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Sex, stress, and prefrontal cortex: influence of biological sex on stress-promoted cocaine seeking.

ABSTRACT: Clinical reports suggest that females diagnosed with substance use disorder experience enhanced relapse vulnerability compared with males, particularly during stress. We previously demonstrated that a stressor (footshock) can potentiate cocaine seeking in male rats via glucocorticoid-dependent cannabinoid type-1 receptor (CB1R)-mediated actions in the prelimbic prefrontal cortex (PrL-PFC). Here, we investigated the influence of biological sex on stress-potentiated cocaine seeking. Despite comparable self-administration and extinction, females displayed a lower threshold for cocaine-primed reinstatement than males. Unlike males, footshock, tested across a range of intensities, failed to potentiate cocaine-primed reinstatement in females. However, restraint potentiated reinstatement in both sexes. While sex differences in stressor-induced plasma corticosterone (CORT) elevations and defensive behaviors were not observed, differences were evident in footshock-elicited ultrasonic vocalizations. CORT administration, at a dose which recapitulates stressor-induced plasma levels, reproduced stress-potentiated cocaine-primed reinstatement in both sexes. In females, CORT effects varied across the estrous cycle; CORT-potentiated reinstatement was only observed during diestrus and proestrus. As in males, CORT-potentiated cocaine seeking in females was localized to the PrL-PFC and both CORT- and restraint-potentiated cocaine seeking required PrL-PFC CB1R activation. In addition, ex vivo whole-cell electrophysiological recordings from female layer V PrL-PFC pyramidal neurons revealed CB1R-dependent CORT-induced suppression of inhibitory synaptic activity, as previously observed in males. These findings demonstrate that, while stress potentiates cocaine seeking via PrL-PFC CB1R in both sexes, sensitivity to cocaine priming injections is greater in females, CORT-potentiating effects vary with the estrous cycle, and whether reactivity to specific stressors may manifest as drug seeking depends on biological sex.

SUBMITTER: Doncheck EM

PROVIDER: S-EPMC7547655 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Sex, stress, and prefrontal cortex: influence of biological sex on stress-promoted cocaine seeking.

Doncheck Elizabeth M EM Liddiard Gage T GT Konrath Chaz D CD Liu Xiaojie X Yu Laikang L Urbanik Luke A LA Herbst Matthew R MR DeBaker Margot C MC Raddatz Nicholas N Van Newenhizen Erik C EC Mathy Jacob J Gilmartin Marieke R MR Liu Qing-Song QS Hillard Cecilia J CJ Mantsch John R JR

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20200417 12

Clinical reports suggest that females diagnosed with substance use disorder experience enhanced relapse vulnerability compared with males, particularly during stress. We previously demonstrated that a stressor (footshock) can potentiate cocaine seeking in male rats via glucocorticoid-dependent cannabinoid type-1 receptor (CB1R)-mediated actions in the prelimbic prefrontal cortex (PrL-PFC). Here, we investigated the influence of biological sex on stress-potentiated cocaine seeking. Despite compar ...[more]

PMID: 32303052

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Project description:The dorsal medial prefrontal cortex (dmPFC) plays a dual role in modulating drug seeking and fear-related behaviors. Learned associations between cues and drug seeking are encoded by a specific ensemble of neurons. This study explored the stability of a dmPFC cocaine seeking ensemble over 2 weeks and its influence on persistent cocaine seeking and fear memory retrieval. In the first series of experiments, we trained TetTag c-fos-driven-EGFP mice in cocaine self-administration and tagged strongly activated neurons with EGFP during the initial day 7 cocaine seeking session. Subsequently, a follow-up seeking test was conducted 2 weeks later to examine ensemble reactivation between two seeking sessions via c-Fos immunostaining. In the second series of experiments, we co-injected viruses expressing TRE-cre and a cre-dependent inhibitory PSAM-GlyR into the dmPFC of male and female c-fos-tTA mice to enable "tagging" of cocaine seeking ensemble or cued fear ensemble neurons with inhibitory chemogenetic receptors. These c-fos-tTA mice have the c-fos promoter that drives expression of the tetracycline transactivator (tTA). The tTA can bind to the tetracycline response element (TRE) site on the viral construct, resulting in the expression of cre-recombinase, which enables the expression of cre-dependent inhibitory chemogenetic receptors and fluorescent reporters. Then we investigated ensemble contribution to subsequent cocaine seeking and fear recall during inhibition of the tagged ensemble by administering uPSEM792s (0.3 mg/kg), a selective ligand for PSAM-GlyR. In both sexes, there was a positive association between the persistence of cocaine seeking and the proportion of reactivated EGFP+ neurons within the dmPFC. More importantly, inhibition of the cocaine seeking ensemble suppressed cocaine seeking, but not recall of fear memory, while inhibition of the fear ensemble reduced conditioned freezing but not cocaine seeking. The results demonstrate that cocaine and fear recall ensembles in the dmPFC are stable, but largely exclusive from one another.

Project description:Psychostimulant use disorder is a major public health issue, and despite the scope of the problem there are currently no Food and Drug Administration (FDA)-approved treatments. There would be tremendous utility in development of a treatment that could help patients both achieve and maintain abstinence. Previous work from our group has identified granulocyte-colony stimulating factor (G-CSF) as a neuroactive cytokine that alters behavioral response to cocaine, increases synaptic dopamine release, and enhances cognitive flexibility. Here, we investigate the role of G-CSF in affecting extinction and reinstatement of cocaine-seeking and perform detailed characterization of its proteomic effects in multiple limbic substructures. Male Sprague Dawley rats were injected with PBS or G-CSF during (1) extinction or (2) abstinence from cocaine self-administration, and drug seeking behavior was measured. Quantitative assessment of changes in the proteomic landscape in the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC) were performed via data-independent acquisition (DIA) mass spectrometry analysis. Administration of G-CSF during extinction accelerated the rate of extinction, and administration during abstinence attenuated cue-induced cocaine-seeking. Analysis of global protein expression demonstrated that G-CSF regulated proteins primarily in mPFC that are critical to glutamate signaling and synapse maintenance. Taken together, these findings support G-CSF as a viable translational research target with the potential to reduce drug craving or seeking behaviors. Importantly, recombinant G-CSF exists as an FDA-approved medication which may facilitate rapid clinical translation. Additionally, using cutting-edge multiregion discovery proteomics analyses, these studies identify a novel mechanism underlying G-CSF effects on behavioral plasticity.SIGNIFICANCE STATEMENT Pharmacological treatments for psychostimulant use disorder are desperately needed, especially given the disease's chronic, relapsing nature. However, there are currently no Food and Drug Administration (FDA)-approved pharmacotherapies. Emerging evidence suggests that targeting the immune system may be a viable translational research strategy; preclinical studies have found that the neuroactive cytokine granulocyte-colony stimulating factor (G-CSF) alters cocaine reward and reinforcement and can enhance cognitive flexibility. Given this basis of evidence we studied the effects of G-CSF treatment on extinction and reinstatement of cocaine seeking. We find that administration of G-CSF accelerates extinction and reduces cue-induced drug seeking after cocaine self-administration. In addition, G-CSF leads to downregulation of synaptic glutamatergic proteins in medial prefrontal cortex (mPFC), suggesting that G-CSF influences drug seeking via glutamatergic mechanisms.

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Sex, stress, and prefrontal cortex: influence of biological sex on stress-promoted cocaine seeking.

Publications

Sex, stress, and prefrontal cortex: influence of biological sex on stress-promoted cocaine seeking.

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