Differences In Addiction Vulnerability Research Articles

Sex Differences in Local Nucleus Accumbens Circuitry and Motivated Behavior

Drug addiction is a chronic, relapsing brain disease characterized by compulsive drug seeking, high levels of drug intake, and repeated cycles of abstinence and relapse. Historically, preclinical addiction research has focused almost entirely on male subjects; however, in humans, women take and use drugs in larger quantities, transition to addiction faster, and are more likely to relapse, thus representing a particularly vulnerable population. There are a variety of factors that could contribute to these sex differences – including estrous cycle dependent ovarian hormone fluctuations ‐ however the precise neural circuits and neurobiological mechanisms that underlie these differences in reward, motivation, and addiction vulnerability is largely unknown. The mesolimbic dopamine pathway, which connects the ventral tegmental area (VTA) to the nucleus accumbens (NAc), is an essential component of this process as it controls motivation and reward‐seeking behavior. To understand how these phenotypic differences in addiction vulnerability could be driven by estrous cycle‐dependent neurochemical mechanisms we took a multipronged approach to outlining sex‐differences in local circuit regulation of VTA dopamine terminals in the NAc. Using fast‐scan cyclic voltammetry (FSCV) paired with site‐specific pharmacology we measured subsecond dopamine kinetics in male and female mice in either diestrus (low circulating hormones) or estrus (high circulating hormones) and defined sex‐differences in local circuit regulation of dopamine release in the NAc. We found an enhanced dynamic range of calcium and presynaptic D2 autoreceptor control of dopamine release in females compared to males. During estrus, D2 autoreceptors were less effective at inhibiting dopamine release. Further, the relationship between calcium and dopamine release was enhanced in estrus. Finally, cholinergic regulation of dopamine signaling in the NAc was altered in a way that promotes and enhances dopamine release in estrus females. Together, these factors converge to increase the responsivity of dopamine terminals in the NAc to incoming stimuli and likely act to drive enhanced motivation and drug effects on this system. Moving forward it will be critical to directly link these sex‐differences to addiction vulnerability.Support or Funding InformationFunding was provided by startup funds from Vanderbilt University School of Medicine Department of Pharmacology (E.S.C, L.J.B.), as well as funding from the National Institutes of Health (NIH). Funds from the National Institute of Drug Abuse (NIDA) DA042111(E.S.C), National Institute of Mental Health (NIMH) MH065215 (A.R.J), the Brain and Behavior Research Foundation (to E.S.C), Whitehall Foundation (to E.S.C), Edward J Mallinckrodt Jr. Foundation (to E.S.C) also supported this work.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Temporally specific miRNA expression patterns in the dorsal and ventral striatum of addiction-prone rats.

MicroRNAs (miRNAs) within the ventral and dorsal striatum have been shown to regulate addiction-relevant behaviours. However, it is unclear how cocaine experience alone can alter the expression of addiction-relevant miRNAs within striatal subregions. Further, it is not known whether differential expression of miRNAs in the striatum contributes to individual differences in addiction vulnerability. We first examined the effect of cocaine self-administration on the expression of miR-101b, miR-137, miR-212 and miR-132 in nucleus accumbens core and nucleus accumbens shell (NAcSh), as well as dorsomedial striatum and dorsolateral striatum (DLS). We then examined the expression of these same miRNAs in striatal subregions of animals identified as being 'addiction-prone', either immediately following self-administration training or following extinction and relapse testing. Cocaine self-administration was associated with changes in miRNA expression in a regionally discrete manner within the striatum, with the most marked changes occurring in the nucleus accumbens core. When we examined the miRNA profile of addiction-prone rats following self-administration, we observed increased levels of miR-212 in the dorsomedial striatum. After extinction and relapse testing, addiction-prone rats showed significant increases in the expression of miR-101b, miR-137, miR-212 and miR-132 in NAcSh, and miR-137 in the DLS. This study identifies temporally specific changes in miRNA expression consistent with the engagement of distinct striatal subregions across the course of the addiction cycle. Increased dysregulation of miRNA expression in NAcSh and DLS at late stages of the addiction cycle may underlie habitual drug seeking, and may therefore aid in the identification of targets designed to treat addiction.

Addiction Circuitry in the Human Brain

A major challenge in understanding substance-use disorders lies in uncovering why some individuals become addicted when exposed to drugs, whereas others do not. Although genetic, developmental, and environmental factors are recognized as major contributors to a person’s risk of becoming addicted, the neurobiological processes that underlie this vulnerability are still poorly understood. Imaging studies suggest that individual variations in key dopamine-modulated brain circuits, including circuits involved in reward, memory, executive function, and motivation, contribute to some of the differences in addiction vulnerability. A better understanding of the main circuits affected by chronic drug use and the influence of social stressors, developmental trajectories, and genetic background on these circuits is bound to lead to a better understanding of addiction and to more effective strategies for the prevention and treatment of substance-use disorders. Reprinted with permission from the Annual Review of Pharmacology and Toxicology 2012; 52:321–336

Tolerance to the locomotor-activating effects of 3,4-methylenedioxymethamphetamine (MDMA) predicts escalation of MDMA self-administration and cue-induced reinstatement of MDMA seeking in rats

Pre-clinical studies of individual differences in addiction vulnerability have been increasing over recent years, but the amphetamine derivative 3,4-methylenedioxymethamphetamine (MDMA; ecstasy) has received relatively little attention in this regard. Previously, we reported large individual differences both in rats’ initial behavioral response to experimenter-administered MDMA and their degree of behavioral sensitization to repeated administration. To determine whether these differences could predict subsequent patterns of MDMA-taking or -seeking behaviors we used the self-administration–extinction–reinstatement model to examine addiction-like behavior (i.e., escalation of MDMA self-administration and cue-induced reinstatement of MDMA seeking) in rats a priori characterized for either locomotor sensitization or tolerance to MDMA. Rats that developed tolerance to the locomotor-activating effects of MDMA had a significantly larger locomotor response to the first MDMA injection relative to rats that developed sensitization. Importantly, rats that developed tolerance subsequently displayed an escalation of MDMA self-administration over days, as well as clear cue-induced reinstatement of MDMA seeking following extinction. Conversely, rats that developed locomotor sensitization to MDMA subsequently maintained relatively stable levels of MDMA self-administration over days and showed no cue-induced reinstatement of MDMA seeking. These results show that differences in the level of psychomotor activation following acute and repeated MDMA administration can reliably predict two important addiction-like behaviors in rats, which may have implications in the prediction of compulsive MDMA use in humans.

Addiction Circuitry in the Human Brain

A major challenge in understanding substance-use disorders lies in uncovering why some individuals become addicted when exposed to drugs, whereas others do not. Although genetic, developmental, and environmental factors are recognized as major contributors to a person's risk of becoming addicted, the neurobiological processes that underlie this vulnerability are still poorly understood. Imaging studies suggest that individual variations in key dopamine-modulated brain circuits, including circuits involved in reward, memory, executive function, and motivation, contribute to some of the differences in addiction vulnerability. A better understanding of the main circuits affected by chronic drug use and the influence of social stressors, developmental trajectories, and genetic background on these circuits is bound to lead to a better understanding of addiction and to more effective strategies for the prevention and treatment of substance-use disorders.

Sex and estrous cycle differences in cocaine‐induced approach‐avoidance conflict

Human and animal research indicates that females may have a higher biological propensity for cocaine abuse than do males. Furthermore, reproductive status modulates the subjective effects of cocaine in women and self-administration rates in rats. Despite the attention that has been given to the modulation of appetitive responses by reproductive status and the well-known mixed positive and negative subjective effects of cocaine, it is unknown if similar effects are observed on aversive responses to cocaine. The present study examines the impact of sex and estrous cycle on approach-avoidance behavior for cocaine as measured in the runway self-administration model. Male and freely cycling female Sprague Dawley rats were trained to traverse a straight alley for single daily injections of 1.0 mg/kg intravenous cocaine over 21 trials. Relative to males, females had significantly longer start latencies but significantly faster approach and shorter run times during the first week of training. Further, estrus females displayed significantly fewer approach-avoidance retreats across all sessions relative to non-estrus females. These results suggest that females initially exhibit greater motivation for cocaine (faster approach) than do males and that the drug's anxiogenic properties have a reduced impact on the motivation to seek cocaine (fewer retreats) in females during the estrus phase relative to other reproductive phases. These findings indicate that both sex and reproductive status contribute to the motivation for cocaine and that sex differences in addiction vulnerability may be attributable in part to differences in the motivational impact of both the appetitive and aversive properties of cocaine.

The emergence of gonadal hormone influences on dopaminergic function during puberty

Adolescence is the developmental epoch during which children become adults—intellectually, physically, hormonally and socially. Brain development in critical areas is ongoing. Adolescents are risk-taking and novelty-seeking and they weigh positive experiences more heavily and negative experiences less than adults. This inherent behavioral bias can lead to risky behaviors like drug taking. Most drug addictions start during adolescence and early drug -taking is associated with an increased rate of drug abuse and dependence. The hormonal changes of puberty contribute to physical, emotional, intellectual and social changes during adolescence. These hormonal events do not just cause maturation of reproductive function and the emergence of secondary sex characteristics. They contribute to the appearance of sex differences in non-reproductive behaviors as well. Sex differences in drug use behaviors are among the latter. The male predominance in overall drug use appears by the end of adolescence, while girls develop the rapid progression from first use to dependence (telescoping) that represent a female-biased vulnerability. Sex differences in many behaviors including drug use have been attributed to social and cultural factors. A narrowing gap in drug use between adolescent boys and girls supports this thesis. However, some sex differences in addiction vulnerability reflect biologic differences in brain circuits involved in addiction. The purpose of this review is to summarize the contribution of sex differences in the function of ascending dopamine systems that are critical to reinforcement, to briefly summarize the behavioral, neurochemical and anatomical changes in brain dopaminergic functions related to addiction that occur during adolescence and to present new findings about the emergence of sex differences in dopaminergic function during adolescence.

Targeting endogenous mu- and delta-opioid receptor systems for the treatment of drug addiction.

Drug addiction is a chronic, relapsing disorder that is characterized by a compulsion to take drug regardless of the adverse consequences that may ensue. Although the involvement of mesoaccumbal dopamine neurons in the initiation of drug abuse is well-established, neuroadaptations within the limbic cortical- striatopallidal circuit that occur as a consequence of repeated drug use are thought to lead to the behavioral dysregulation that characterizes addiction. Opioid receptors and their endogenous ligands are enriched in brain regions comprising this system and are, thus, strategically located to modulate neurotransmission therein. This article will review data suggesting an important role of mu-opioid receptor (MOPr) and delta opioid receptor (DOPr) systems in mediating the rewarding effects of several classes of abused drugs and that aberrant activity of these opioid systems may not only contribute to the behavioral dysregulation that characterizes addiction but to individual differences in addiction vulnerability.