Behavioral genetics of alcohol's effects in three zebrafish (Danio rerio) populations.

Alcohol abuse is one of the most dangerous and serious problems for patients and society. Interpopulation studies are important in understanding how genetic background contributes to the effects of alcohol. In this study, we applied a chronic alcohol exposure protocol in three zebrafish populations (Danio rerio; both sexes; AB, TU, and outbred fish - OB). We analyzed the behavioral responses and mRNA expression involved in neurotransmitter metabolism - th1, tph1, ache, ada1, gaba1, gad1b, and bdnf. Locomotion patterns were similar between populations (increased speed after acute alcohol and unaltered locomotion after chronic and withdrawal treatments). All populations exhibited increased expression of genes associated with locomotion (th1, gad1b, and gaba1) after acute alcohol exposure. Anxiety-like responses increased in AB and TU fish during withdrawal and decreased in AB fish after acute alcohol exposure. Genes related to anxiety-like behavior (tph1 and ada1) were overexpressed in AB and TU fish after acute and withdrawal treatments, while OB fish exhibited unaltered responses. Bdnf levels decreased during withdrawal in AB and OB fish, while TU showed upregulated levels in both chronic and withdrawal treatments. Our results suggest that zebrafish populations respond differently to alcohol exposure, which may contribute to understanding the mechanisms underlying alcohol use and dependence. Moreover, we found that a more diverse genetic background (OB) was related to higher variability in behavioral and mRNA expression, demonstrating that inbred populations (AB and TU) may be useful tools in identifying alcohol use and abuse mechanisms.

Sex differences in progestogen- and androgen-derived neurosteroids in vulnerability to alcohol and stress-related disorders.

Stress and trauma exposure disturbs stress regulation systems and thus increases the vulnerability for stress-related disorders which are characterized by negative affect, including major depressive disorder, anxiety disorders and posttraumatic stress disorder. Similarly, stress and trauma exposure results in increased vulnerability to problematic alcohol use and alcohol use disorder, especially among women, who are more likely to drink to cope with negative affect than their male counterparts. Given these associations, the relationship between stress-related disorders and alcohol use is generally stronger among women leading to complex comorbidities across these disorders and alcohol misuse. This review highlights the therapeutic potential for progestogen- and androgen-derived neurosteroids, which affect both stress- and alcohol-related disorders, to target the overlapping symptoms related to negative affect. This article is part of the special issue on 'Vulnerabilities to Substance Abuse.'

Escalated Alcohol Self-Administration and Sensitivity to Yohimbine-Induced Reinstatement in Alcohol Preferring Rats: Potential Role of Neurokinin-1 Receptors in the Amygdala.

Genetic factors significantly contribute to the risk for developing alcoholism. To study these factors and other associated phenotypes, rodent lines have been developed using selective breeding for high alcohol preference. One of these models, the alcohol preferring (P) rat, has been used in hundreds of preclinical studies over the last few decades. However, very few studies have examined relapse-like behavior in this rat strain. In this study, we used operant self-administration and yohimbine-induced reinstatement models to examine relapse-like behavior in P rats. Our previous work has demonstrated that P rats show increased expression of the neurokinin-1 receptor (NK1R) in the central nucleus of the amygdala (CeA), and this functionally contributes to escalated alcohol consumption in this strain. We hypothesized that P rats would show increased sensitivity to yohimbine-induced reinstatement that is also mediated by NK1R in the CeA. Using Fos staining, site-specific infusion of NK1R antagonist, and viral vector overexpression, we examined the influence of NK1R on the sensitivity to yohimbine-induced reinstatement of alcohol seeking. We found that P rats displayed increased sensitivity to yohimbine-induced reinstatement as well as increased neuronal activation in the CeA after yohimbine injection compared to the control Wistar strain. Intra-CeA infusion of NK1R antagonist attenuates yohimbine-induced reinstatement in P rats. Conversely, upregulation of NK1R within the CeA of Wistar rats increases alcohol consumption and sensitivity to yohimbine-induced reinstatement. These findings suggest that NK1R upregulation in the CeA contributes to multiple alcohol-related phenotypes in the P rat, including alcohol consumption and sensitivity to relapse.

CRF modulation of central monoaminergic function: Implications for sex differences in alcohol drinking and anxiety.

Decades of research have described the importance of corticotropin-releasing factor (CRF) signaling in alcohol addiction, as well as in commonly co-expressed neuropsychiatric diseases, including anxiety and mood disorders. However, CRF signaling can also acutely regulate binge alcohol consumption, anxiety, and affect in non-dependent animals, possibly via modulation of central monoaminergic signaling. We hypothesize that basal CRF tone is particularly high in animals and humans with an inherent propensity for high anxiety and alcohol consumption, and thus these individuals are at increased risk for the development of alcohol use disorder and comorbid neuropsychiatric diseases. The current review focuses on extrahypothalamic CRF circuits, particularly those stemming from the bed nucleus of the stria terminalis (BNST), found to play a role in basal phenotypes, and examines whether the intrinsic hyperactivity of these circuits is sufficient to escalate the expression of these behaviors and steepen the trajectory of development of disease states. We focus our efforts on describing CRF modulation of biogenic amine neuron populations that have widespread projections to the forebrain to modulate behaviors, including alcohol and drug intake, stress reactivity, and anxiety. Further, we review the known sex differences and estradiol modulation of these neuron populations and CRF signaling at their synapses to address the question of whether females are more susceptible to the development of comorbid addiction and stress-related neuropsychiatric diseases because of hyperactive extrahypothalamic CRF circuits compared to males.

The Role of Neuropeptide Y (NPY) in Alcohol and Drug Abuse Disorders.

Neuropeptide Y (NPY) is a neuromodulator that is widely expressed throughout the central nervous system (CNS) and which is cosecreted with classic neurotransmitters including GABA and glutamate. There is a long history of research implicating a role for NPY in modulating neurobiological responses to alcohol (ethanol) as well as other drugs of abuse. Both ethanol exposure and withdrawal from chronic ethanol have been shown to produce changes in NPY and NPY receptor protein levels and mRNA expression in the CNS. Importantly, manipulations of NPY Y1 and Y2 receptor signaling have been shown to alter ethanol consumption and self-administration in a brain region-specific manner, with Y1 receptor activation and Y2 receptor blockade in regions of the extended amygdala promoting robust reductions of ethanol intake. Similar observations have been made in studies examining neurobiological responses to nicotine, psychostimulants, and opioids. When taken together with observations of potential genetic linkage between the NPY system and the human alcohol abuse disorders, NPY represents a promising target for treating problematic alcohol and drug use, and in protecting individuals from relapse during abstinence.

The Role of the Ghrelin System in Drug Addiction.

In the past years, a significant volume of research has implicated the appetitive hormone ghrelin in the mechanisms underlying drug use and addiction. From a neuroscientific standpoint, ghrelin modulates both reward and stress pathways, two key drivers of substance use behaviors. Previous investigations support a connection between the ghrelin system and alcohol, stimulants, and tobacco use in both animals and humans, while the research on opioids and cannabis is scarce. In general, upregulation of the ghrelin system seems to enhance craving for drugs as well as substances use. On the other hand, acute and chronic exposure to drugs of abuse influences the ghrelin system at different levels. This chapter summarizes the literature on the relationship between the ghrelin system and substance-related behaviors. We also review recent work investigating the ghrelin system as a potential pharmacological target for treating substance use disorders and discuss the need for additional research.

Development, Prevention, and Treatment of Alcohol-Induced Organ Injury: The Role of Nutrition.

Alcohol and nutrition have the potential to interact at multiple levels. For example, heavy alcohol consumption can interfere with normal nutrition, resulting in overall malnutrition or in deficiencies of important micronutrients, such as zinc, by reducing their absorption or increasing their loss. Interactions between alcohol consumption and nutrition also can affect epigenetic regulation of gene expression by influencing multiple regulatory mechanisms, including methylation and acetylation of histone proteins and DNA. These effects may contribute to alcohol-related organ or tissue injury. The impact of alcohol-nutrition interactions has been assessed for several organs and tissues, including the intestine, where heavy alcohol use can increase intestinal permeability, and the liver, where the degree of malnutrition can be associated with the severity of liver injury and liver disease. Alcohol-nutrition interactions also play a role in alcohol-related lung injury, brain injury, and immune dysfunction. Therefore, treatment involving nutrient supplementation (e.g., with zinc or S-adenosylmethionine) may help prevent or attenuate some types of alcohol-induced organ damage.

Long-term alcohol exposure elicits hippocampal nonsynaptic epileptiform activity changes associated with expression and functional changes in NKCC1, KCC2 co-transporters and Na+/K+-ATPase.

Nonsynaptic mechanism changes, particularly the enhancement of NKCC1 expression in the dentate gyrus (DG) after 4weeks of ethanol consumption, motivate the present work, in which rats were submitted to a period of chronic consumption (12weeks). Four groups of six animals (6-week-old male Wistar rats) were formed, including the control (C), ethanol 1 (E1), ethanol 2 (E2) and ethanol 3 (E3) groups. The rats in the E1, E2 and E3 groups were treated daily with a 30% v/v solution of ethanol, administered via oral gavage (1.0, 2.0 and 3.0g/kg, respectively). Nonsynaptic epileptiform activities (NEA) were induced by means of the zero-Ca2+ and high-K+ model using hippocampal slices and were recorded in the DG. The presence of NKCC1, KCC2, α1-Na+/K+-ATPase and GFAP immunoreactivity was analyzed. The results demonstrate that alcohol consumption changes NEA, and these changes are more prominent at the lower dosage. An increase in the DC shifts associated with epileptiform discharges was present with the low dose. This increase was correlated with the increment of NKCC1 expression. Confocal microscopy images indicate the NKCC1 increase was pronounced in the initial axonal segment of granule cells. The blockage of these cotransporters during NEA induction with bumetanide suppressed the DC shift increase and diminished all parameters of NEA that were quantified for all groups treated with ethanol. Therefore, the increase in NKCC1 expression and the effective activity of this cotransporter, which were observed in the treated groups, suggest that drugs that act for block NKCC1 represent promising strategies for diminishing the effects of alcohol damage on the brain.

Guardian of Genetic Messenger-RNA-Binding Proteins.

RNA in cells is always associated with RNA-binding proteins that regulate all aspects of RNA metabolism including RNA splicing, export from the nucleus, RNA localization, mRNA turn-over as well as translation. Given their diverse functions, cells express a variety of RNA-binding proteins, which play important roles in the pathologies of a number of diseases. In this review we focus on the effect of alcohol on different RNA-binding proteins and their possible contribution to alcohol-related disorders, and discuss the role of these proteins in the development of neurological diseases and cancer. We further discuss the conventional methods and newer techniques that are employed to identify RNA-binding proteins.

Alveolar macrophage inflammatory mediator expression is elevated in the setting of alcohol use disorders.

Alcohol use disorders (AUDs) are associated with increased susceptibility to pulmonary diseases, including bacterial pneumonia and acute respiratory distress syndrome (ARDS). Alveolar macrophages (AMs) play a vital role in the clearance of pathogens and regulation of inflammation, but these functions may be impaired in the setting of alcohol exposure. We examined the effect of AUDs on profiles of cytokines, chemokines, and growth factors in human AMs isolated from bronchoalveolar lavage (BAL) samples from 19 AUD subjects and 20 age-, sex-, and smoking-matched control subjects. By multiplex bead array, the lysates of AMs from subjects with AUDs had significant elevation in the cytokine tumor necrosis factor α (TNF-α), as well as chemokine (C-X-C motif) ligand 8 (CXCL8), CXCL10, and chemokine (C-C motif) ligand 5 (CCL5) (p < 0.05). Additionally, a 1.8-fold increase in IL-1ß, 2.0-fold increase in IL-6, 2.3-fold increase in interferon gamma (IFN-γ), 1.4-fold increase in CCL3, and a 2.3-fold increase in CCL4 was observed in the AUD group as compared to the control group. We also observed compensatory increases in the anti-inflammatory cytokine IL-1RA (p < 0.05). AUD subjects had 5-fold higher levels of CXCL11 mRNA expression (p < 0.05) and a 2.4-fold increase in IL-6 mRNA expression by RT-PCR as well. In these investigations, alcohol use disorders were associated with functional changes in human AMs, suggesting that chronic alcohol exposure portends a chronically pro-inflammatory profile in these cells.

Critical needs in drug discovery for cessation of alcohol and nicotine polysubstance abuse.

Polysubstance abuse of alcohol and nicotine has been overlooked in our understanding of the neurobiology of addiction and especially in the development of novel therapeutics for its treatment. Estimates show that as many as 92% of people with alcohol use disorders also smoke tobacco. The health risks associated with both excessive alcohol consumption and tobacco smoking create an urgent biomedical need for the discovery of effective cessation treatments, as opposed to current approaches that attempt to independently treat each abused agent. The lack of treatment approaches for alcohol and nicotine abuse/dependence mirrors a similar lack of research in the neurobiology of polysubstance abuse. This review discusses three critical needs in medications development for alcohol and nicotine co-abuse: (1) the need for a better understanding of the clinical condition (i.e. alcohol and nicotine polysubstance abuse), (2) the need to better understand how these drugs interact in order to identify new targets for therapeutic development and (3) the need for animal models that better mimic this human condition. Current and emerging treatments available for the cessation of each drug and their mechanisms of action are discussed within this context followed by what is known about the pharmacological interactions of alcohol and nicotine. Much has been and will continue to be gained from studying comorbid alcohol and nicotine exposure.

[Alcohol use disorders in elderly people calls for treatment]. / Ældres alkoholproblemer kræver behandling.

The complications related to use of alcohol occur at lower levels of alcohol use in the elderly. Alcohol use disorders (AUD) in the elderly are underestimated and often incorrectly diagnosed. However, evidence indicates that elderly are as likely to benefit from treatment as younger. Screening using Alcohol Use Disorders Identification Test seems to be accurate in identifying AUD among elderly, if the cut-off point is tailored for this age group. The recommended treatment strategy is naltrexone and brief approaches such as motivational interview and supportive consultation in general practice.

TLR2 and TLR4 Expression and Inflammatory Cytokines are Altered in the Airway Epithelium of Those with Alcohol Use Disorders.

BACKGROUND: The lung has a highly regulated system of innate immunity to protect itself from inhaled microbes and toxins. The first line of defense is mucociliary clearance, but if invaders overcome this, inflammatory pathways are activated. Toll-like receptors (TLRs) are expressed on the airway epithelium. Their signaling initiates the inflammatory cascade and leads to production of inflammatory cytokines such as interleukin (IL)-6 and IL-8. We hypothesized that airway epithelial insults, including heavy alcohol intake or smoking, would alter the expression of TLRs on the airway epithelium. METHODS: Bronchoscopy with bronchoalveolar lavage and brushings of the airway epithelium was performed in otherwise healthy subjects who had normal chest radiographs and spirometry. A history of alcohol use disorders (AUDs) was ascertained using the Alcohol Use Disorders Identification Test (AUDIT), and a history of cigarette smoking was also obtained. Age, gender, and nutritional status in all groups were similar. We used real-time polymerase chain reaction (PCR) to quantitate TLR1 to 9 and enzyme-linked immune assay to measure tumor necrosis factor-α, IL-6, and IL-8. RESULTS: Airway brushings were obtained from 26 nonsmoking/non-AUD subjects, 28 smoking/non-AUD subjects, 36 smoking/AUD subjects, and 17 nonsmoking/AUD subjects. We found that TLR2 is up-regulated in AUD subjects, compared to nonsmoking/non-AUD subjects, and correlated with their AUDIT scores. We also measured a decrease in TLR4 expression in AUD subjects that correlated with AUDIT score. IL-6 and IL-8 were also increased in bronchial washings from AUD subjects. CONCLUSIONS: We have previously demonstrated in normal human bronchial epithelial cells that in vitro alcohol exposure up-regulates TLR2 through a NO/cGMP/PKG-dependent pathway, resulting in up-regulation of inflammatory cytokine production after Gram-positive bacterial product stimulation. Our current translational study confirms that TLR2 is also up-regulated in humans with AUDs.

[Changes in the pattern of substance use after bariatric surgery: report of one case]. / Cambio en el patrón de consumo de sustancias posterior a cirugía bariátrica: presentación de un caso clínico.

Even though the benefits of bariatric surgery are supported by scientific evidence, its indications and contraindications must be revised to avoid its indiscriminate use. Substance use is more common in patients subjected to bariatric surgery than in the general population. After surgery, an increase in alcohol abuse has been reported. We report a 41 years old male, with morbid obesity, alcohol and cocaine use. After bariatric surgery, his alcohol tolerance significantly decreased, increasing the doses of cocaine and starting to consume it without alcohol. His high anxiety level and paranoid delusions, motivated him to seek help in a rehabilitation center where a Substance Dependence Disorder was diagnosed and received initial treatment. The cause of this adverse effect needs further research. Functional and anatomic changes in the digestive tract lead to a greater alcohol absorption and reduced alcohol dehydrogenase activity. Also neurochemical alterations may produce a displacement from compulsive use of food to compulsive use of addictive substances.

Inhibition of protein phosphatase 1 reverses alcohol-induced ciliary dysfunction.

Airway mucociliary clearance is a first-line defense of the lung against inhaled particles and debris. Among individuals with alcohol use disorders, there is an increase in lung diseases. We previously identified that prolonged alcohol exposure impairs mucociliary clearance, known as alcohol-induced ciliary dysfunction (AICD). Cilia-localized enzymes, known as the ciliary metabolon, are key to the pathogenesis of AICD. In AICD, cyclic nucleotide-dependent ciliary kinases, which modulate phosphorylation to regulate cilia beat, are desensitized. We hypothesized that alcohol activates cilia-associated protein phosphatase 1 (PP1) activity, driving phosphorylation changes of cilia motility regulatory proteins. To test this hypothesis we identified the effects of prolonged alcohol exposure on phosphatase activity, cilia beat, and kinase responsiveness and cilia-associated phosphorylation targets when stimulated by ß-agonist or cAMP. Prolonged alcohol activated PP1 and blocked cAMP-dependent cilia beat and protein kinase A (PKA) responsiveness and phosphorylation of a 29-kDa substrate of PKA. Importantly, prolonged alcohol-induced phosphatase activation was inhibited by the PP1 specific inhibitor, inhibitor-2 (I-2), restoring cAMP-stimulated cilia beat and PKA responsiveness and phosphorylation of the 29-kDa substrate. The I-2 inhibitory effect persisted in tissue, cell, and isolated cilia-organelle models, highlighting the association of ciliary metabolon-localized enzymes to AICD. Prolonged alcohol exposure drives ciliary metabolon-localized PP1 activation. PP1 activation modifies phosphorylation of a 29-kDa protein related to PKA activity. These data reinforce our previous findings that alcohol is acting at the level of the ciliary metabolon to cause ciliary dysfunction and identifies PP1 as a therapeutic target to prevent or reverse AICD.

Brain proton magnetic resonance spectroscopy of alcohol use disorders.

This chapter critically reviews brain proton magnetic resonance spectroscopy ((1)H MRS) studies performed since 1994 in individuals with alcohol use disorders (AUD). We describe the neurochemicals that can be measured in vivo at the most common magnetic field strengths, summarize our knowledge about their general brain functions, and briefly explain some basic human (1)H MRS methods. Both cross-sectional and longitudinal research of individuals in treatment and of treatment-naïve individuals with AUD are discussed and interpreted on the basis of reported neuropathology. As AUDs are highly comorbid with chronic cigarette smoking and illicit substance abuse, we also summarize reports on their respective influences on regional proton metabolite levels. After reviewing research on neurobiologic correlates of relapse and genetic influences on brain metabolite levels, we finish with suggestions on future directions for (1)H MRS studies in AUDs. The review demonstrates that brain metabolic alterations associated with AUDs as well as their cognitive correlates are not simply a consequence of chronic alcohol consumption. Future MR research of AUDs in general has to be better prepared - and supported - to study clinically complex relationships between personality characteristics, comorbidities, neurogenetics, lifestyle, and living environment, as all these factors critically affect an individual's neurometabolic profile. (1)H MRS is uniquely positioned to tackle these complexities by contributing to a comprehensive biopsychosocial profile of individuals with AUD: it can provide non-invasive biochemical information on select regions of the brain at comparatively low overall cost for the ultimate purpose of informing more efficient treatments of AUDs.

[Alcohol use disorders in elderly people calls for treatment].

The complications related to use of alcohol occur at lower levels of alcohol use in the elderly. Alcohol use disorders (AUD) in the elderly are underestimated and often incorrectly diagnosed. However, evidence indicates that elderly are as likely to benefit from treatment as younger. Screening using Alcohol Use Disorders Identification Test seems to be accurate in identifying AUD among elderly, if the cut-off point is tailored for this age group. The recommended treatment strategy is naltrexone and brief approaches such as motivational interview and supportive consultation in general practice.

The impact of alcohol and tobacco use on in vivo glutathione in youth with bipolar disorder: an exploratory study.

Risky alcohol consumption and tobacco smoking is highly prevalent in bipolar disorder (BD) and is associated with increased formation of neural reactive oxygen species. Proton magnetic resonance spectroscopy ((1)H-MRS) is an in vivo imaging modality that allows quantification of glutathione (GSH) concentration, the brains primary antioxidant. Sixty-four patients with BD and 49 controls (18-30 years) completed self-report questionnaires regarding alcohol and tobacco use and underwent (1)H-MRS. Levels of GSH in the hippocampus and anterior cingulate cortex (ACC) were determined. Within-group Pearson's correlations were used to explore the relationship between alcohol use and GSH concentration for BD and controls, covarying for age, gender, family history of alcohol dependence and smoking status. Relationships between GSH and presence/severity of alcohol-induced blackouts were determined using Spearman's correlations. In BD, reduced hippocampal-GSH associated with higher alcohol use (R = -0.489, p < 0.021). Reduction of ACC-GSH with increased drinking was non-significant when controlling for tobacco use. Independent samples t-test revealed a significantly decreased ACC-GSH in smokers with BD (t (53) = 4.162, p < 0.001). In controls, alcohol use was not correlated to GSH in either region. In both patients and controls, reduced hippocampal-GSH was associated with blackout presence/severity, supporting a role for the hippocampus in the continuum of alcohol-induced memory impairments. Our preliminary findings suggest that in youth with BD reduced hippocampal-GSH is associated with risky alcohol use and alcohol and tobacco use is associated with reduced ACC-GSH, highlighting the role of these substances as modifiable risk factors for decreased anti-oxidant capacity in BD.

GDNF is a novel ethanol-responsive gene in the VTA: implications for the development and persistence of excessive drinking.

Glial cell line-derived neurotrophic factor (GDNF) is a potent inhibitor of ethanol consumption and relapse, and GDNF heterozygous knockout mice display increased reward sensitivity to ethanol and consume more ethanol after a period of abstinence than their wild-type littermates. Here, we tested whether ethanol alters GDNF expression in the ventral tegmental area (VTA; GDNF's site of action) and/or the nucleus accumbens (NAc; the main source of GDNF), and if so, determine the role of the endogenous growth factor in the regulation of ethanol consumption. Systemic administration of ethanol increased GDNF expression and protein levels in the VTA, but not the NAc. Additionally, GDNF levels were elevated after an ethanol-drinking session in rats that consumed ethanol in the intermittent-access two-bottle choice procedure for 1 week, but not 7 weeks. Deprivation following 7 weeks of excessive ethanol intake reduced GDNF levels, while a short ethanol binge drinking period following deprivation upregulated GDNF expression. Importantly, knockdown of GDNF within the VTA using adenovirus expressing short hairpin RNA facilitated the escalation of ethanol drinking by ethanol-naïve rats, but not by rats with a history of excessive ethanol consumption. These results suggest that during initial ethanol-drinking experiences, GDNF in the VTA is increased and protects against the development of excessive ethanol intake. However, the growth factor's protective response to ethanol breaks down after protracted excessive ethanol intake and withdrawal, resulting in persistent, excessive ethanol consumption.

Adenosine signaling in striatal circuits and alcohol use disorders.

Adenosine signaling has been implicated in the pathophysiology of alcohol use disorders and other psychiatric disorders such as anxiety and depression. Numerous studies have indicated a role for A1 receptors (A1R) in acute ethanol-induced motor incoordination, while A2A receptors (A2AR) mainly regulate the rewarding effect of ethanol in mice. Recent findings have demonstrated that dampened A2AR-mediated signaling in the dorsomedial striatum (DMS) promotes ethanol-seeking behaviors. Moreover, decreased A2AR function is associated with decreased CREB activity in the DMS, which enhances goal-oriented behaviors and contributes to excessive ethanol drinking in mice. Interestingly, caffeine, the most commonly used psychoactive substance, is known to inhibit both the A1R and A2AR. This dampened adenosine receptor function may mask some of the acute intoxicating effects of ethanol. Furthermore, based on the fact that A2AR activity plays a role in goal-directed behavior, caffeine may also promote ethanol-seeking behavior. The A2AR is enriched in the striatum and exclusively expressed in striatopallidal neurons, which may be responsible for the regulation of inhibitory behavioral control over drug rewarding processes through the indirect pathway of the basal ganglia circuit. Furthermore, the antagonistic interactions between adenosine and dopamine receptors in the striatum also play an integral role in alcoholism and addiction-related disorders. This review focuses on regulation of adenosine signaling in striatal circuits and the possible implication of caffeine in goal-directed behaviors and addiction.