Abstract

Although both men and women become addicted to drugs of abuse, women transition to addiction faster, experience greater difficulties remaining abstinent, and relapse more often than men. In both humans and rodents, hormonal cycles are associated with females’ faster progression to addiction. Higher concentrations and fluctuating levels of ovarian hormones in females modulate the mesolimbic reward system and influence reward-directed behavior. For example, in female rodents, estradiol (E2) influences dopamine activity within the mesolimbic reward system such that drug-directed behaviors that are normally rewarding and reinforcing become enhanced when circulating levels of E2 are high. Therefore, neuroendocrine interactions, in part, explain sex differences in behaviors motivated by drug reward. Here, we review sex differences in the physiology and function of the mesolimbic reward system in order to explore the notion that sex differences in response to drugs of abuse, specifically cocaine and opiates, are the result of molecular neuroadaptations that differentially develop depending upon the hormonal state of the animal. We also reconsider the notion that ovarian hormones, specifically estrogen/estradiol, sensitize target neurons thereby increasing responsivity when under the influence of either cocaine or opiates or in response to exposure to drug-associated cues. These adaptations may ultimately serve to guide the motivational behaviors that underlie the factors that cause women to be more vulnerable to cocaine and opiate addiction than men.

Highlights

  • Drug addiction or substance use disorder is a chronic, relapsing, neuropsychiatric illness characterized by a loss of control over drug seeking and intake, persistent drug craving, and high motivation to take the drug (Reid et al, 2012)

  • Basal firing rates of DA neurons of the ventral tegmental area (VTA) vary during the different phases of the rodent estrous cycle: DA firing rates are highest in estrus, lowest in proestrus, and intermediate in diestrus (Zhang et al, 2008)

  • Sex differences and sensitivity to gonadal hormones within the structure and functions of the mesolimbic reward system are linked to sex differences in the neurobehavioral response to drugs of abuse

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Summary

Introduction

Drug addiction or substance use disorder is a chronic, relapsing, neuropsychiatric illness characterized by a loss of control over drug seeking and intake, persistent drug craving, and high motivation to take the drug (Reid et al, 2012). Females consume larger quantities of drug (under some but not all conditions) and experience increased rewarding effects of cocaine and morphine compared to their male counterparts (reviewed in Becker and Koob, 2016).

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