Brain Reward Mechanisms Research Articles

Aerobic Exercise and Endocannabinoids: A Narrative Review of Stress Regulation and Brain Reward Systems.

Aerobic exercise is a widely adopted practice, not solely for enhancing fitness and reducing the risk of various diseases but also for its ability to uplift mood and aid in addressing depression and anxiety disorders. Within the scope of this narrative review, we seek to consolidate current insights into the endocannabinoid-mediated regulation of stress and the brain's reward mechanism resulting from engaging in aerobic exercise. A comprehensive search was conducted across Medline, SPORTDiscus, Pubmed, and Scopus, encompassing data available until November 30, 2023. This review indicates that a bout of aerobic exercise, particularly of moderate intensity, markedly augments circulating levels of endocannabinoids-N-arachidonoyl-ethanolamine (AEA) and 2-acylglycerol (2-AG), that significantly contributes to mood elevation and reducing stress in healthy individuals. The current understanding of how aerobic exercise impacts mental health and mood improvement is still unclear. Moderate and high-intensity aerobic exercise modulatesstress through a negative feedback mechanism targeting both the hypothalamus-pituitary-adrenal (HPA) axis and the sympathetic nervous system, thereby facilitating stress regulation crucial role in endocannabinoid synthesis, ultimately culminating in the orchestration of negative feedback across multiple tiers of the HPA axis, coupled with its influence over cortical and subcortical brain structures. The endocannabinoid has been observed to govern the release of neurotransmitters from diverse neuronal populations, implying a universal mechanism that fine-tunes neuronal activity and consequently modulates both emotional and stress-related responses. Endocannabinoids further assume a pivotal function within brain reward mechanisms, primarily mediated by CB1 receptors distributed across diverse cerebral centers. Notably, these endocannabinoids partake in natural reward processes, as exemplified in aerobic exercise, by synergizing with the dopaminergic reward system. The genesis of this reward pathway can be traced to the ventral tegmental area, with dopamine neurons predominantly projecting to the nucleus accumbens, thereby inciting dopamine release in response to rewarding stimuli.

Playing With Objects Engages Brain Reward System and Counteracts Stress-Induced Depressive-like Behavior

This commentary discusses brain reward mechanisms, which are notoriously centered on the mesoaccumbens system, dopamine (DA) transmission, and behavioral correlates of chronic or repeated exposures to stress, such as depressive-like, or more appropriately, coping behaviors.

Morphine Exposure Reduces Nicotine-Induced Upregulation of Nicotinic Receptors and Decreases Volitional Nicotine Intake in a Mouse Model.

IntroductionNicotine addiction remains a primary health concern as tobacco smoking remains the number one cause of preventable death in America. At the same time, America is still facing the threat of the opioid epidemic. While the prevalence of smoking combustible cigarettes or electronic nicotine delivery systems in the United States varies between 12% and 35%, the smoking rates among the opioid use dependent (OUD) population is 74%–97%. We examined changes in brain reward mechanisms in which co-use of nicotine and opioids may result in enhanced reward and reinforcement.Aims and MethodsAdult male and female α4-mCherryα6-GFP mice (C57BL/6J) were used in conditioned place preference (CPP) and microscopy assays to examine reward-related behavior and nicotinic acetylcholine receptor (nAChR) upregulation following treatments with saline, nicotine, morphine, or nicotine plus morphine. Following this, separate mice were trained in e-Vape self-administration assays to examine morphine’s impact on nicotine reinforcement.ResultsWe observed that nicotine and morphine coexposure in a CPP assay did not produce enhanced reward-related behavior when compared with nicotine or morphine alone. In parallel we observed coexposure reduced nicotine-induced upregulation of nAChRs on ventral tegmental area dopamine and GABA neurons. Additionally, we observed that concurrent morphine exposure reduced nicotine (plus menthol) vapor self-administration in male and female mice.ConclusionsWhile nicotine use is high among OUD individuals, our CPP assays suggest coexposure not only fails to enhance reward-related behavior but also reduces nicotine-induced changes in ventral tegmental area neurobiology. Our self-administration assays suggest that morphine exposure during nicotine acquisition reduces nicotine reinforcement-related behavior.ImplicationsWhile some may postulate that the co-use of opioids and nicotine may be driven by reward-related mechanisms, our data indicate that opioid exposure may hinder nicotine intake due to reduced upregulation of nAChRs critical for nicotine reward and reinforcement. Thus, the high co-use in OUD individuals may be a result of other mechanisms and this warrants further investigations into nicotine and opioid co-use.

Brain Site-Specific Inhibitory Effects of the GLP-1 Analogue Exendin-4 on Alcohol Intake and Operant Responding for Palatable Food.

Approximately 14.4 million Americans are experiencing alcohol use disorder (AUD) and about two-thirds of people who experience drug addiction will relapse, highlighting the need to develop novel and effective treatments. Glucagon-like peptide-1 (GLP-1) is a peptide hormone implicated in the mesocorticolimbic reward system and has become a peptide of interest with respect to its putative inhibitory effects on drug reward. In order to further develop treatments for those diagnosed with AUD, the interplay between GLP-1 receptor signaling and ethanol consumption must be elucidated. In the present study, we investigated the ability of the GLP-1 analogue, exendin-4 (Ex-4), to alter alcohol intake and operant responding for sucrose pellets in order to further understand the role of this compound in mediating reward. We selected multiple sites throughout the prosencephalic and mesencephalic regions of the brain, where we directly administered various doses of Ex-4 to male Sprague Dawley rats. In alcohol investigations, we utilized a two-bottle choice intermittent access protocol. In separate groups of rats, we adopted an operant paradigm in order to examine the effect of Ex-4 on motivated responding for palatable food. Results indicated that GLP-1 receptor signaling effectively suppressed voluntary alcohol intake when injected into the ventral tegmental area (VTA), the accumbens core (NAcC) and shell (NAcS), the dorsomedial hippocampus (DMHipp), and the lateral hypothalamus (LH), which are all structures linked to brain reward mechanisms. The arcuate nucleus (ARcN) and the paraventricular nucleus (PVN) of the hypothalamus were unresponsive, as was the basolateral amygdala (BLA). However, Ex-4 treatment into the ArcN and PVN suppressed operant responding for sucrose pellets. In fact, the VTA, NAcC, NAcS, LH, and the DMHipp all showed comparable suppression of sucrose responding. Overall, our findings suggest that these central structures are implicated in brain reward circuitry, including alcohol and appetitive motivation, which may be mediated by GLP-1 receptor mechanisms. GLP-1, therefore, may play a critical role in modifying addictive behaviors via activation of multiple GLP-1 systems throughout the brain.

Leptin levels and its correlation with crack-cocaine use severity: A preliminary study

BackgroundCrack-cocaine is an important public health problem in Brazil and worldwide. It is a potent form of cocaine which results in rapid and damaging stimulating effects on the central nervous system through inhibition of the dopamine transporter. Some studies have suggested that both food and drugs – including crack, can act on the same brain reward mechanisms, altering the dopamine pathways that modulate behavioral responses. Our hypothesis was that leptin, a well-known peptide that modulates energy metabolism and appetite, can be used as a biomarker for drug use. MethodsAnthropometric data, drug use profiles, and leptin serum levels were evaluated in a cross-sectional study of 40 crack-cocaine users. ResultsLeptin showed an inverse correlation with the severity of crack use, and this correlation remained when corrected by body mass index (BMI) and body composition by bioimpedance (BIA). The majority of subjects were eutrophic or overweight/obese considering BMI and BIA, and these variables were not significantly associated with the severity of crack use, but positively correlated with leptin levels. ConclusionsOur preliminary findings suggest that leptin could be involved in drug use severity, perhaps through pathways similar to those whereby it modulates food intake. Considering the anthropometric parameters, these findings provide additional evidence that low weight is not predominant in crack users.

The epidemiology and genetics of binge eating disorder (BED).

This narrative review provides an overview of the epidemiology of binge eating disorder (BED), highlighting the medical history of this disorder and its entry as an independent condition in the Feeding and Eating Disorders section of the recently published Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Estimates of prevalence are provided, as well as recognition that the female to male ratio is lower in BED than in other eating disorders. Evidence is also provided of the most common comorbidities of BED, including mood and anxiety disorders and a range of addiction disorders. In addition, discussion of the viewpoint that BED itself may be an addiction - at least in severe cases - is presented. Although the genetic study of BED is still in its infancy, current research is reviewed with a focus on certain neurotransmitter genes that regulate brain reward mechanisms. To date, a focal point of this research has been on the dopamine and the μ-opioid receptor genes. Preliminary evidence suggests that a predisposing risk factor for BED may be a heightened sensitivity to reward, which could manifest as a strong dopamine signal in the brain's striatal region. Caution is encouraged, however, in the interpretation of current findings, since samples are relatively small in much of the research. To date, no genome-wide association studies have focused exclusively on BED.

Differences in bingeing behavior and cocaine reward following intermittent access to sucrose, glucose or fructose solutions

Daily intermittent access to sugar solutions results in intense bouts of sugar intake (i.e. bingeing) in rats. Bingeing on sucrose, a disaccharide of glucose and fructose, has been associated with a “primed” mesolimbic dopamine (DA) pathway. Recent studies suggest glucose and fructose engage brain reward and energy-sensing mechanisms in opposing ways and may drive sucrose intake through unique neuronal circuits. Here, we examined in male Sprague–Dawley rats whether or not (1) intermittent access to isocaloric solutions of sucrose, glucose or fructose results in distinctive sugar-bingeing profiles and (2) previous sugar bingeing alters cocaine locomotor activation and/or reward, as determined by conditioned place preference (CPP). To encourage bingeing, rats were given 24-h access to water and 12-h-intermittent access to chow plus an intermittent bottle that contained water (control) or 8% solutions of sucrose, glucose or fructose for 9days, followed by ad libitum chow diet and a 10-day cocaine (15mg/kg; i.p.) CPP paradigm. By day 4 of the sugar-bingeing diet, sugar bingeing in the fructose group surpassed the glucose group, with the sucrose group being intermediate. All three sugar groups had similar chow and water intake throughout the diet. In contrast, controls exhibited chow bingeing by day 5 without altering water intake. Similar magnitudes of cocaine CPP were observed in rats with a history of sucrose, fructose or chow (control) bingeing. Notably, the glucose-bingeing rats did not demonstrate a significant cocaine CPP despite showing similar cocaine-induced locomotor activity as the other diet groups. Overall, these results show that fructose and glucose, the monosaccharide components of sucrose, produce divergent degrees of bingeing and cocaine reward.

Cannabinoid Regulation of Brain Reward Processing with an Emphasis on the Role of CB1 Receptors: A Step Back into the Future.

Over the last decades, the endocannabinoid system has been implicated in a large variety of functions, including a crucial modulation of brain-reward circuits and the regulation of motivational processes. Importantly, behavioral studies have shown that cannabinoid compounds activate brain reward mechanisms and circuits in a similar manner to other drugs of abuse, such as nicotine, alcohol, cocaine, and heroin, although the conditions under which cannabinoids exert their rewarding effects may be more limited. Furthermore, there is evidence on the involvement of the endocannabinoid system in the regulation of cue- and drug-induced relapsing phenomena in animal models. The aim of this review is to briefly present the available data obtained using diverse behavioral experimental approaches in experimental animals, namely, the intracranial self-stimulation paradigm, the self-administration procedure, the conditioned place preference procedure, and the reinstatement of drug-seeking behavior procedure, to provide a comprehensive picture of the current status of what is known about the endocannabinoid system mechanisms that underlie modification of brain-reward processes. Emphasis is placed on the effects of cannabinoid 1 (CB1) receptor agonists, antagonists, and endocannabinoid modulators. Further, the role of CB1 receptors in reward processes is investigated through presentation of respective genetic ablation studies in mice. The vast majority of studies in the existing literature suggest that the endocannabinoid system plays a major role in modulating motivation and reward processes. However, much remains to be done before we fully understand these interactions. Further research in the future will shed more light on these processes and, thus, could lead to the development of potential pharmacotherapies designed to treat reward-dysfunction-related disorders.

Curcumin, demethoxycurcumin and bisdemethoxycurcumin differentially inhibit morphine's rewarding effect in rats.

Recent animal studies reported that curcumin, the active constituent of Curcuma longa, has several central actions and may attenuate morphine tolerance. In the present study, we utilized the intracranial self-stimulation (ICSS) paradigm to examine the effects of the commercially available curcuminoid mixture and each one of its components, individually, on brain stimulation reward and on the reward-facilitating effect of morphine. Male Sprague-Dawley rats were implanted with an electrode into the medial forebrain bundle and trained to respond for electrical stimulation using a rate-frequency paradigm. In the first study, rats were injected with graded doses either of the curcuminoid mixture, or curcumin I, or II, or III. In the second study, we examined whether a low dose of the curcuminoid mixture or each individual curcumin analogue composing it could counteract the reward-facilitating effect of morphine. At low doses, both the curcuminoid mixture and curcumin I did not affect brain stimulation reward, whereas, higher doses increased ICSS thresholds. Curcumin II and curcumin III did not affect brain stimulation reward at any doses. Subthreshold doses of the curcuminoid mixture and curcumin I inhibited the reward-facilitating effect of morphine. Both the curcuminoid mixture and curcumin I lack hedonic properties and moderate the reward-facilitating effect of morphine. Our data suggest that curcumin interferes with brain reward mechanisms responsible for the expression of the acute reinforcing properties of opioids and provide evidence that curcumin may be a promising adjuvant for attenuating morphine's rewarding effects in patients who are under long-term opioid therapy.

Music Biology: All This Useful Beauty

Some healthy people fail to derive pleasure from music despite otherwise preserved perceptual and reward responses. Such 'musical anhedonia' implies the existence of music-specific brain reward mechanisms, which could provide a substrate for music to acquire biological value.

The endocannabinoid system and its possible role in neurobiology of psychiatric disorders

In the last years, numerous researches led to identify endocannabinoid system, a sophisticated short-range signaling system which is located both in Central Nervous System (CNS) and in whole organism. Because of its flexibility of expression, it plays a modulatory role in controlling the answers to stimuli which disturb homeostasis. On one hand it lets them occur whilst on the other it limits them in order to protect organism from consequences due to excessive reaction. In the CNS, endocannabinoid system is able to control the release of several neurotransmitters thanks to its retrograde signaling, modulating synaptic activity. Analysing this property during preclinical studies, it came out that the endocannabinoid system is involved in numerous physiologic processes, such as neuroendocrine axes, food consumption, brain reward and satisfaction mechanisms, memories storing and extinction, emotions and neurodevelopment regulation. Such discoveries have led researchers to suppose and investigate an alteration of this system in the physiopathology of some psychiatric disorders such as anxiety disorder, depression, eating disorders, addiction and schizophrenia. Results of such studies on animal models show a possible involvement of this system and were quickly followed by clinical studies which seem to confirm it. These findings might open new scenarios for understanding the pathogenesis of several psychiatric disorders and, at same time, they show new prospects for their treatment.

Substance Use and Brain Reward Mechanisms in Older Adults

Substance use among older adults is on the rise, with statistics indicating this to be a growing health problem. Brain changes in the reward center of the brain that naturally occur with aging are offered as one source of these statistics. Aging is generally associated with increased prevalence of chronic disease, disability, and death, and therefore a public health goal for older adults is to maintain health, independence, and function. Psychiatric-mental health nurses are uniquely positioned to assist older adults in achievement of these goals through health assessment and promotion. The use of client-centered counseling approaches that recognize the older adult's developmental need for autonomy and choice in decision making have been shown to be effective in increasing motivation in this adult population.

Advances in studying phasic dopamine signaling in brain reward mechanisms

The last sixty years of research has provided extraordinary advances of our knowledge of the reward system. Since its discovery as a neurotransmitter by Carlsson and colleagues (1), dopamine (DA) has emerged as an important mediator of reward processing. As a result, a number of electrochemical techniques have been developed to measure DA in the brain. Together, these techniques have begun to elucidate the complex roles of tonic and phasic DA signaling in reward processing and addiction. In this review, we will first provide a guide for the most commonly used electrochemical methods for DA detection and describe their utility in furthering our knowledge about DA's role in reward and addiction. Second, we will review the value of common in vitro and in vivo preparations and describe their ability to address different types of questions. Last, we will review recent data that has provided new mechanistic insight of in vivo phasic DA signaling and its role in reward processing and reward-mediated behavior.

A Narrative Review of Binge Eating and Addictive Behaviors: Shared Associations with Seasonality and Personality Factors

Binge-eating disorder and seasonal affective disorder were first described as clinically relevant conditions in very close temporal proximity a few decades ago. Both disorders have a higher prevalence rate in woman than in men, are characterized by a high proneness-to-stress and manifest heightened responsiveness to high-calorie, hyper-palatable foods. In recent years, a compelling body of evidence suggests that foods high in sugar and fat have the potential to alter brain reward circuitry in a manner similar to that seen when addictive drugs like alcohol and heroin are consumed in excess. These findings have led to suggestions that some cases of compulsive overeating may be understood as an addiction to sweet, fatty, and salty foods. In this paper, it is proposed that high seasonality is a risk factor for binge eating, especially in those characterized by anxious and impulsive personality traits – associations that could only occur in an environment with a superfluity of, and easy access to, rich and tasty foods. Given the well-established links between binge eating and addiction disorders [Ref. (1–3) for reviews], it is also suggested that seasonality, together with the same high-risk psychological profile, exacerbates the likelihood of engaging in a broad range of addictive behaviors. Data from a community sample (n = 412) of adults tested these models using linear regression procedures. Results confirmed that symptoms of binge eating and other addictive behaviors were significantly inter-correlated, and that seasonality, gender, and addictive personality traits were strong statistical predictors of the variance in binge-eating scores. Seasonality and addictive personality traits also accounted for a significant proportion of the variance in the measure of addictive behaviors. Conclusions are discussed in the context of brain reward mechanisms, motivational alternations in response to chronic over-consumption, and their relevance for the treatment of excessive appetitive behaviors.

Cannabidiol inhibits the reward‐facilitating effect of morphine: involvement of 5‐HT1A receptors in the dorsal raphe nucleus

Cannabidiol is a non-psychotomimetic constituent of Cannabis sativa, which induces central effects in rodents. It has been shown that cannabidiol attenuates cue-induced reinstatement of heroin seeking. However, to the best of our knowledge, its effects on brain stimulation reward and the reward-facilitating effects of drugs of abuse have not yet been examined. Therefore, we investigated the effects of cannabidiol on brain reward function and on the reward-facilitating effect of morphine and cocaine using the intracranial self-stimulation (ICSS) paradigm. Rats were prepared with a stimulating electrode into the medial forebrain bundle (MFB), and a guide cannula into the dorsal raphe (microinjection experiments), and were trained to respond for electrical brain stimulation. A low dose of cannabidiol did not affect the reinforcing efficacy of brain stimulation, whereas higher doses significantly elevated the threshold frequency required for MFB ICSS. Both cocaine and morphine lowered ICSS thresholds. Cannabidiol inhibited the reward-facilitating effect of morphine, but not cocaine. This effect was reversed by pre-treatment with an intra-dorsal raphe injection of the selective 5-HT1A receptor antagonist WAY-100635. The present findings indicate that cannabidiol does not exhibit reinforcing properties in the ICSS paradigm at any of the doses tested, while it decreases the reward-facilitating effects of morphine. These effects were mediated by activation of 5-HT1A receptors in the dorsal raphe. Our results suggest that cannabidiol interferes with brain reward mechanisms responsible for the expression of the acute reinforcing properties of opioids, thus indicating that cannabidiol may be clinically useful in attenuating the rewarding effects of opioids.

Beyond the Brain: The Role of Bullying in Adolescent Substance Abuse

Among the most important contributions to the understanding and treatment of addiction is the abandonment of the notion that substance abuse is a moral failing, a lifestyle choice, or character flaw, but instead has biological, hereditary contributions that predict its occurrence and course. Defining addiction as a chronic, relapsing brain disease characterized by compulsive drug seeking and use, despite negative consequences, has transformed the medical and psychological study of addiction since the 1930’s [1]. Indeed, scientists estimate that genetic factors account for approximately 40% to 60% of an individual’s vulnerability to addiction, including the role of the environment on gene expression and function [1]. Specifically, since abnormalities in the reward system of the brain (e.g. liking, wanting, and learning) are believed to play a role in numerous psychiatric disorders, including substance abuse, study of the functional neuroanatomy of reward has been seen as critically important in neuropsychiatry [2]. From a neurobiological perspective, addiction is a disorder of brain reward mechanisms (e.g. the dopamine pathway, among other neurotransmitters) that are critical for survival [2].

Food reward functions as affected by obesity and bariatric surgery

Roux-en-Y gastric bypass surgery (RYGB) remains to be the most effective long-term treatment for obesity and its associated comorbidities, but the specific mechanisms involved remain elusive. Because RYGB patients appear to no longer be preoccupied with thoughts about food and are satisfied with much smaller meals and calorically dilute foods, brain reward mechanisms could be involved. Just as obesity can produce maladaptive alterations in reward functions, reversal of obesity by RYGB could normalize these changes or even further reset the food reward system through changes in gut hormone secretion, aversive conditioning and/or secondary effects of weight loss. Future studies with longitudinal assessments of reward behaviors and their underlying neural circuits before and after surgery will be necessary to uncover the specific mechanisms involved. Such new insights could be the base for future 'knifeless' pharmacological and behavioral approaches to obesity.

Feeding and reward: Perspectives from three rat models of binge eating

Research has focused on understanding how overeating can affect brain reward mechanisms and subsequent behaviors, both preclinically and in clinical research settings. This work is partly driven by the need to uncover the etiology and possible treatments for the ongoing obesity epidemic. However, overeating, or non-homeostatic feeding behavior, can occur independent of obesity. Isolating the variable of overeating from the consequence of increased body weight is of great utility, as it is well known that increased body weight or obesity can impart its own deleterious effects on physiology, neural processes, and behavior. In this review, we present data from three selected animal models of normal-weight non-homeostatic feeding behavior that have been significantly influenced by Bart Hoebel's 40+-yr career studying motivation, feeding, reinforcement, and the neural mechanisms that participate in the regulation of these processes. First, a model of sugar bingeing is described (Avena/Hoebel), in which animals with repeated, intermittent access to a sugar solution develop behaviors and brain changes that are similar to the effects of some drugs of abuse, serving as the first animal model of food addiction. Second, another model is described (Boggiano) in which a history of dieting and stress can perpetuate further binge eating of palatable and non-palatable food. In addition, a model (Boggiano) is described that allows animals to be classified as having a binge-prone vs. binge-resistant behavioral profile. Lastly, a limited access model is described (Corwin) in which non-food deprived rats with sporadic limited access to a high-fat food develop binge-type behaviors. These models are considered within the context of their effects on brain reward systems, including dopamine, the opioids, cholinergic systems, serotonin, and GABA. Collectively, the data derived from the use of these models clearly show that behavioral and neuronal consequences of bingeing on a palatable food, even when at a normal body weight, are different from those that result from simply consuming the palatable food in a non-binge manner. These findings may be important in understanding how overeating can influence behavior and brain chemistry.

Dopamine for “Wanting” and Opioids for “Liking”: A Comparison of Obese Adults With and Without Binge Eating

Obesity research suffers from an overinclusion paradigm whereby all participants with a BMI beyond a certain cutoff value (e.g., 30) are typically combined in a single group and compared to those of normal weight. There has been little attempt to identify meaningful subgroups defined by their salient biobehavioral differences. In order to address this limitation, we examined genetic and psychological indicators of hedonic eating in obese adults with (n=66) and without (n=70) binge eating disorder (BED). Our analyses focused on dopamine (DA) and opioid genetic markers because of their conjoint association with the functioning of brain reward mechanisms. We targeted three functional polymorphisms related to the D2 receptor (DRD2) gene, as well as the functional A118G polymorphism of the mu-opioid receptor (OPRM1) gene. We found that significantly more obese controls had the "loss-of-function" A1 allele of Taq1A compared to their BED counterparts, whereas the "gain-of-function" G allele of A118G occurred with greater frequency in the BED group. A significant gene-gene combination chi2 analysis also indicated that of those participants with the gain-gain genotype (G+ and A1), 80% were in the BED group whereas only 35% with the loss-loss genotype (G- and A1+) were in this group. Finally, BED subjects had significantly higher scores on a self-report measure of hedonic eating. Our findings suggest that BED is a biologically based subtype of obesity and that the proneness to binge eating may be influenced by a hyper-reactivity to the hedonic properties of food--a predisposition that is easily exploited in our current environment with its highly visible and easily accessible surfeit of sweet and fatty foods.

Features of men with anabolic-androgenic steroid dependence: A comparison with nondependent AAS users and with AAS nonusers

Background Anabolic-androgenic steroid (AAS) dependence has been a recognized syndrome for some 20 years, but remains poorly understood. Methods We evaluated three groups of experienced male weightlifters: (1) men reporting no history of AAS use ( N = 72); (2) nondependent AAS users reporting no history of AAS dependence ( N = 42); and (3) men meeting adapted DSM-IV criteria for current or past AAS dependence ( N = 20). We assessed demographic indices, lifetime history of psychiatric disorders by the Structured Clinical Interview for DSM-IV, variables related to AAS use, and results from drug tests of urine and hair. Results Nondependent AAS users showed no significant differences from AAS nonusers on any variable assessed. Dependent AAS users, however, differed substantially from both other groups on many measures. Notably, they reported a more frequent history of conduct disorder than nondependent AAS users (odds ratio [95% CI]: 8.0 [1.7, 38.0]) or AAS nonusers (13.1 [2.8, 60.4]) and a much higher lifetime prevalence of opioid abuse and dependence than either comparison group (odds ratios 6.3 [1.2, 34.5] and 18.6 [3.0, 116.8], respectively). Conclusions Men with AAS dependence, unlike nondependent AAS users or AAS nonusers, showed a distinctive pattern of comorbid psychopathology, overlapping with that of individuals with other forms of substance dependence. AAS dependence showed a particularly strong association with opioid dependence – an observation that recalls recent animal data suggesting similarities in AAS and opioid brain reward mechanisms. Individuals with AAS dependence and individuals with “classical” substance dependence may possibly harbor similar underlying biological and neuropsychological vulnerabilities.