Mesolimbic Dopaminergic System Research Articles

Impact of Early Consumption of High-Fat Diet on the Mesolimbic Dopaminergic System.

Increasing evidence suggest that consumption of high-fat diet (HFD) can impact the maturation of brain circuits, such as during adolescence, which could account for behavioral alterations associated with obesity. In the present study, we used behavioral sensitization to amphetamine to investigate the effect of periadolescent HFD exposure (pHFD) in rats on the functionality of the dopamine (DA) system, a central actor in food reward processing. pHFD does not affect responding to an acute injection, however, a single exposure to amphetamine is sufficient to induce locomotor sensitization in pHFD rats. This is paralleled by rapid neurobiological adaptations within the DA system. In pHFD-exposed animals, a single amphetamine exposure induces an increase in bursting activity of DA cells in the ventral tegmental area (VTA) as well as higher DA release and greater expression of (tyrosine hydroxylase, TH) in the nucleus accumbens (NAc). Post-synaptically, pHFD animals display an increase in NAc D2 receptors and c-Fos expression after amphetamine injection. These findings highlight the vulnerability of DA system to the consumption of HFD during adolescence that may support deficits in reward-related processes observed in obesity.

Behavioral and Neural Manifestations of Reward Memory in Carriers of Low-Expressing versus High-Expressing Genetic Variants of the Dopamine D2 Receptor.

Dopamine is critically important in the neural manifestation of motivated behavior, and alterations in the human dopaminergic system have been implicated in the etiology of motivation-related psychiatric disorders, most prominently addiction. Patients with chronic addiction exhibit reduced dopamine D2 receptor (DRD2) availability in the striatum, and the DRD2 TaqIA (rs1800497) and C957T (rs6277) genetic polymorphisms have previously been linked to individual differences in striatal dopamine metabolism and clinical risk for alcohol and nicotine dependence. Here, we investigated the hypothesis that the variants of these polymorphisms would show increased reward-related memory formation, which has previously been shown to jointly engage the mesolimbic dopaminergic system and the hippocampus, as a potential intermediate phenotype for addiction memory. To this end, we performed functional magnetic resonance imaging (fMRI) in 62 young, healthy individuals genotyped for DRD2 TaqIA and C957T variants. Participants performed an incentive delay task, followed by a recognition memory task 24 h later. We observed effects of both genotypes on the overall recognition performance with carriers of low-expressing variants, namely TaqIA A1 carriers and C957T C homozygotes, showing better performance than the other genotype groups. In addition to the better memory performance, C957T C homozygotes also exhibited a response bias for cues predicting monetary reward. At the neural level, the C957T polymorphism was associated with a genotype-related modulation of right hippocampal and striatal fMRI responses predictive of subsequent recognition confidence for reward-predicting items. Our results indicate that genetic variations associated with DRD2 expression affect explicit memory, specifically for rewarded stimuli. We suggest that the relatively better memory for rewarded stimuli in carriers of low-expressing DRD2 variants may reflect an intermediate phenotype of addiction memory.

Suppression of reward-induced dopamine release in the nucleus accumbens in animal models of depression: Differential responses to drug treatment

Anhedonia, the loss of interest or pleasure in previously enjoyable activities, is a core symptom of major depressive disorder, suggesting that the brain reward system may be dysfunctional in this condition. Neurochemical changes in the mesolimbic dopamine (DA) system are not fully understood in animal models of depression. We investigated reward (30% sucrose intake)-induced DA release in the nucleus accumbens (NAc) and the effect of chronic treatment with the antidepressant escitalopram (5mg/kg, intraperitoneally twice daily for 3 weeks) in two animal models of depression. Exposure to chronic mild stress (CMS) during adulthood completely suppressed reward-induced intra-NAc DA release; however, this effect was reversed by chronic treatment with escitalopram. Our findings suggest that reward-induced intra-NAc DA release may be an indicator of depression severity and therapeutic efficacy. Exposure to neonatal maternal separation (MS) and CMS in adulthood completely suppressed reward-induced intra-NAc DA release. Chronic treatment with escitalopram did not restore reward-induced DA release in these animals, suggesting that this paradigm may serve as an animal model for treatment-resistant depression. Further study of the mesolimbic dopaminergic system in these animal models of depression may clarify the neural mechanisms underlying depression and treatment resistance.

Neurobiological correlates of learning and decision-making in alcohol dependence

The mesolimbic dopaminergic system has been implicated in two kinds of reward processing, one in reinforcement learning (e.g prediction error) and another in incentive salience attribution (e.g. cue-reactivity). Both functions have been implicated in alcohol dependence with the former contributing to the persistence of chronic alcohol intake despite severe negative consequences and the latter playing a crucial role in cue-induced craving and relapse. The bicentric study “Learning in alcohol dependence (LeAD)” aims to bridge a gap between these processes by investigating reinforcement learning mechanisms and the influence that Pavlovian cues exert over behavior. We here demonstrate that alcohol dependent subjects show alterations in goal-directed, model-based reinforcement learning (Sebold et al., 2014) and demonstrate that prospective relapsing patients show reductions in the medial prefrontal cortex activation during goal-directed control. Moreover we show that in alcohol dependent patients compared to healthy controls, Pavlovian cues exert pronounced control over behavior (Garbusow et al., 2016). Again, prospective relapsing patients showed increased Nucleus accumbens activation during these cue-induced responses. These findings point to an important role of the mesolimbic dopaminergic system as a predictor of treatment outcome in alcohol dependence.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Dopamine D2 receptors mediate the increase in reinstatement of the conditioned rewarding effects of cocaine induced by acute social defeat

Social stress modifies the activity of brain areas involved in the rewarding effects of psychostimulants, inducing neuroadaptations in the dopaminergic mesolimbic system and modifying the sensitivity of dopamine receptors. In the present study we evaluated the effect of the dopamine D1- and D2-like receptor antagonists (SCH23390 and raclopride, respectively) on the short-time effects of acute social defeat (ASD). Male OF1 mice were socially defeated before each conditioning session of the conditioned place preference (CPP) induced by 1mg/kg or 25mg/kg of cocaine plus the corresponding dopamine antagonist. A final experiment was designed to evaluate the effect of the dopamine antagonists on the CPP induced by 3mg/kg of cocaine with or without a stress experience. Mice exposed to ASD showed an increase in reinstatement of the conditioned reinforcing effects of cocaine that was blocked by all of the dopamine receptor antagonists. Blockade of dopamine D2-like receptors with raclopride specifically prevented the effects of stress without affecting the rewarding properties of cocaine. However, SCH23390 inhibited cocaine-induced preference in the control groups and even induced aversion in defeated mice conditioned with the lower dose of cocaine. Moreover, the lowest dose of SCH23390 blocked the rewarding effects of 3mg/kg of cocaine-induced CPP. Our results confirm that the dopamine D2 receptor is involved in the short-term effects of ASD on the rewarding effects of cocaine. The dopamine D1 receptor is clearly involved in the rewarding effects of cocaine, but its role in the effects of ASD remains to be demonstrated.

Nalmefene Reduces Reward Anticipation in Alcohol Dependence: An Experimental Functional Magnetic Resonance Imaging Study

BackgroundNalmefene is a µ and δ opioid receptor antagonist, κ opioid receptor partial agonist that has recently been approved in Europe for treating alcohol dependence. It offers a treatment approach for alcohol-dependent individuals with “high-risk drinking levels” to reduce their alcohol consumption. However, the neurobiological mechanism underpinning its effects on alcohol consumption remains to be determined. Using a randomized, double-blind, placebo-controlled, within-subject crossover design we aimed to determine the effect of a single dose of nalmefene on striatal blood oxygen level–dependent (BOLD) signal change during anticipation of monetary reward using the monetary incentive delay task following alcohol challenge. MethodsTwenty-two currently heavy-drinking, non–treatment-seeking alcohol-dependent males were recruited. The effect of single dose nalmefene (18 mg) on changes in a priori defined striatal region of interest BOLD signal change during reward anticipation compared with placebo was investigated using functional magnetic resonance imaging. Both conditions were performed under intravenous alcohol administration (6% vol/vol infusion to achieve a target level of 80 mg/dL). ResultsDatasets from 18 participants were available and showed that in the presence of the alcohol infusion, nalmefene significantly reduced the BOLD response in the striatal region of interest compared with placebo. Nalmefene did not alter brain perfusion. ConclusionsNalmefene blunts BOLD response in the mesolimbic system during anticipation of monetary reward and an alcohol infusion. This is consistent with nalmefene’s actions on opioid receptors, which modulate the mesolimbic dopaminergic system, and provides a neurobiological basis for its efficacy.

Amphetamines: Potent Recreational Drug of Abuse

Amphetamines are central nervous system (CNS) stimulants and belong to psychoactive drugs that affect chemicals in the brain, nerves and exert a constant contribution to hyperactivity and impulse control. The communal group of amphetamines comprises amphetamine, dextroamphetamine and methamphetamine. Amphetamines show its action on the mesolimbic dopaminergic reward system by inducing release of dopamine and to some extent norepinephrine, in the synaptic clefts of the nucleus accumbens and other terminal areas. They offer not only a sense of euphoric state, but also addiction. Amphetamines are frequently prescribed for the treatment of attention deficit hyperactivity disorder (ADHD) in children, adolescents and adults, narcolepsy and obesity. At therapeutic doses, amphetamine causes emotional and cognitive effects such as euphoria, change in desire for sex, increased wakefulness, improved cognitive control, etc. The balance of benefit/risk is the main challenge for its clinical use. When overused these medications can be highly addictive, are often diverted from the user to be used as recreational drugs. Adverse effects include anxiety, aggression, headache, insomnia, hyperactivity, palpitations, increased breathing rate, increased blood pressure, tachycardia, arrhythmia, dilated pupils, paranoia, etc. However, at large doses, these drugs may impair cognitive function and induce rapid muscle breakdown. Even higher doses may give rise to hallucinations, paranoia, psychosis and potentially lifethreatening conditions such as convulsions, stroke, kidney failure, etc. The furthermost serious health implications of amphetamine resulting from chronic use are dependence, considered by compulsive drug-seeking and drug use and a phenomenon notorious as amphetamine psychosis. Therefore the objective of this study was to explore the functions of the amphetamines as recreation drug of abuse.

Mechanisms underlying δ- and μ-opioid receptor agonist-induced increases in extracellular dopamine level in the nucleus accumbens of freely moving rats.

The nucleus accumbens is a terminal area of the mesolimbic dopaminergic system that arises in the ventral tegmental area. Opioids are thought to enhance dopaminergic activity in the nucleus accumbens by activating δ- and μ-opioid receptors in the ventral tegmental area. However, δ- and μ-opioid receptor agonists increase extracellular levels of accumbal dopamine when infused directly into the nucleus accumbens of rats. Therefore, the roles of δ- and μ-opioid receptors in regulation of accumbal dopaminergic neural activity have been analyzed by using δ- and μ-opioid receptor ligands. This review describes the mechanisms underlying the stimulatory effects on accumbal dopamine efflux, which are induced by local administration of δ- and μ-opioid receptor agonists into the nucleus accumbens of freely moving rats. The focus of this article is neurochemical studies that use in vivo microdialysis techniques. Taken together, the in vivo neurochemical evidence from these studies indicates that δ- and μ-opioid receptor agonists increase accumbal dopamine efflux by activating naloxone-sensitive opioid receptors, and by mechanisms independent of naloxone-sensitive opioid receptors, in the nucleus accumbens.

Intra-accumbal and Peripheral administration of nicotine reduces the side-effects of Inescapable Stress

Suppressive effect of Ginkgo biloba extract (EGb 761) on topsin induced ovarian toxicity and oxidative stress in albino ratsSaber A. Sakr,Hoda A. Mahran, Asmaa M. Abdel-Maksoud

Novelty seeking mediates the effect of DRD3 variation on onset age of amphetamine dependence in Han Chinese population.

The dopamine receptor D3 (DRD3) gene, one of the candidate genes for amphetamine dependence (AD), is involved in the mesolimbic dopaminergic system, implicated as the underlying mechanism of addiction. Our case-control study aimed to investigate whether the DRD3 gene is associated with the susceptibility to AD and specific personality traits in AD patients. A total of 1060 unrelated Han Chinese subjects (559 AD patients and 501 controls) were screened using the same assessment tool and genotyped for eight DRD3 polymorphisms. All patients met the DSM-IV-TR criteria for AD, and personality traits of 539 were assessed using a Tridimensional Personality Questionnaire. Furthermore, AD individuals were divided into four clinical subgroups based on gender and psychosis status, to reduce the clinical heterogeneity. We found that the ATA haplotype combination for SNPs rs324029, rs6280, and rs9825563, respectively, was significantly associated with total AD patients (p=0.0003 after 10,000 permutations). Similar results were observed in the both male and non-psychosis subgroup but not in other subgroups. In addition, DRD3 rs9825563 may influence onset age of drug use, partially mediated by novelty seeking in the non-psychosis AD group. In conclusion, DRD3 is a potential genetic factor in the susceptibility to AD and is associated with onset age of drug use through interaction with novelty seeking in a specific patient group in the Han Chinese population.

The impact of the appetite-regulating, orexigenic peptide ghrelin on alcohol use disorders: A systematic review of preclinical and clinical data

Ghrelin, which is mainly released from the stomach, is the most important orexigenic regulator of food intake, inducing appetite, enhancing adiposity and releasing growth hormone. Besides the hypothalamus, ghrelin receptors (GHS-R1A) are also expressed in the mesolimbic dopaminergic system, which increases the possibility that ghrelin plays an important role in reward regulation for substance use disorders such as alcohol addiction, especially through activating the cholinergic-dopaminergic reward link. In this review we focus on the impact of ghrelin on the development and maintenance of alcohol addiction/dependence, alcohol consumption, alcohol craving and alcohol withdrawal, attempting to integrate preclinical and clinical studies concerning the intriguing relationship between appetite regulation, reward and alcohol addiction.Integrating the existing preclinical and clinical data on ghrelin antagonism, specifically at the GHS-R1A receptor in mesolimbic dopaminergic pathways, may reveal a new and innovative target for the treatment of alcohol dependence in the future.

The new designer drug buphedrone produces rewarding properties via dopamine D1 receptor activation

Substituted cathinones are synthetic analogs of the active components of natural products and are widely abused worldwide. However, the rewarding properties of these agents have not yet been evaluated. In this study, we investigated the abuse potential of buphedrone [2-(methylamino)-1-phenylbutan-1-one, α-methylamino-butyrophenone] and its effects on the mesolimbic dopaminergic system in mice using conditioned place preference (CPP) analysis, a self-administration test, a locomotor activity test, a behavioral sensitization test and Western blot analysis. Treatment with buphedrone supported CPP and self-administration, enhanced locomotor activity and produced behavioral sensitization when mice were challenged with methamphetamine. SCH23390, a D1 dopamine antagonist, prevented buphedrone-induced CPP, whereas raclopride, a D2 dopamine antagonist, had no effect. SCH23390 also blocked locomotor activity increase by buphedrone, while raclopride partially attenuated locomotor activation. Western blot analysis revealed that repeated buphedrone treatment increased D1 dopamine receptor expression in the dorsal striatum and nucleus accumbens in mice. Collectively, these findings suggest the abuse potential of buphedrone and demonstrate the involvement of the dopaminergic system in the establishment of its rewarding properties.

Involvement of D1 and D2 dopamine receptors in the antidepressant-like effects of selegiline in maternal separation model of mouse

Mother-infant interactions are known to be associated with the psychological well-being of an individual in adulthood. It is well accepted that emotional stress in early life, such as maternal separation (MS), leads to alterations in the neurotransmission systems of various brain regions, especially the mesolimbic dopaminergic system, and subsequently can increase the risk for development of psychiatric disorders including depression in adulthood. Selegiline is an irreversible monoamine oxidase (MAO) type B inhibitor which increases striatal dopamine levels and exerts an antidepressant effect. In this study, 180min of MS stress was applied to mice at postnatal day (PND) 2–14 followed by behavioral tests for determining depressive-like behaviors, such as forced swimming test (FST), splash test and sucrose preference test (SPT) in adult mice (PND 50). The open field test (OFT) also was applied to validate FST results. We used SCH23390 (D1 antagonist) and sulpiride (D2 antagonist) in order to determine the role of D1 and D2 dopamine receptors in antidepressant-like effects of selegiline. Our results revealed that MS provoked depressive-like behaviors in adult male mice, and the administration of selegiline attenuated depressive-like behaviors in MS mice. Our findings showed that D1 dopamine receptors facilitate the positive effects of selegiline on the passive behavior in the FST. Furthermore, antidepressant effects of selegiline on hedonic difficulties are mediated via D2 receptor in the SPT. The results of the splash test revealed that both D1 and D2 receptors mediate the protective effect of selegiline against motivational and self-care problems. Based on our results, we conclude that both D1 and D2 dopamine receptors are involved in mediating the antidepressant-like effect of selegiline. We found that D1 receptors mediate an effect on despair behavior, D2 receptors mediate an effect on anhedonia, and both D1 and D2 receptors contribute to the protective effects of selegiline on motivational complications.

Inhibition of the reward system by antipsychotic treatment

The mesolimbic dopaminergic reward system is responsible for the negative affective symptomatology of schizophrenia, which may be related to a low dopamine tonus within the ventral striatum. The monetary incentive delay (MID) task can be used to study the response of the ventral striatum to incentive stimuli. We show that activation of the ventral striatum is low in patients with schizophrenia, and that this low activation is related to primary and secondary negative symptoms induced by neuroleptics, also known as antipsychotics. Switching from first-(typical) to second-generation (atypical) antipsychotics increased activation of the ventral striatum due to less blocking of dopamine D2 receptors. This and similar studies show that functional magnetic resonance imaging (fMRI) tasks are suitable to investigate important aspects of antipsychotic mechanisms.

Attenuation of cue-induced reinstatement of nicotine seeking by URB597 through cannabinoid CB1 receptor in rats.

The endocannabinoid system is composed of endocannabinoids (such as anandamide), their target receptors (CB1 and CB2 receptors, CB1Rs and CB2Rs), the enzymes that degrade them (fatty-acid-amide-hydrolase (FAAH) for anandamide), and an endocannabinoid transporter. FAAH inhibition has been recently identified as having a critical involvement in behaviors related to nicotine addiction and has been shown to reduce the effect of nicotine on the mesolimbic dopaminergic system via CB1R and peroxisome proliferator-activated receptor alpha (PPARα). Thus, inhibition of FAAH may represent a novel strategy for smoking cessation, but its mechanism of action on relapse to nicotine seeking is still unknown. The study aims to explore the mechanism of action of the inhibitor of FAAH activity, URB597, on relapse to nicotine seeking by evaluating the effect of the CB1R, CB2R, and PPARα antagonists on the attenuating effect of URB597 on cue-induced reinstatement of nicotine seeking in rats. URB597 reduced cue-induced reinstatement of nicotine seeking, an effect that was reversed by the CB1R antagonist rimonabant, but not by the CB2R or PPARα antagonists AM630 and MK886, respectively. These results indicate that URB597 reduces cue-induced reinstatement in rats through a CB1 receptor-dependent mechanism, and not via CB2R or PPARα. Since FAAH inhibition represent a novel and promising strategy for tobacco smoking cessation, dissecting how it produces its action may lead to a better understanding of the neurobiological mechanisms underlying nicotine addiction.

Differential activation of dopaminergic systems in rat brain basal ganglia by morphine and methamphetamine

Typical abused drug-induced behavioral changes are ordinarily mediated by the mesolimbic dopaminergic system and even the phenotypes of behavior are different from each other. However, the mechanisms that underlie the behavioral changes induced by these abused drugs have not yet been elucidated. The present study was designed to investigate the mechanisms that underlie how abused drugs induce distinct behavioral changes using neurochemical as well as behavioral techniques in rats. Methamphetamine (2mg/kg) more potently increased dopamine release from the striatum more than that from the nucleus accumbens. In contrast, the administration of morphine (10mg/kg) produced a significant increase in the release of dopamine from the nucleus accumbens, but not the striatum, which is accompanied by a decrease in the release of GABA in the ventral tegmental area. These findings indicate that morphine and methamphetamine differentially regulate dopaminergic systems to produce behavioral changes, even though both drugs have abuse potential through activation of the mesolimbic dopaminergic system.

Involvement of opioid signaling in food preference and motivation: Studies in laboratory animals.

Motivation is a complex neurobiological process that initiates, directs, and maintains goal-oriented behavior. Although distinct components of motivated behavior are difficult to investigate, appetitive and consummatory phases of motivation are experimentally separable. Different neurotransmitter systems, particularly the mesolimbic dopaminergic system, have been associated with food motivation. Over the last two decades, however, research focusing on the role of opioid signaling has been particularly growing in this area. Opioid receptors seem to be involved, via neuroanatomically distinct mechanisms, in both appetitive and consummatory aspects of food reward. In the present chapter, we review the pharmacology and functional neuroanatomy of opioid receptors and their endogenous ligands, in the context of food reinforcement. We examine literature aimed at the development of laboratory animal techniques to better understand different components of motivated behavior. We present recent data investigating the effect of opioid receptor antagonists on food preference and effort-related decision making in rats, which indicate that opioid signaling blockade selectively affects intake of relatively preferred foods, resulting in reduced willingness to exert effort to obtain them. Finally, we elaborate on the potential role of opioid system manipulations in disorders associated with excessive eating and obesity.

The Nociceptin Receptor as an Emerging Molecular Target for Cocaine Addiction.

Cocaine addiction is a global public health and socioeconomic issue that requires pharmacological and cognitive therapies. Currently there are no FDA-approved medications to treat cocaine addiction. However, in preclinical studies, interventions ranging from herbal medicine to deep-brain stimulation have shown promise for the therapy of cocaine addiction. Recent developments in molecular biology, pharmacology, and medicinal chemistry have enabled scientists to identify novel molecular targets along the pathways involved in drug addiction. In 1994, a receptor that showed a great deal of homology to the traditional opioid receptors was characterized. However, endogenous and exogenous opioids failed to bind to this receptor, which led scientists to name it opioid receptor-like receptor, now referred to as the nociceptin receptor. The endogenous ligand of NOPr was identified a year later and named orphanin FQ/nociceptin. Nociceptin and NOPr are widely distributed throughout the CNS and are involved in many physiological responses, such as food intake, nociceptive processing, neurotransmitter release, etc. Furthermore, exogenous nociceptin has been shown to regulate the activity of mesolimbic dopaminergic neurons, glutamate, and opioid systems, and the stress circuit. Importantly, exogenous nociceptin has been shown to reduce the rewarding and addictive actions of a number of drugs of abuse, such as psychostimulants, alcohol, and opioids. This paper reviews the existing literature on the role of endogenous nociceptin in the rewarding and addictive actions of cocaine. The effect of exogenous nociceptin on these processes is also reviewed. Furthermore, the effects of novel small-molecule NOPr ligands on these actions of cocaine are discussed. Overall, a review of the literature suggests that NOPr could be an emerging target for cocaine addiction pharmacotherapy.

Proposition pour une physiologie de la jouissance

Objectives(1) This article aims to articulate the Lacanian concept of jouissance in view of applying this definition to the physiological sphere. (2) It aims to develop a proposal for an instantiation of jouissance in the physiological sphere. Methods(1) Distinction is made, with reference to Freudian and Lacanian texts, of four different aspects of the concept: for the body (a) drive, (b) the experience of satisfaction, and (c) excess body tension, and for the history, (d) the historical imprint. (2) This interpretative framework is applied to the domain of the neurosciences. Results(1) Jouissance at once entails the following: (a) the bodily tension underlying the action that satisfies the drive, (b) the experience accompanying the inaugural satisfaction event, (c) the accumulation of body tension due to the encounter with das Ding or to the revival of the wishful state, and (d) the inscription in the body of the history of its commemoration, which drives it to re-enact. (2) The mesolimbic dopaminergic system, linking the most archaic parts of the brainstem with the most developed motor cortices, via the nucleus accumbens in the limbic system, underpins each of these four distinct aspects of jouissance: (a) it was previously characterized as the instantiation of the Freudian drive; (b) dopamine release rewards each unanticipated satisfaction; (c) subsequently, each new encounter announcing the renewal of the satisfaction leads to dopamine release which puts the body under tension to act; (d) more specifically, this system can generate long-term neuronal adaptations leading to hypersensitivity towards actions that were previously mediated by dopamine release. In addition, this system, dissociating the action from its result, structurally implies its own derailment, the so-called autoshaping, just as jouissance implies a derailment in clinical terms. DiscussionWhile we propose here a “physiology of jouissance”, the idea is not to present this physiological correlate as actually being the Lacanian jouissance. Indeed, this jouissance is a clinical concept and, in the proposed epistemological approach, while the clinical approach enables an interpretation of the physiology, the reverse is not true – physiology does not enable an interpretation of what is played out at mental level. ConclusionThe mesolimbic dopaminergic system appears as a good candidate for an instantiation of the concept of jouissance on a physiological level. Consequently, this physiological instantiation corroborates the coherence of this clinically-derived theoretical concept.

Noradrenergic inputs from locus coeruleus to posterior ventral tegmental area are essential to support ethanol reinforcement.

Although dysregulation of the dopaminergic mesolimbic system is generally considered central to addiction, the involvement of other circuits is increasingly being appreciated. An interaction between locus coeruleus (LC) noradrenergic neurons and the posterior ventral tegmental area (pVTA) dopaminergic system, in the processing of drug-triggered reward, has been suggested, but not demonstrated in behaving animals. Herein, we try to tease out the precise role of noradrenergic neurons in the LC-VTA circuit in mediating reward and reinforcement behavior associated with ethanol. In the standard two-lever (active/inactive) operant paradigm, the rats were trained to self-administer ethanol in pVTA and subjected to pharmacological intervention. Intra-pVTA administration of phenylephrine (alpha-1 adrenoceptor agonist) increased ethanol self-administration, while prazosin and disulfiram (agents that reduce noradrenergic tone) produced opposite effects. While degeneration [N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride, DSP-4, intraperitoneal route] or silencing (lidocaine or muscimol, both via intra-LC route) of the LC noradrenergic neurons decreased, phenylephrine via the intra-LC route reinstated ethanol self-administration. Furthermore, lidocaine reduced ethanol self-administration, but the effect was fully attenuated by noradrenaline given directly in the pVTA. This suggests that the feedback signals from LC to pVTA are necessary to sustain the ethanol self-infusion activity. Ethanol self-administration significantly increased tyrosine hydroxylase immunoreactivity in pVTA and LC; the response was blocked by DSP-4 pre-treatment. While dopamine D1 , but not D2 , receptors were localized on noradrenergic LC neurons, pre-treatment with SCH-23390 (intra-LC) dampened the lever press activity. We suggest that two-way communications between VTA and LC regions is essential for ethanol-triggered reinforcement behavior.