Neuronal biomarkers as potential therapeutic targets for drug addiction related to sex differences in the brain: Opportunities for personalized treatment approaches

Biological sex disparities manifest at various stages of drug addiction, including craving, substance abuse, abstinence, and relapse. These discrepancies are underpinned by notable distinctions in neurobiological substrates, encompassing brain structures, functions, and neurotransmitter systems implicated in drug addiction. Neuronal biomarkers, such as neurotransmitters, signaling proteins, and genes may be associated with the diagnosis, prognosis, and treatment outcomes in both biological sexes afflicted by drug abuse. Sex differences in the neural reward system, mainly through dopaminergic transmission during drug abuse, can be attributed to modifications in neurotransmitter systems and signaling pathways. This results in distinct patterns of neural activation and responsiveness to addictive substances in males and females. Sex hormones, the estrus/menstrual cycle, and cerebral neurochemistry contribute to the progression of psychological and physiological dependence in both male and female individuals grappling with addiction. Moreover, the alteration of sex hormone balance and neurotransmitter release plays a pivotal role in substance use disorders, subsequently modulating cognitive functions pertinent to reward, including memory formation, decision-making, and locomotor activity. Comparative investigations reveal distinctions in brain region volume, gene expression, neuronal firing, and circuitry in substance use disorders affecting individuals of both biological sexes. This review examines prevalent substance use disorders to elucidate the impact of sex hormones as therapeutic biomarkers on the mesocorticolimbic neurotransmitter systems via diverse mechanisms within the addicted brain. We underscore the imperative necessity of considering these variations to gain a deeper comprehension of addiction mechanisms and potentially discern sex-specific neuronal biomarkers for tailored therapeutic interventions.