Sex differences in the neuroadaptations associated with incubated cocaine-craving: A focus on the dorsomedial prefrontal cortex

Abstract

IntroductionWomen have a shorter course from initial cocaine use to meeting the criteria for cocaine use disorder as compared to men. Preclinical findings similarly indicate that females develop key features of an addiction-like phenotype faster than males, including an enhanced motivation for cocaine and compulsive use, indicating that this phenomenon is biologically based. The goals of this study were to determine whether cocaine-craving, another key feature of addiction, also develops sooner during withdrawal in females than males and to determine whether there are sex differences in the molecular mechanisms associated with its development focusing on markers known to mediate cocaine-craving in males (i.e., dorsomedial prefrontal cortex, dmPFC, expression of brain-derived neurotrophic factor exon-IV, Bdnf-IV, and NMDA receptor subunits, Grin2a, Grin2b, and Grin1).MethodsCocaine-craving was assessed following extended-access cocaine self-administration and 2, 7, or 14 days of withdrawal using an extinction/cue-induced reinstatement procedure. Tissue was obtained from the dmPFC immediately after reinstatement testing and gene expression changes were analyzed using real-time qPCR.ResultsIn males, cocaine-craving (total extinction and cue-induced reinstatement responding) progressively increased from early to later withdrawal time-points whereas in females, cocaine-craving was already elevated during early withdrawal (after 2 days) and did not further increase at later withdrawal time-points. Levels of cocaine-craving, however, were similar between the sexes. Gene expression changes differed markedly between the sexes such that males showed the expected relapse- and withdrawal-associated changes in Bdnf-IV, Grin2a, Grin2b, and Grin1 expression, but females only showed a modest increase Grin1 expression at the intermediate withdrawal timepoint.DiscussionThese findings indicate that cocaine-craving is similarly expressed in males and females although the time-course for its incubation appears to be accelerated in females; the molecular mechanisms also likely differ in females versus males.

Decoding cocaine-induced proteomic adaptations in the mouse nucleus accumbens

“…Similarly, SLC9A3R1, a regulator of vesicle-mediated transport, also was down-regulated. These proteins have been previously highlighted in CUD research (65)(66)(67)(68)(69). The observed modulation in membrane Fig.…”

“…A detailed exploration of the transporter activity cluster revealed several proteins with known associations to cocaine withdrawal, including GRIN2A (glutamate receptor ionotropic, NMDA 2A), ANK2 (ankyrin-2), and cyclin-dependent kinase 5 (CDK5) (Fig. 5E) (65)(66)(67)(68). The cluster delineating the regulation of transport in downregulated membrane proteins during withdrawal also offered corroborative insights.…”

Impact of SMAASH-C, a novel nutritional supplement, on drug-seeking and toxicity in female and male rats

“…We use an intermittent, extended-access procedure (4 trials/hr; 24-hr/day for 10 days) that was developed to approximate the use patterns observed in humans (e.g., binge/abstinent patterns;[ 5 , 6 ]. We have confirmed that this procedure induces binge/abstinent patterns of drug intake in both males and females [ 4 ], as well as other key features of addiction, including an enhanced vulnerability to relapse assessed using an extinction/cue-induced reinstatement procedure [ 7 ], and reversal of this phenotype using treatments known to decrease drug-craving and prevent relapse in humans (e.g., exercise and alternative rewards for cocaine and buprenorphine for fentanyl; [ 7 – 10 ].…”

“…Drug-seeking was examined on abstinence day 15 using an extinction/cue-induced reinstatement procedure [ 7 – 10 , 21 – 23 ]. Estrous cycle phase on the test day was determined from vaginal cytology samples by an experimenter blinded to the experimental conditions, as previously described [ 24 , 25 ].…”

EcoHIV Infection Modulates the Effects of Cocaine Exposure Pattern and Abstinence on Cocaine Seeking and Neuroimmune Protein Expression in Male Mice

“…Nevertheless, it is important to note that only male mice were tested here, and the results may therefore be restricted to only males. Indeed, there are sex differences in the temporal pattern of cocaine seeking across abstinence, as well as associated corticolimbic cellular adaptations (Kim et al, 2022; Towers et al, 2023), though this may depend on estrous phase (Corbett et al, 2021). Thus, examination of sex differences in cocaine seeking across the various factors and levels of analysis tested here represents an important future direction of this work.…”