the mPFC of the rats having had MA sensitization can compliment and address the probable neurochemical mechanism to the recent clinical reports on therapeutic potentials in the drug-related behavior of psychotic subjects with drug addiction.

Neuromarketing is a relatively new concept. It is simply focused on the relationship between consumer behavior and the brain. For this purpose, it analyzes various customer behaviors towards the product and purchase by using various brain imaging techniques and behavioral methodology. Some limbic structures of brain such as ventral tegmental area (VTA), nucleus acumbens (NAc), and amygdala have a link to prefrontal cortex (PFC) by dopaminergic mesocorticolimbic pathway. This functional link is called brain reward system (BRS). BRS has a crucial role in the decision-making process of humans during shopping as well as addiction processes of brain. Studies investigating BRS in neuromarketing are very limited. In the chapter, working principles of BRS in neuromarketing and association with human shopping behaviors and shopping addiction/dependence has been investigated and discussed.

The theory that dopaminergic mechanisms play a role in psychosis has evolved since the mid-twentieth century. This followed research which found that the clinical potency of antipsychotics was directly related to their affinity for dopamine receptors and drugs that cause dopamine release caused psychotic symptoms. Molecular imaging studies have found consistent evidence that elevated striatal dopamine synthesis capacity is associated with psychotic symptoms including in people with schizophrenia, people at risk of psychosis and first-degree relatives of people with schizophrenia. Importantly, dopamine elevation has been positively correlated with severity of psychotic symptoms. There is also evidence that dopamine dysfunction may be a transdiagnostic feature of psychosis. The dopamine system plays a key role in cognition, including reward prediction error signaling and salience processing. Dopaminergic dysfunction has been hypothesized to give rise to psychosis through aberrant salience processing. Since stressful experiences are highly salient for an organism’s survival, the dopamine system plays a key role in the brain’s response to stressors. Chronic stressors occurring during development can induce long-term changes in dopamine function and may thus provide a pathway through which environmental risk factors for psychosis alter neurobiology to give rise to psychosis. At least some genetic risk factors for psychosis also converge on the dopamine system. These findings have given rise to a “dual hit” model of dopaminergic dysfunction involving genetic vulnerability and responses to environmental stressors.

Alcohol is one of the most frequently used substances, and alcohol-related disorders are common, especially in western societies. While there is no safe lower drinking level, a clear dose–response relationship has been shown between alcohol intake and organ damage. Conceptualization and diagnostic classification of alcohol use disorders have changed over time, focusing most recently on aspects of craving, loss of control, and continued use despite negative consequences. Alcohol acts via various binding sites in the brain and via downstream effects, including glutamatergic, GABAergic, serotonergic, dopaminergic, opioid, and neuroendocrine pathways. For its long-lasting, habit-forming effects, sensitization within the mesolimbic–mesocortical system is crucial. Psychological treatments traditionally focus on motivational enhancement, cognitive behaviour therapy, and the community reinforcement approach. Pharmacological treatment approaches range from aversive and reward-inhibiting to anti-craving compounds and cognitive enhancers, which target opioid, glutamatergic, and monoamine receptors. Improvement of treatment effects can be achieved by polypharmacy and use of personalized medicine, based on clinical characteristics, biomarkers, and genetic indicators.