Sex, stress, and prefrontal cortex: influence of biological sex on stress-promoted cocaine seeking
- 17 April 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Neuropsychopharmacology
- Vol. 45 (12), 1974-1985
- https://doi.org/10.1038/s41386-020-0674-3
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.Keywords
Funding Information
- U.S. Department of Health & Human Services | NIH | National Institute on Drug Abuse (DA038663, DA038663, DA032895, DA038663)
- U.S. Department of Health & Human Services | NIH | National Institute on Drug Abuse
- U.S. Department of Health & Human Services | NIH | National Institute on Drug Abuse
- U.S. Department of Health & Human Services | NIH | National Institute on Drug Abuse
This publication has 61 references indexed in Scilit:
- Recruitment of Prefrontal Cortical Endocannabinoid Signaling by Glucocorticoids Contributes to Termination of the Stress ResponseJournal of Neuroscience, 2011
- Enhancement of cue-induced reinstatement of cocaine-seeking in rats by yohimbine: sex differences and the role of the estrous cyclePsychopharmacology, 2011
- Gender Differences in Alcohol Treatment: An Analysis of Outcome From the COMBINE StudyAlcohol: Clinical and Experimental Research, 2010
- Dopaminergic Modulation of Endocannabinoid-Mediated Plasticity at GABAergic Synapses in the Prefrontal CortexJournal of Neuroscience, 2010
- Plasma progesterone levels and cocaine-seeking in freely cycling female rats across the estrous cycleDrug and Alcohol Dependence, 2007
- Estrogen Receptor β, but not α, Mediates Estrogen's Effect on Cocaine-Induced Reinstatement of Extinguished Cocaine-Seeking Behavior in Ovariectomized Female RatsNeuropsychopharmacology, 2006
- Sex Differences and Hormonal Influences on Acquisition of Cocaine Self-Administration in RatsNeuropsychopharmacology, 2005
- Predictors of success in smoking cessation among hospitalized patientsRespirology, 2005
- Sex differences in the escalation of intravenous cocaine intake following long- or short-access to cocaine self-administrationPharmacology Biochemistry and Behavior, 2004
- Cannabinoid receptors in rat brain areas: Sexual differences, fluctuations during estrous cycle and changes after gonadectomy and sex steroid replacementLife Sciences, 1994