Elsevier

Experimental Neurology

Volume 259, September 2014, Pages 64-74
Experimental Neurology

Review
Sex differences in the neurobiology of drug addiction

https://doi.org/10.1016/j.expneurol.2014.01.022Get rights and content

Abstract

Epidemiological data demonstrate that while women report lower rates of drug use than men, the number of current drug users and abusers who are women continues to increase. In addition women progress through the phases of addiction differently than men; women transition from casual drug use to addiction faster, are more reactive to stimuli that trigger relapse, and have higher rates of relapse then men. Sex differences in physiological and psychological responses to drugs of abuse are well documented and it is well established that estrogen effects on dopamine (DA) systems are largely responsible for these sex differences. However, the downstream mechanisms that result from interactions between estrogen and the effects of drugs of abuse on the DA system are just beginning to be explored. Here we review the basic neurocircuitry which underlies reward and addiction; highlighting the neuroadaptive changes that occur in the mesolimbic dopamine reward and anti-reward/stress pathways. We propose that sex differences in addiction are due to sex differences in the neural systems which mediate positive and negative reinforcement and that these differences are modulated by ovarian hormones. This forms a neurobehavioral basis for the search for the molecular and cellular underpinnings that uniquely guide motivational behaviors and make women more vulnerable to developing and sustaining addiction than men.

Introduction

Addiction is a chronic, potentially relapsing, neurological illness characterized by a loss of control over drug seeking and intake. Addictive substances include illicit drugs like cocaine and heroin, as well as legally available nicotine and alcohol. Moreover, prescription drugs, such as opioids, stimulants, and depressants are also increasingly being used for non-medical reasons (Compton and Volkow, 2006). Chronic repeated use of these drugs hijacks normal motivated behaviors via the dysregulation of brain reward circuitry (Hyman et al., 2006). While contributions of the neural substrates underlying addiction are being characterized with increasing precision, the overwhelming majority of investigations into brain reward and anti-reward circuitry has been – and continues to be – conducted in men and/or male animals. Until the early 1990s research on the etiology and treatment of addiction was conducted on a male only population because prior to this time the notion that men and women differed only in their reproductive abilities and secondary sex characteristics was embedded in clinical research. Over the past few decades, awareness of the importance of sex differences in addiction has grown and, as a result, an emergent field devoted to characterizing sex differences has and continues to develop (Evans, 2007).

Results of the 2012 National Survey on Drug Use and Health (NSDUH), estimated 9.2% (23.9 million) of Americans, age 12 or older were current (had used in the past 30 days) illicit drug users. While women exhibit lower rates of drug use and addiction than men, prevalence rates indicate that the number of female drug abusers has increased and continues to escalate (SAMHSA, 2012). Evidence identifying important differences in the pattern of drug use and abuse between men and women suggests that gender also influences the course and treatment of substance use disorder. In general, women progress from casual drug use to dependence more rapidly, experience higher levels of craving and relapse during periods of abstinence, take larger amounts of the substance during bouts of relapse, and are less likely to seek treatment for their addiction than men (Brady and Randall, 1999, Ignjatova and Raleva, 2009, Kosten et al., 1985) In addition, women who enter drug abuse treatment programs have a more severe addiction syndrome and higher prevalence of co-occurring mental health disorders (Back et al., 2011, Yates et al., 1993).

Section snippets

Human studies

The acute subjective effects of most drugs of abuse, except stimulants (cocaine and amphetamine), do not differ between men and women (Terner and de Wit, 2006). In the case of psychostimulants, men often report (but, not reliably) greater subjective effects than women (Lukas et al., 1996). This lack of reliability is likely due to the fact that women's reporting of the subjective effects of their response to psychostimulants varies with the menstrual cycle (Fig. 1). Women have greater

Mesolimbic reward circuitry

It has been long known that dopamine (DA) is important for reinforcement and motivation of actions. However most of what we know about DA, reinforcement and motivation comes from studies of male animals. For the purposes of this review, we will review the literature on the mesolimbic DA system as it is collectively dogmatized and add in where females have been shown to demonstrate structural and functional differences. Almost sixty years ago, Olds and Milner reported that male rats would press

Negative reinforcement, opponent process and neural stress systems

The loss of control over drug seeking and intake is not just a product of the positive reinforcing properties of drugs and drug-related stimuli; drug-seeking and taking behaviors are also elicited via negative-reinforcement motivation (Gardner, 2011, Koob et al., 2014). This concept of a shift in motivation and neural systems is used to explain the characteristic persistent changes in motivation that are associated with drug dependence in states of addiction (Koob and Le Moal, 2001, Koob and Le

Summary/conclusions

Males and females differ in their magnitude of response to various properties of drugs of abuse. It is likely that the molecular neuroadaptations, which develop over the course of addiction, contribute to female increased sensitivity to drug-associated cues and stress that influence individual vulnerability to drug addiction and relapse. Furthermore, it is becoming increasingly apparent that females are more susceptible to the negative reinforcing motivation to seek and take drugs than males.

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