Consideration of sex as a biological variable in the translation of pharmacotherapy for stress-associated drug seeking

Abstract

Stress is a frequent precipitant of relapse to drug use. Pharmacotherapies targeting a diverse array of neural systems have been assayed for efficacy in attenuating stress-induced drug-seeking in both rodents and in humans, but none have shown enough evidence of utility to warrant routine use in the clinic. We posit that a critical barrier in effective translation is inattention to sex as a biological variable at all phases of the research process. In this review, we detail the neurobiological systems implicated in stress-induced relapse to cocaine, opioids, methamphetamine, and cannabis, as well as the pharmacotherapies that have been used to target these systems in rodent models, the human laboratory, and in clinical trials. In each of these areas we additionally describe the potential influences of biological sex on outcomes, and how inattention to fundamental sex differences can lead to biases during drug development that contribute to the limited success of large clinical trials. Based on these observations, we determine that of the pharmacotherapies discussed only α 2 -adrenergic receptor agonists and oxytocin have a body of research with sufficient consideration of biological sex to warrant further clinical evaluation. Pharmacotherapies that target β-adrenergic receptors, other neuroactive peptides, the hypothalamic-pituitary-adrenal axis, neuroactive steroids, and the endogenous opioid and cannabinoid systems require further assessment in females at the preclinical and human laboratory levels before progression to clinical trials can be recommended.

Oxytocin moderates corticolimbic social stress reactivity in cocaine use disorder and healthy controls

“…In light of some other findings on sex differences in CUD stress reactivity [ 14 , 21 , 25 ], it was somewhat surprising that there were no sex differences or moderation of amygdala connectivity by sex in the present study. For example, Joseph et al (2020) showed that CUD males with childhood trauma had greater amygdala reactivity in response to cocaine cues on PBO and OT reduced this reactivity whereas the opposite was true for CUD females with childhood trauma.…”

“…In addition, childhood trauma history was expected to moderate these effects such that individuals with CUD who reported a history of childhood trauma (CUD/TRAUMA+) were expected to show the greatest difference in connectivity compared to other groups (CUD/TRAUMA-, HC/TRAUMA+, HC/TRAUMA-) on PBO. Sex was also explored as a moderator of the effect of OT on corticolimbic connectivity, given the culmination of preclinical and clinical findings of sex differences in drug-seeking and other addiction-related behaviors and outcomes [ 25 ].…”

Preventing Phosphorylation of the GABAAR β3 Subunit Compromises the Behavioral Effects of Neuroactive Steroids

“…For behavioral testing, animals were acclimatized to the testing room for 1 h before the start of all procedures. Because of the confounds of studying behavioral effects of neurosteroids in female mice, only male mice were used in the current study ( Martin et al, 2021 ). This study was carried out in accordance with the recommendations of the Institutional Animal Care and Use Committee of Tufts University and Tufts Medical Center.…”

The effect of stress on opioid addiction-related behaviors: A review of preclinical literature.

“…For example, mice lacking the μ-opioid receptor have a lower corticosterone response to a variety of stressors compared to wild-type animals (Ide et al, 2010), and chronic stress can affect opioid receptor expression (Nakamoto et al, 2020;Nikulina et al, 1999Nikulina et al, , 2005. An important caveat here is that many of the above aspects of stress and endorphin signaling are differentially modulated between the sexes (Martin et al, 2021). This background provides a basis to understand how stress may affect an individual's sensitivity, preference, and use, of exogenous opioids.…”