Date of Award

Summer 2019

Document Type


Degree Name

Doctor of Philosophy (PhD)


Biological Sciences

First Advisor

Mantsch, John

Second Advisor

Gasser, Paul

Third Advisor

Ghasemzadeh, M. Behnam


Clinical observations imply that females diagnosed with substance use disorder experience enhanced relapse vulnerability compared to males, particularly within contexts of stress or peak levels of the primary estrogen 17β-estradiol (E2). We previously demonstrated that stress can potentiate cocaine seeking in male rats. The present studies investigated the influence of biological sex on stress-potentiated cocaine seeking, the ability of E2 to potentiate cocaine seeking in females, mechanisms underlying potentiated reinstatement, and sex and stress hormone effects on PrL-PFC synaptic physiology.Initial investigations revealed that, despite comparable self-administration and extinction, females display a lower threshold for cocaine-primed reinstatement than males. Unlike males, footshock stress (15-min) failed to potentiate reinstatement to subthreshold cocaine in females, while restraint stress (15-min) potentiated reinstatement in both sexes. Divergent footshock responding corresponded to sex differences in ultrasonic vocalizations, but not plasma corticosterone (CORT) or defensive behaviors. Systemic stress-level CORT administration (2 mg/kg, ip) reproduced stress-potentiated reinstatement in both sexes, but CORT-potentiation was only observed in females during diestrus and proestrus. As in males, CORT-potentiating effects were localized to the PrL-PFC (50 ng/0.3 µL) and found to be CB1R-dependent (300 ng/0.3 µL). In parallel investigations, potentiated reinstatement to subthreshold cocaine was observed during proestrus, and systemic proestrus-reproducing E2 (10 µg/kg, i.p.) potentiated reinstatement through actions in the PrL-PFC involving CB1Rs, estrogen receptor-β (ERβ), and g-protein coupled estrogen receptor (GPER) activation. Ex vivo whole-cell electrophysiological recording from female layer V/VI PrL-PFC pyramidal neurons revealed both CORT and E2 suppress inhibitory synaptic activity in a CB1R-dependent manner, and E2 effects additionally required ERβ and, to a lesser extent, GPER activation.In summary, stress and peak physiological E2 superimpose upon the inherently greater relapse vulnerability in females to potentiate reactivity to ordinarily weak triggers in females. Despite sex divergence in stressor responsivity, stress-level CORT reproduces potentiation in an estrous cycle-dependent manner. CORT and E2 regulate PrL-PFC synaptic activity and cocaine seeking in a CB1R-dependent manner, and E2 furthermore acts through PrL-PFC ERβ and GPER. These studies implicate the PrL-PFC as an integration site for hormonal regulation of behavior and highlight the nuanced influence of sex as a biological variable.

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