Cocaine self-administration induces sex-dependent protein expression in the nucleus accumbens

Abstract

Substance use disorder (SUD) is a chronic neuropsychiatric condition characterized by long-lasting alterations in the neural circuitry regulating reward and motivation. Substantial work has focused on characterizing the molecular substrates that underlie these persistent changes in neural function and behavior. However, this work has overwhelmingly focused on male subjects, despite mounting clinical and preclinical evidence that females demonstrate dissimilar progression to SUD and responsivity to stimulant drugs of abuse, such as cocaine. Here, we show that sex is a critical biological variable that defines drug-induced plasticity in the nucleus accumbens (NAc). Using quantitative mass spectrometry, we assessed the protein expression patterns induced by cocaine self-administration and demonstrated unique molecular profiles between males and females. We show that 1. Cocaine self-administration induces non-overlapping protein expression patterns in significantly regulated proteins in males and females and 2. Critically, cocaine-induced protein regulation differentially interacts with sex to eliminate basal sexual dimorphisms in the proteome. Finally, eliminating these baseline differences in the proteome is concomitant with the elimination of sex differences in behavior for non-drug rewards. Together, these data suggest that cocaine administration is capable of rewriting basal proteomic function and reward-associated behaviors.

A multivariate regressor of patterned dopamine release predicts relapse to cocaine

“…Cocaine-evoked GrabDA 2m signals were compared using waveform (bootstrapped 95% CI procedure) and summary (averaged Δ F/F 0 z-scores within time window of interest) analyses. Results show that both sexes consumed and pursued cocaine at similar levels (Figure 4A, B), as previously documented 28 . Despite a common behavioral phenotype, males exhibited higher dopamine release at cue onset and cocaine infusion (Figure 4C-D) than females (FR1).…”

Abstinence-Dependent Effects of Long-Access Cocaine Self-Administration on Nucleus Accumbens Astrocytes Are Observed in Male, But Not Female, Rats

“…The current study adds to the growing list of sexually divergent effects of drugs of abuse on the brain (for review, see Becker and Chartoff, 2019 ; Giacometti and Barker, 2020 ; Kokane and Perrotti, 2020 ). Notably, sex differences and estrogen-dependent effects have been observed among the cellular consequence of cocaine in the NAc, including magnitude of dopamine release ( Calipari et al, 2017 ), and changes in protein ( López et al, 2021 ) and gene expression ( Savell et al, 2020 ).…”

A functional eEF2K-eEF2 pathway in the NAc is critical for the expression of cocaine-induced psychomotor sensitisation and conditioned place preference

“…We also observed decreased eEF2 phosphorylation correlating with cocaine-mediated synaptic plasticity suggesting that protein targets which underpin the machinery of learning and memory may alter their expression. Such targets may include CaMKIIα, p70S6K and GluA1 [ 36 ], however more recently, profound and widespread cocaine-induced changes in the proteome, both specifically in the NAc and more widely throughout the brain, have been identified [ 37 , 38 ]. One limitation of our study (and that of the field in general) is that research has focused on responses in male mice.…”

“…One limitation of our study (and that of the field in general) is that research has focused on responses in male mice. The recent proteomics studies, however, make it clear that there are significant sex-specific differences in the response to cocaine exposure [ 38 ]. Future work focused on deriving the mechanistic differences between the male and female responses is critical to determine clinically relevant interventions for male and female users of cocaine.…”