Opioid withdrawal produces sex-specific effects on fentanyl-vs.-food choice and mesolimbic transcription

Abstract

BackgroundOpioid withdrawal is a key driver of opioid addiction and an obstacle to recovery. However, withdrawal effects on opioid reinforcement and mesolimbic neuroadaptation are understudied and the role of sex is largely unknown.MethodsMale (n=10) and female (n=9) rats responded under a fentanyl-vs.-food “choice” procedure during daily 2h sessions. In addition to the daily choice sessions, rats were provided extended access to fentanyl during 12h sessions. After two weeks of this self-administration regimen, the nucleus accumbens (NAc) and ventral tegmental area (VTA) of a subset of rats were subjected to RNA sequencing. In the remaining rats, a third week of this self-administration regimen was conducted, during which methadone effects on fentanyl-vs.-food choice were determined.ResultsPrior to opioid dependence, male and female rats similarly allocated responding between fentanyl and food. Abstinence from extended fentanyl access elicited a similar increase in somatic withdrawal signs in both sexes. Despite similar withdrawal signs and extended access fentanyl intake, opioid withdrawal was accompanied by a maladaptive increase in fentanyl choice in males, but not females. Behavioral sex differences corresponded with transcriptional hyperfunction in the NAc and VTA of opioid-withdrawn females relative to males. Methadone blocked withdrawal-associated increases in fentanyl choice in males, but failed to further decrease fentanyl choice in females.ConclusionsThese results provide foundational evidence of sex-specific neuroadaptations to opioid withdrawal, which may be relevant to the female-specific resilience to withdrawal-associated increases in opioid choice and aid in the identification of novel therapeutic targets.

Confronting the challenge of failed translation in medications development for substance use disorders

“…The heuristic framework of Heterologous Reinforcer Desensitization can be conceptualized as one particularly relevant manifestation of drug-induced “negative affect” proposed to be a driver of drug addiction ( Hogarth, 2020 ; Koob, 2021 ); however, Heterologous Reinforcer Desensitization suggests a subtly different research approach that focuses on drug vs. non-drug choice rather than on rates of drug self-administration in SODs. Indeed, the first drug self-administration study ever conducted in animals demonstrated a withdrawal-induced increase in opioid-vs.-food choice in morphine-dependent chimpanzees ( Spragg, 1940 ), and this phenomenon has been replicated in opioid-dependent baboons ( Griffiths et al, 1975 ), rhesus monkeys ( Negus, 2006 ; Negus and Rice, 2009 ), and rats ( Townsend et al, 2021 ) ( Fig. 1 D).…”

“…Rats were trained to choose between fentanyl and 18% Ensure, then rendered opioid dependent by introducing daily sessions of extended fentanyl access and withdrawal. After two weeks, there was an increase in fentanyl choice and a decrease in 18% Ensure choice ( Townsend et al, 2021 ). …”

Negative emotional behavior during fentanyl abstinence is mediated by adaptations in nucleus accumbens neuron subtypes

“…Numerous studies have identified molecular changes in the NAc that arise during opioid abstinence, or as a consequence of opioid use (Cahill et al, 2018; Ferguson et al, 2013; Lefevre et al, 2020; Martin et al, 2019; Mayberry et al, 2022; Spijker et al, 2004; Sun et al, 2016; Townsend et al, 2021), including recent work in postmortem human brain (Seney et al, 2021). Some notable similarities arise between our findings, and those of recent publications: neuronal morphology related genes are downregulated across species and paradigm (Lefevre et al, 2020; Mayberry et al, 2022; Townsend et al, 2021). Like our work in abstinent mice, Mayberry et al found downregulated Green Module genes in the NAc of male morphine self-administering rats (e.g.…”

“…The nucleus accumbens (NAc) is a key locus in brain reward-circuitry that undergoes distinct molecular, cellular, and structural changes during opioid abstinence. Opioid withdrawal reduces dopamine release in the NAc (Acquas et al, 1991; Fox et al, 2017; Pothos et al, 1991; Rossetti et al, 1992) and induces numerous transcriptional changes dependent on opioid, sex, and abstinence duration (Cahill et al, 2018; Ferguson et al, 2013; Hofford et al, 2021; Martin et al, 2019; Mayberry et al, 2022; Spijker et al, 2004; Sun et al, 2016; Townsend et al, 2021). Opioid cessation also causes morphological and electrophysiological changes to NAc neurons.…”

Functional genomic mechanisms of opioid action and opioid use disorder: a systematic review of animal models and human studies

“…Next, we compared the 2 NAc studies (Seney et al [29], Townsend et al [28]) for which full genome-wide results were available. While both included males and females, only Townsend et al reported sex-specific results.…”