Sex differences in neural mechanisms mediating reward and addiction

Abstract

There is increasing evidence in humans and laboratory animals for biologically based sex differences in every phase of drug addiction: acute reinforcing effects, transition from occasional to compulsive use, withdrawal-associated negative affective states, craving, and relapse. There is also evidence that many qualitative aspects of the addiction phases do not differ significantly between males and females, but one sex may be more likely to exhibit a trait than the other, resulting in population differences. The conceptual framework of this review is to focus on hormonal, chromosomal, and epigenetic organizational and contingent, sex-dependent mechanisms of four neural systems that are known-primarily in males-to be key players in addiction: dopamine, mu-opioid receptors (MOR), kappa opioid receptors (KOR), and brain-derived neurotrophic factor (BDNF). We highlight data demonstrating sex differences in development, expression, and function of these neural systems as they relate-directly or indirectly-to processes of reward and addictive behavior, with a focus on psychostimulants and opioids. We identify gaps in knowledge about how these neural systems interact with sex to influence addictive behavior, emphasizing throughout that the impact of sex can be highly nuanced and male/female data should be reported regardless of the outcome.

No basal or drug‐induced sex differences in striatal dopaminergic levels: a cluster and meta‐analysis of rat microdialysis studies

“…Thereby, the spatiotemporal scale of consideration and context are critical. While functional systems level studies question the presence of sexual dimorphisms within reward circuitry with respect to sexual arousal (Mitricheva, et al, ; Stark, et al, ), cellular and molecular sex differences associated with addiction may still be present within the same network (Sanchis‐Segura and Becker, ; Huber, et al, ; Becker and Chartoff, ). In addition to context and scales of consideration, the proper sample size, choice of statistical methods and data convergence may further influence the outcome of investigations and thus, conclusions made on sex differences.…”

Sex differences: Transcriptional signatures of stress exposure in male and female brains

“…Lastly, the nucleus accumbens (NAc) is the only region showing highly similar stress signatures between the sexes. However, the reward system, to which the NAc belongs, has been shown in human and animal models to be affected by stress exposure in a sex‐specific fashion. Investigating how similar gene expression changes might lead to divergent functional outcome may be of great interest to the field.…”

“…Lastly, the nucleus accumbens (NAc) is the only region showing highly similar stress signatures between the sexes. However, the reward system, to which the NAc belongs, has been shown in human and animal models [88][89][90] Nevertheless, studies on human tissues are unfortunately strongly affected by unavoidable complications, like intrinsic variability because of treatment history, age, post-mortem indices, and processing. These factors are known to confound studies, especially when looking for transcriptional alterations.…”

Prospects for finding the mechanisms of sex differences in addiction with human and model organism genetic analysis

“…There are several reviews addressing sex differences in SUD and addiction . A multitude of rodent studies of addiction‐related phenomena have evaluated drug effects across different drug classes including alcohol, opioids, psychostimulants like cocaine and amphetamines, nicotine and cannabinoids.…”