Psychostimulant Dependence Research Articles

Stimulation of future thinking in stimulant–depending patients using questionnaire–based structured interview

INTRODUCTION: Impaired future thinking (FT) a human ability to imagine and comprehend images and scenarios of the personal future may contribute to the severity of psychoactive substance dependence. Spontaneous mental images of the impacts of using psychoactive substances and/or of one’s own death (‘flash-forwards’), as well as impaired arbitrary modeling of future images (for example, overgeneralization and lack of reflection) interfere with adherence to treatment and stability of remission in addictions. AIM: To evaluate the influence of FT-activating intervention on treatment outcomes in patients with narcotic psychostimulant dependence. MATERIALS AND METHODS: A randomized prospective controlled clinical trial conducted in 2021–2023 involved 112 inpatients with stimulant dependence (F15.2). Of them, the main group consisted of 56 patients (age 24.0 [21.0; 27.0] years; 30.4% of men), who underwent FT stimulation in the form of semi-structured interview based on the Russian pilot version of the Impact of Future Events Scale (IFES). The control group consisted of 56 patients (age 23.5 [22.0; 26.0] years; 39.3% of men) who received a standard drug addiction conversation of equal duration. The treatment result parameters included the score on the Stages of Change Readiness and Treatment Eagerness Scale (SOCRATES); duration of remission, participation in long-term therapy, in outpatient rehabilitation, inpatient rehabilitation, confirmation of the fact of prescheduled discharge, infringement of regime, incarcerations. The test was conducted upon admission and after discharge. Hospitals stay period — 21 days, follow-up period — 6 months. RESULTS: At the hospitalization stage, the groups did not differ in socio-demographic and main clinical parameters (p 0.05). SOCRATES scores were higher in the control group 49.0 [47.0; 49.0] versus 48.0 [47.0; 49.0] (p = 0.040). At the stage of re-test before discharge, the main group showed an improvement in motivation according to SOCRATES and significantly outperformed the control group: 67.0 [65.3; 68.0] versus 50.0 [48.0; 53.8] points (p 0.001). The main group had a longer duration of remission — 3.3 [0.5; 5.4] months versus 0.5 [0.4; 1.0] months (p = 0.001); fewer prescheduled discharges — 12.5% versus 50.0% (p = 0.001); more frequent visits to long-term therapy — 30.4% versus 8.9% (p = 0.01) and outpatient rehabilitation — 21.4% versus 1.8% (p = 0.001) respectively. CONCLUSIONS: FT-activating intervention directed to stimulating reflection of anxious and positive aspects of the personal future, contributes to increase in duration of remission in the catamnesis, increases motivation and adherence to treatment in patients with addiction to narcotic psychostimulants.

Nalmefene attenuates reinstatement of methamphetamine-seeking behavior in rats through group II metabotropic glutamate receptors (mGluR2/3)

Nalmefene, an analog to naltrexone, is an antagonist at the μ opioid receptor and a partial agonist at the κ opioid receptor. Both agents are approved for the treatment of alcohol use disorder and opioid addiction. Here, we evaluated the potential of nalmefene for treating psychostimulant dependence using a methamphetamine (METH) self-administration rat model. Rats were trained to press a lever for 0.02-mg intravenous METH infusions paired with drug-associated cues (light and tone) under a fixed ratio 1 schedule. After a 10-day METH self-administration acquisition phase, rats underwent extinction training. A reinstatement test was conducted after fulfilment of the extinction criterion under saline infusions. Re-exposure to METH-associated cues or a priming injection of METH (1.0 mg/kg, i.p.) significantly reinstated METH-seeking behaviors. Pretreatment with nalmefene (10 mg/kg, i.p.) immediately before reinstatement tests significantly attenuated the METH-seeking behaviors induced by both cues and METH priming injection. To investigate the mechanism of effect of nalmefene, we also tested the ability of a group II metabotropic glutamate receptors (mGluR2/3) antagonist, LY341495, to the ameliorating effects of nalmefene. Pretreatment with LY341495 (1.0 mg/kg, i.p.) before nalmefene administration antagonized the effect of nalmefene on reinstatement. LY341495 alone did not affect the reinstatement of lever pressing. We found that nalmefene attenuates METH-seeking behaviors during withdrawal, and this attenuation of reinstatement is mediated by the activation of mGluR2/3. The present findings suggest that nalmefene could decrease incentive motivation for drug use in psychostimulant dependence.

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Cyanidin prevents MDPV withdrawal-induced anxiety-like effects and dysregulation of cytokine systems in rats

Psychostimulant exposure and withdrawal cause neuroimmune dysregulation and anxiety that contributes to dependence and relapse. Here, we tested the hypothesis that withdrawal from the synthetic cathinone MDPV (methylenedioxypyrovalerone) produces anxiety-like effects and enhanced levels of mesocorticolimbic cytokines that are inhibited by cyanidin, an anti-inflammatory flavonoid and nonselective blocker of IL-17A signaling. For comparison, we tested effects on glutamate transporter systems that are also dysregulated during psychostimulant free period. Rats injected for 9 d with MDPV (1 mg/kg, IP) or saline were pretreated daily with cyanidin (0.5 mg/kg, IP) or saline, followed by behavioral testing on the elevated zero maze (EZM) 72 h after the last MDPV injection. MDPV withdrawal caused a reduction in time spent on the open arm of the EZM that was prevented by cyanidin. Cyanidin itself did not affect locomotor activity or time spent on the open arm, or cause aversive or rewarding effects in place preference experiments. MDPV withdrawal caused enhancement of cytokine levels (IL-17A, IL-1β, IL-6, TNF=α, IL-10, and CCL2) in the ventral tegmental area, but not amygdala, nucleus accumbens, or prefrontal cortex, that was prevented by cyanidin. During MDPV withdrawal, mRNA levels of glutamate aspartate transporter (GLAST) and glutamate transporter subtype 1 (GLT-1) in the amygdala were also elevated but normalized by cyanidin treatment. These results show that MDPV withdrawal induced anxiety, and brain-region specific dysregulation of cytokine and glutamate systems, that are both prevented by cyanidin, thus identifying cyanidin for further investigation in the context of psychostimulant dependence and relapse.

Analysis of Protein Markers in Plasma of Patients with Drug Dependence Syndrome: Observational Clinical Study

Background. In drug addiction treatment, the diagnostic process is based on the chemical toxicological determination of the intoxication substrate or its metabolite. Laboratory monitoring and prediction issues that could form the basis of secondary prevention remain unresolved. Specific nervous tissue proteins are considered to be the most promising laboratory markers of drug pathology.Objective — to determine some potential biomarkers of protein-chemical nature in the plasma of patients with drug dependence syndrome.Methods. The study was conducted according to the design of an observational clinical trial at the Narcological Dispensary of Krasnodar Krai in the period from 07.2021 to 07.2022. The main group (group 2) included 31 patients diagnosed with substance dependence syndrome. The control group (group 1, n = 15) consisted of healthy subjects submitted to occupational medical examinations. During the detoxification-stabilization therapy and rehabilitation, 5 proteins were determined in the plasma: brainand glial-derived neurotrophic factors, neuron-specific enolase, alpha-synuclein and calcium-binding protein S100B. Statistical analysis of the data involved the Mann-Whitney test for comparing the values of the control and experimental groups and the Wilcoxon test for comparing the values of one group obtained at different stages of observation. The calculations were carried out using StatPlus version 7 (AnalystSoft Inc., USA).Results. A total of 31 patients were included in the main group, 18 of them were followed up with a diagnosis of opioid dependence syndrome (n = 11) or psychostimulant dependence syndrome (n = 7). Patients dropped out of the study due to their refusal to participate in the study or undergo rehabilitation, or due to relapse of the disease. When admitted to the hospital, patients indicated a 45% decrease in brain-derived neurotrophic factor in the plasma ( p < 0.001), and a 3.9-fold decrease after rehabilitation course ( p < 0.001). Glial-derived neurotrophic factor in the plasma exceeded the controls 1.9 times ( p < 0.001) upon admission to hospital, but rapidly returned to normal values thereafter. Level of neuron-specific enolase in the plasma was also poor, 36% lower than the controls ( p <0.001), but approached the control values by the end of rehabilitation.Conclusion. The study obtained data indicating the changes in neurotrophic factors in the blood plasma of patients with opioid or psychostimulant dependence. The rehabilitation period was marked by a relatively rapid improving level of neurotrophins; however, brain-derived neurotrophic factor remained reduced despite the successful treatment, which may indicate the irreversible changes.

A mechanistic overview of approaches for the treatment of psychostimulant dependence.

Psychostimulant use disorder is a major health issue around the world with enormous individual, family-related and societal consequences, yet there are no effective pharmacological treatments available. In this review, a target-based overview of pharmacological treatments toward psychostimulant addiction will be presented. We will go through therapeutic approaches targeting different aspects of psychostimulant addiction with focus on three major areas; 1) drugs targeting signalling, and metabolism of the dopamine system, 2) drugs targeting either AMPA receptors or metabotropic glutamate receptors of the glutamate system and 3) drugs targeting the severe side-effects of quitting long-term psychostimulant use. For each of these major modes of intervention, findings from pre-clinical studies in rodents to clinical trials in humans will be listed, and future perspectives of the different treatment strategies as well as their potential side-effects will be discussed. Pharmaceuticals modulating the dopamine system, such as antipsychotics, DAT-inhibitors, and disulfiram, have shown some promising results. Cognitive enhancers have been found to increase aspects of behavioural control, and drugs targeting the glutamate system such as modulators of metabotropic glutamate receptors and AMPA receptors have provided interesting changes in relapse behaviour. Furthermore, CRF-antagonists directed toward alleviating the symptoms of the withdrawal stage have been examined with interesting resulting changes in behaviour. There are promising results investigating therapeutics for psychostimulant addiction, but further preclinical work and additional human studies with a more stratified patient selection are needed to prove sufficient evidence of efficacy and tolerability.

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Editorial introductions.

The effect of brain neurotrophic factor gene polymorphism on the effectiveness of therapeutic and rehabilitation measures in patients with psychostimulant dependence

Justification. Along with the rising consumption of psychostimulants, the number of patients with dependence on psychostimulants is increasing all over the world and in Russia in particular. At the same time, the number of patients with dependence on drug combinations is increasing, most of which are psychostimulants.
 Aim. The aim of the work is to develop a personalized approach to the therapy of patients with dependence on psychostimulants, taking into account the polymorphism of the neurotrophic factor gene of the brain.
 Material and methods. 305 patients with dependence on psychostimulants, men and women from 18 to 50 years old, were studied. Depending on the drug used and their combinations, as well as the presence of comorbid psychiatric pathology, all patients were divided into 6 groups. Research methods: molecular-genetic, clinical-psychopathological, catamnestic, statistical (parametric and nonparametric methods using Statistica 10.0 programs of STAT Soft Inc., USA). The effect of polymorphism of the neurotrophic factor gene of the brain on the effectiveness of therapeutic and rehabilitation measures in patients in different groups was evaluated.
 Results. It was found that patients who use only psychostimulants and psychostimulants with cannabinoids, having a homozygous (GG) genotype of the neurotrophic factor gene of the brain, are longer in the rehabilitation program and have the longest remissions.
 Conclusion. Polymorphism of the neurotrophic factor gene of the brain affects the effectiveness of therapeutic and rehabilitation measures in patients with dependence on psychostimulants.

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Oxidative stress markers in patients suffering from opioid and psychostimulant dependence syndrome

Background. The available data from clinical studies suggest the essential role of free radical processes in the pathogenesis of drug dependence syndrome. At the same time, there is a limited understanding of using markers of oxidative stress in laboratory monitoring and prediction of drug pathology.Objective. To characterize changes in promising indicators of oxidative stress in patients with psychostimulant and opioid dependence syndrome.Material and Methods. The total study population was divided into three groups of men aged 23–35: healthy controls (n = 20), patients with the opioid (n = 20) and psychostimulant (n = 20) dependence syndrome. Patients were analyzed for the oxidative stress markers while being in therapy for addiction syndrome aimed at treating mental disorders and detoxification.Results. The study of antioxidant activity and blood plasma thiol groups did not reveal any significant differences between patients suffering from opioid and psychostimulant addiction. The values of the parameters mentioned above were maintained by 20–30% lower than the control indices throughout the entire study. The nature of changes in erythrocyte suspension parameters was not so unambiguous. Thus, patients with opioid dependence syndrome were characterized by a 91% increase in thiobarbituric acid (TBA)-reactive materials in the setting of a slightly altered state of the glutathione system parameters. Psychostimulant dependent patients revealed relatively low level of the products of biomolecule oxidative modifications in the erythrocytes that is 52% higher compared to the control values. It decreased during the therapy, but glutathione concentration reduction by 33% and an imbalance of glutathione metabolism were determined.Conclusion. The course of the opioid dependence syndrome is characterized by a pronounced intensification of free radical processes while the common trait for psychostimulant abusers is significant changes in the antioxidant defense system. Therefore, in the first case, it is most justified to conduct a laboratory assessment of indicators of oxidative damage, and in the second one, it is also advisable to determine the markers of the state of individual links of the antioxidant system.

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Изменения биохимических показателей у больных с зависимостью от психостимуляторов на фоне метаболической коррекции

Изменения биохимических показателей у больных с зависимостью от психостимуляторов на фоне метаболической коррекции

Clinical symptoms and personality traits in patients using psychostimulant drugs and other psychoactive substances

To obtain preliminary data on personality and clinical/psychopathological predictors of combined use of psychoactive drugs in patients with psychostimulant dependence. Eighty-nine inpatients were examined. Family history of drug dependence, personality disorders, clinical/psychopathological characteristics and disease course (breakdowns, relapses, remissions) were compared in patients with psychostimulant dependence (n=35) and patients who used other psychoactive substances (n=54). Combined use of psychoactive substances is predicted by a complex of factors, including genetic, biological (neurochemical), psychological (personality characteristics of comorbidity and social influences). Based on their proportion, three types of psychostimulant dependence were determined.

Dynamic Expression Changes in the Transcriptome of the Prefrontal Cortex after Repeated Exposure to Cocaine in Mice.

Prefrontal cortex (PFC)-dependent functions, such as executive function, explicit learning, and memory, are negatively affected in cocaine abusers and experimental animal models of cocaine treatment. However, its molecular mechanisms are less understood. In the present study, we performed transcriptome profiling of the dynamic changes in the PFC after repeated cocaine administration in mice. We found 463, 14, and 535 differentially expressed genes (DEGs) at 2 h, 24 h, and 7 days, respectively, after the withdrawal of chronic cocaine treatment. Time-series correlation analysis identified 5 clusters of statistically significant expression patterns. The expression levels of DEGs in Clusters 1 and 5 exhibited a gradual or fluctuant decrease, Cluster 2 exhibited an initial increase followed by a decrease or return to the baseline level, and Clusters 3 and 4 exhibited a fluctuant increase in the expression of DEGs. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that genes related to oxidative phosphorylation, ribosomes, and neurodegenerative disorder were enriched in Cluster 1; genes related to the mitogen activated protein kinase (MAPK), transforming growth factor (TGF)-β, insulin signaling, and circadian pathways were enriched in Cluster 2; genes related to plasticity-related pathways were enriched in Clusters 3 and 4; and genes related to the proteasome were enriched in Cluster 5. Our results suggest that maladaptive neural plasticity associated with psychostimulant dependence may be an ongoing degenerative process with dynamic changes in the gene network at different stages of withdrawal. Furthermore, it could be helpful to develop new therapeutic approaches according to different periods of abstinence.

Commentary on Singh et al. (2016): Still searching for the answer.

Pharmacotherapy trials for psychostimulant dependence have a long history, and no proven, effective drug has emerged. With attention turning to anticonvulsants, the work by Singh et al. is cautionary in that, again, the drug in question did not emerge as clearly effective. In their Introduction, Singh and colleagues note that cocaine dependence is a world-wide clinical and public health problem 1. Indeed, this has been the case for a considerable time, with the first cocaine ‘epidemic’ being seen in during the 1920s. The lack of progress in finding effective pharmacotherapies over this period is remarkable. Drugs trialled have included antidepressants, antipsychotics, dopamine agonists and other psychostimulants 1-4. To date, no drug has shown unequivocal efficacy in reducing use and craving. In recent years there has been interest in anticonvulsants as a treatment option. Singh et al.'s 1 review of the anticonvulsant topiramate continues this long-standing pattern, with the results indicating that the drug did not improve treatment retention but may, possibly, improve abstinence in the short term. There was certainly no compelling evidence that this was the pharmacological solution so desperately sought. This is a problem for the treatment of psychostimulants more broadly. As with cocaine, there is no proven pharmacological agent for the treatment of methamphetamine dependence 2, 5. Indeed, the psychostimulants stand in stark contrast to the treatment of opioids and nicotine, where effective pharmacological treatments have long been available 3. In terms of the search for agonists, we have argued recently that such a drug may never be found, due to the characteristics and harms of psychostimulants 3. Whether this is true for other types of pharmacological agents remains to be seen. The track record, however, is not encouraging. The work by Singh et al. 1 is an important contribution. It is only by analyses of this kind, taking stock across a number of studies, that the true picture emerges. Consistent with the long line of research preceding it the results were equivocal, although, as with previous drugs trialled, providing some hint of encouragement. Psychostimulants present a particularly difficult treatment problem. Given all that has preceded this work, it is open to question as to whether such an effective drug treatment actually exists. None.

Factors affecting severity of positive and negative symptoms of psychosis in a polysubstance using population with psychostimulant dependence

Approximately half of psychostimulant users experience psychotic symptoms, which include both positive and negative symptoms. Prior reports have exclusively used positive symptoms to characterize psychostimulant associated psychosis. Symptoms vary dramatically in severity, though most investigations categorize psychosis as a dichotomous occurrence. To explore the association between different substances of abuse and the severity of psychotic symptoms, we investigated 171 individuals meeting DSM-IV-TR criteria for psychostimulant (cocaine or methamphetamine) dependence in an observational cross-sectional study. Participants were predominantly male (72.5%), recruited from a socially disadvantaged neighborhood in Vancouver, Canada, with a mean age of 45.5(±8.8) years. Of the total sample, 85% were dependent on cocaine, and 28.1% were dependent on methamphetamine. Participants had a median total PANSS score of 63, ranging from 37 to 111. Demographic information, current substance use and early substance exposure were used to predict positive and negative psychotic symptom severity in linear regression models. Increased severity of positive psychotic symptoms was significantly related to greater methamphetamine and marijuana use in the past 28 days, and methadone-abstinence. Negative symptom severity was related to increased opioid use in the past 28 days. There was no overlap between predictors of positive and negative symptom severity.

Hypothesizing that, A Pro-Dopamine Regulator (KB220Z) Should Optimize, but Not Hyper-Activate the Activity of Trace Amine-Associated Receptor 1 (TAAR-1) and Induce Anti-Craving of Psychostimulants in the Long-Term.

Unlike other drugs of abuse such as alcohol, nicotine, opiates/opioids, the FDA has not approved any agent to treat psychostimulant dependence. Certainly, it is widely acceptable that dopaminergic signaling is a key factor in both the initiation and continued motivation to abuse this class of stimulant substances. It is also well accepted that psychostimulants such as cocaine affect not only the release of neuronal dopamine at the nucleus accumbens (NAc), but also has powerful inhibitory actions on the dopamine transporter system. Understandably, certain individuals are at high risk and very vulnerable to abuse this class of substances. Trace-amine-associated receptor 1 (TAAR1) is a G -protein coupled receptor activated by trace amines. The encoded protein responds little or not at all to dopamine, serotonin, epinephrine, or histamine, but responds well to beta-phenylethylamine, p-tyramine, octopamine, and tryptamine. This gene is thought to be intronless. TAAR1 agonists reduce the neurochemical effects of cocaine and amphetamines as well as attenuate addiction and abuse associated with these two psychostimulants. The mechanism involves blocking the firing rate of dopamine in the limbic system thereby decreasing a hyperdopaminergic trait/state, whereby the opposite is true for TAAR1 antagonists. Based on many studies, it is accepted that in Reward Deficiency Syndrome (RDS), there is weakened tonic and improved phasic dopamine discharge leading to a hypodopaminergic/glutamatergic trait. The dopamine pro-complex mixture KB220, following many clinical trials including neuroimaging studies, has been shown to enhance resting state functional connectivity in humans (abstinent heroin addicts), naïve rodent models, and regulates extensive theta action in the cingulate gyrus of abstinent psychostimulant abusers. In this article, we are hypothesizing that KB220 may induce its action on resting state functional connectivity, for example, by actually balancing (optimizing) the effects of TAAR1 on the glutamatergic system allowing for optimization of this system. This will lead to a normalized and homeostatic release of NAc dopamine. This proposed optimization, and not enhanced activation of TAAR1, should lead to well-being of the individual. Hyper-activation instead of optimizing the TAAR1 system unfortunately will lead to a prolonged hypodopaminergic state and as such, will cause enhanced craving for not only psychoactive substances, but also other drug-related and even non-drug related RDS behaviors. This hypothesis will require extensive research, which seems warranted based on the global epidemic of drug and behavioral addictions.

Dopaminergic mediation of the discriminative stimulus functions of modafinil in rats.

Modafinil is a wake-promoting drug with FDA approval for the treatment of excessive daytime sleepiness that has been prescribed for ADHD and recently assessed as a potential treatment for psychostimulant dependence. Previous research indicates that modafinil modestly increases locomotor activity and produces similar discriminative stimulus effects to psychostimulants in rodents, although the subjective effects of modafinil are reportedly distinct from those of cocaine or amphetamine in humans with a history of psychostimulant abuse. The current study employed drug discrimination procedures in rats to examine the pharmacological actions contributing to modafinil's discriminative stimulus functions. Eight male Sprague-Dawley rats were trained to discriminate intragastric administration of 256 mg/kg modafinil from vehicle (5% arabic gum) under a FR 20 schedule of food reinforcement. Substitution tests were conducted with various dopaminergic agents (d-amphetamine, cocaine, PNU-91356A, GBR 12909, methylphenidate) and nondopaminergic agents (nicotine, ethanol). Antagonist tests were conducted with the selective D1 antagonist, SCH 39166, and the nonselective D2 antagonist, haloperidol. Rats trained to discriminate modafinil displayed complete stimulus generalization to cocaine, methylphenidate, and GBR 12909 and the discrimination was completely blocked by both SCH 39166 and haloperidol. Evidence for significant partial substitution was obtained with d-amphetamine, PNU-91356A, and nicotine. Results strongly support the role of dopaminergic mechanisms in the discriminative stimulus functions of modafinil, although further evaluation regarding the contribution of other neurotransmitter systems to these effects should be continued. The findings are discussed in light of clinical research efforts with modafinil as a treatment for psychostimulant dependence.

Metabotropic Glutamate Receptor 7 (mGluR7) as a Target for the Treatment of Psychostimulant Dependence.

Although few medications have been approved by the U.S. Food and Drug Administration (FDA) to assist people to quit tobacco smoking, there are no FDA-approved medications to treat dependence on other psychostimulant drugs, such as cocaine. The motivation to maintain psychostimulant drug seeking and self-administration involves alterations in glutamatergic neurotransmission. Thus, medications that modulate glutamate transmission may be effective treatments for psychostimulant dependence. One presynaptic inhibitory glutamate receptor that critically regulates glutamate transmission is the metabotropic glutamate 7 receptor (mGluR7). This review summarizes nonhuman experimental animal data that indicate a critical role for mGluR7 in drug-taking and drug-seeking behaviors for the psychostimulants cocaine and nicotine. AMN082, the only commercially available allosteric receptor agonist, has been used to investigate the role of mGluR7 in psychostimulant dependence. Systemic administration or microinjection of AMN082 into brain sites within the mesocorticolimbic system decreased self-administration and reinstatement of both cocaine and nicotine seeking. In vivo microdialysis results indicated that a nucleus accumbens-ventral pallidum γ-aminobutyric acid-ergic mechanism may underlie AMN082-induced antagonism of the reinforcing effects of cocaine, whereas a glutamate mGlu2/3 receptor mechanism underlies the AMN082-induced blockade of cocaine seeking. These findings indicate an important role for mGluR7 in mesolimbic areas in modulating the reinforcing effects of psychostimulant drugs, such as nicotine and cocaine, and the conditioned behaviors associated with drugs of abuse. Thus, selective mGluR7 agonists or positive allosteric modulators may have the potential to treat psychostimulant dependence.

Dopamine in the Brain: Hypothesizing Surfeit or Deficit Links to Reward and Addiction.

Recently there has been debate concerning the role of brain dopamine in reward and addiction. David Nutt and associates eloquently proposed that dopamine (DA) may be central to psycho stimulant dependence and some what important for alcohol, but not important for opiates, nicotine or even cannabis. Others have also argued that surfeit theories can explain for example cocaine seeking behavior as well as non-substance-related addictive behaviors. It seems prudent to distinguish between what constitutes “surfeit” compared to” deficit” in terms of short-term (acute) and long-term (chronic) brain reward circuitry responsivity. In an attempt to resolve controversy regarding the contributions of mesolimbic DA systems to reward, we review the three main competing explanatory categories: “liking”, “learning”, and “wanting”. They are (a) the hedonic impact -liking reward, (b) the ability to predict rewarding effects-learning and (c) the incentive salience of reward-related stimuli -wanting. In terms of acute effects, most of the evidence seems to favor the “surfeit theory”. Due to preferential dopamine release at mesolimbic-VTA-caudate-accumbens loci most drugs of abuse and Reward Deficiency Syndrome (RDS) behaviors have been linked to heightened feelings of well-being and hyperdopaminergic states.The “dopamine hypotheses” originally thought to be simple, is now believed to be quite complex and involves encoding the set point of hedonic tone, encoding attention, reward expectancy, and incentive motivation. Importantly, Willuhn et al. shows that in a self-administration paradigm, (chronic) excessive use of cocaine is caused by decreased phasic dopamine signaling in the striatum. In terms of chronic addictions, others have shown a blunted responsivity at brain reward sites with food, nicotine, and even gambling behavior. Finally, we are cognizant of the differences in dopaminergic function as addiction progresses and argue that relapse may be tied to dopamine deficiency. Vulnerability to addiction and relapse may be the result of the cumulative effects of dopaminergic and other neurotransmitter genetic variants and elevated stress levels. We therefore propose that dopamine homeostasis may be a preferred goal to combat relapse.