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

Abstract

Accumulating evidence indicates significant consequences for astrocytes associated with drug abuse. For example, reductions in structural features and synaptic colocalization of male rat nucleus accumbens (NAc) astrocytes are observed following short-access (ShA, 2 hours/day) self-administration and extinction from cocaine, methamphetamine, and heroin. However, it is unknown whether these observations extend to other rodent models of drug abuse, how enduring these effects may be, and whether similar effects are observed in female rats. Here we assess the effects of long-access (LgA, 6 hours/day) cocaine self-administration and abstinence on NAc astrocytes separately in male and female rats, employing a commonly used behavioral approach to investigate the incubation of cocaine craving. NAc astrocytes from male rats exhibit extensive (~40%) reductions in surface area, volume, and postsynaptic colocalization 45 days, but not 24 hours after the last self-administration session. In contrast, no effect of self-administration and abstinence was observed in astrocytes from female rats. Moreover, no effect of LgA selfadministration and abstinence was observed on NAc GLT-1 expression in female rats, an effect that has been well described in males. These results indicate striking and sexually dimorphic effects of abstinence subsequent to LgA self-administration on astrocytes. Taken together, these results indicate a pivotal role of prolonged abstinence in the effects of cocaine selfadministration on NAc astrocytes, and extend a growing body of evidence regarding sex differences in the cellular consequences of drug self-administration in the brain. Effects of cocaine abstinence on astrocytes 3 Significance StatementPrevious studies have reported changes in astrocytes following short-access (ShA, 2 hours/day) cocaine self-administration and extinction. However, it is unknown if these changes occur following other rodent models of drug intake. Accordingly, we examined the morphometric properties and synaptic colocalization of NAc astrocytes in male rats following long-access (LgA, 6 hours/day) cocaine self-administration and prolonged abstinence (45 days).NAc astrocytes demonstrated a profound decrease (~40%) in surface area, volume, and synaptic colocalization. Importantly, these changes are greater following LgA and abstinence, vs. ShA and extinction. Furthermore, these changes are not observed 24 hours following LgA cocaine self-administration and not observed in female rats. These results indicate abstinence and sexdependent changes in NAc astrocytes following prolonged abstinence from LgA cocaine selfadministration.

Impaired extinction of cocaine seeking in HIV-infected mice is accompanied by peripheral and central immune dysregulation

“…Both Tat and cocaine exposure independently alter astrocyte metabolism, resulting in reduced lactate transport to neurons, suggesting HIV-1 proteins may drive impairments in neuronal function indirectly through dysregulation of astrocytes (Natarajaseenivasan et al, 2018). We and others speculate that targeting astrocytes as regulators of dysregulated reward seeking behavior will be a promising therapeutic strategy across classes of addictive drugs (Sco eld et al, 2015; Walker et al, 2020; Kim et al, 2022;Kruyer et al, 2022). The current ndings suggest that astrocyte dysregulation is common across models of HIV, including infection and protein expression models, suggesting that astrocyte function and structure may further be promising for reversing HIV-associated changes in drug seeking behavior.…”

The estrous cycle has no effect on incubation of methamphetamine craving and associated Fos expression in dorsomedial striatum and anterior intralaminar nucleus of thalamus

“…Extending these studies, we demonstrated the time-dependent increase of methamphetamine seeking after abstinence was independent of the estrous cycles, and Fos expression in DMS and AIT-L was independent of either sex or estrous cycles. Overall, our data suggest that in contrast to cocaine [ 34 – 39 ], the estrous cycle is not a critical factor that influences incubation of methamphetamine craving and the role of AIT-L and DMS in methamphetamine relapse, at least in terms of circuit activity, might generalize across sexes and estrous cycles in female rats.…”

“…Sex differences in incubation of cocaine craving are indeed attributed to the effect of estrous cycle with estrus females exhibiting higher cue-induced cocaine seeking after prolonged abstinence than non-estrus females [ 34 – 36 ]. Further, recent studies demonstrated sex- and estrous cycle-dependent neural mechanisms underlying incubation of cocaine craving [ 37 – 39 ]. For example, inhibition of metabotropic glutamate receptor 5 (mGlu5) in basolateral amygdala (BLA) prevents incubated cocaine seeking in estrus-female, but not in non-estrus female or male rats [ 37 ].…”

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.…”