Sex Differences and the Role of Estradiol in Mesolimbic Reward Circuits and Vulnerability to Cocaine and Opiate Addiction

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 drugdirected 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.

Continuous High Frequency Deep Brain Stimulation of the Rat Anterior Insula Attenuates the Relapse Post Withdrawal and Strengthens the Extinction of Morphine Seeking

“…During abstinence, females experience stronger drug cravings ( 74 ). This is mainly due to the ovarian hormone cycle in females, and short-term exposure to estradiol will increase drug availability ( 75 ). Animal studies further indicate that estradiol may be necessary for the development of substance use disorder.…”

A Gender Perspective of Addictive Disorders

“…In a recent revision [ 35 ], estradiol level fluctuations are associated with sex differences in dopamine signaling in the mesolimbic reward system; in animal models, it has been demonstrated that striatal dopamine release is increased during phases of the cycle with high levels of estradiol [ 36 ]. Also, high levels of estradiol are related to increased responses to cocaine and cocaine-related cues [ 37 ].…”

Cocaine Reduces the Neuronal Population While Upregulating Dopamine D2-Receptor-Expressing Neurons in Brain Reward Regions: Sex-Effects

“…This is relevant since women when compared to men transition faster from occasional to compulsive cocaine intake and those with cocaine use disorder experience more cravings, withdrawal symptoms, and worse outcomes (Griffin et al, 1989;Robbins et al, 1999;Van Etten and Anthony, 2001;Becker and Koob, 2016). Similarly, studies in laboratories animals have reported significant sex differences in the locomotor and rewarding effects of cocaine (Kokane and Perrotti, 2020).…”