17β-Estradiol Potentiates the Reinstatement of Cocaine Seeking in Female Rats: Role of the Prelimbic Prefrontal Cortex and Cannabinoid Type-1 Receptors

Authors

Elizabeth M. Doncheck, Marquette University
Luke A. Urbanik, Marquette University
Margot C. DeBaker, Marquette University
Laura M. Barron, Marquette University
Gage T. Liddiard, Marquette University
Jennifer J. Tuscher, University of Wisconsin - Milwaukee
Karyn M. Frick, University of Wisconsin - Milwaukee
Cecilia J. Hillard, Medical College of WisconsinFollow
John Mantsch, Marquette UniversityFollow

Document Type

Article

Language

eng

Publication Date

2018

Publisher

Nature Publishing Group (Macmillan Publishers Limited)

Source Publication

Neuropsychopharmacology

Source ISSN

0893-133X

Abstract

Clinical observations imply that female cocaine addicts experience enhanced relapse vulnerability compared with males, an effect tied to elevated estrogen phases of the ovarian hormone cycle. Although estrogens can enhance drug-seeking behavior, they do not directly induce reinstatement on their own. To model this phenomenon, we tested whether an estrogen could augment drug-seeking behavior in response to an ordinarily subthreshold reinstatement trigger. Following cocaine self-administration and extinction, female rats were ovariectomized to isolate estrogen effects on reinstatement. Although neither peak proestrus levels of the primary estrogen 17β-estradiol (E2; 10 μg/kg, i.p., 1-h pretreatment) nor a subthreshold cocaine dose (1.25 mg/kg, i.p.) alone were sufficient to reinstate drug-seeking behavior, pretreatment with E2 potentiated reinstatement to the ordinarily subthreshold cocaine dose. Furthermore, E2 microinfusions revealed that E2 (5 μg/0.3 μl, 15-min pretreatment) acts directly within the prelimbic prefrontal cortex (PrL-PFC) to potentiate reinstatement. As E2 has been implicated in endocannabinoid mobilization, which can disinhibit PrL-PFC projection neurons, we investigated whether cannabinoid type-1 receptor (CB1R) activation is necessary for E2 to potentiate reinstatement. The CB1R antagonist AM251 (1 or 3 mg/kg, i.p., 30-min pretreatment) administered prior to E2 and cocaine suppressed reinstatement in a dose-dependent manner. Finally, PrL-PFC AM251 microinfusions (300 ng/side, 15-min pretreatment) also suppressed E2-potentiated reinstatement. Together, these results suggest that E2 can augment reactivity to an ordinarily subthreshold relapse trigger in a PrL-PFC CB1R activation-dependent manner.

Comments

Accepted version. Neuropsychopharmacology, Vol. 43 (2018): 781-790. DOI. © 2018 Springer Nature Publishing AG. Used with permission.

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Recommended Citation

Doncheck, Elizabeth M.; Urbanik, Luke A.; DeBaker, Margot C.; Barron, Laura M.; Liddiard, Gage T.; Tuscher, Jennifer J.; Frick, Karyn M.; Hillard, Cecilia J.; and Mantsch, John, "17β-Estradiol Potentiates the Reinstatement of Cocaine Seeking in Female Rats: Role of the Prelimbic Prefrontal Cortex and Cannabinoid Type-1 Receptors" (2018). Biomedical Sciences Faculty Research and Publications. 183.
https://epublications.marquette.edu/biomedsci_fac/183