Doncheck Elizabeth M, Liddiard Gage T, Konrath Chaz D, Liu Xiaojie, Yu Laikang, Urbanik Luke A, Herbst Matthew R, DeBaker Margot C, Raddatz Nicholas, Van Newenhizen Erik C, Mathy Jacob, Gilmartin Marieke R, Liu Qing-Song, Hillard Cecilia J, Mantsch John R
Department of Biomedical Sciences, Marquette University, Milwaukee, WI, 53233, USA.
Department of Neuroscience, Medical University of South Carolina, Charleston, SC, 29425, USA.
Neuropsychopharmacology. 2020 Nov;45(12):1974-1985. doi: 10.1038/s41386-020-0674-3. Epub 2020 Apr 17.
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.
临床报告表明，与男性相比，被诊断为物质使用障碍的女性复吸易感性更高，尤其是在压力期间。我们之前证明，应激源（足部电击）可通过糖皮质激素依赖的1型大麻素受体（CB1R）介导的作用，在雄性大鼠的前边缘前额叶皮质（PrL-PFC）中增强可卡因觅求行为。在此，我们研究了生物性别对应激增强的可卡因觅求行为的影响。尽管自我给药和消退情况相当，但雌性大鼠对可卡因引发的复吸的阈值低于雄性。与雄性不同，在一系列强度下测试的足部电击未能增强雌性大鼠的可卡因引发的复吸。然而，束缚应激增强了两性的复吸。虽然未观察到应激源诱导的血浆皮质酮（CORT）升高和防御行为存在性别差异，但在足部电击引发的超声波发声方面存在明显差异。给予能重现应激源诱导的血浆水平的剂量的CORT，可在两性中重现应激增强的可卡因引发的复吸。在雌性中，CORT的作用在发情周期中有所不同；仅在动情间期和发情前期观察到CORT增强的复吸。与雄性一样，CORT增强的雌性大鼠可卡因觅求行为定位于PrL-PFC，且CORT和束缚应激增强的可卡因觅求行为均需要PrL-PFC中的CB1R激活。此外，对雌性PrL-PFC第V层锥体神经元的离体全细胞膜片钳记录显示，CORT诱导的抑制性突触活动的抑制依赖于CB1R，这与之前在雄性中观察到的情况相同。这些发现表明，虽然应激通过PrL-PFC中的CB1R在两性中增强可卡因觅求行为，但雌性对可卡因引发注射的敏感性更高，CORT增强作用随发情周期而变化，并且对特定应激源的反应性是否表现为药物觅求行为取决于生物性别。
