title: Estrogen receptors mediate estradiol's effect on sensitization and CPP to cocaine in female rats: role of contextual cues.
abstract: Preclinical studies show that estradiol enhances sensitization to cocaine in females by mechanisms not fully understood. These studies consistently show that ovariectomized (OVX) rats exhibit little or no sensitization to cocaine compared to OVX rats administered estradiol. In this study we varied the dose of cocaine (10, 15, and 30mg/kg), the length of cocaine treatment (from 5 to 10days) and the context of cocaine injections to determine if these factors play a role on estradiol's effects on cocaine sensitization. Because OVX rats are hormonally compromised, they are not representative of the natural state of the animal, and thus the physiological context of these studies remains unclear. To address this issue, we blocked ERs in gonadally intact females by icv administration of the antiestrogen ICI-182,780. Varying the dose or length of exposure to cocaine does not alter estradiol's effect on cocaine sensitization. In contrast, a highly context-dependent sensitization protocol results in robust sensitization even in OVX rats. Interestingly, using this protocol, sensitization in OVX rats diminished with time, suggesting that estradiol is necessary for the maintenance of cocaine sensitization. Blocking brain ERs with ICI completely abolishes the development and expression of cocaine sensitization in gonadally intact female rats, even when tested in a highly context-dependent sensitization protocol. Given these findings, we propose that activation of brain ERs is required for the development and maintenance of sensitization and CPP.
authors.affiliation: University of Puerto Rico, Physiology Department, Medical Sciences Campus, P.O. Box 365067, San Juan 00936-5067, Puerto Rico. Electronic address: annabell.segarra@upr.edu.
authors.forename: Annabell C
authors.initials: AC
authors.lastname: Segarra
authors.affiliation: University of Puerto Rico, Physiology Department, Medical Sciences Campus, P.O. Box 365067, San Juan 00936-5067, Puerto Rico.
authors.forename: Yvonne M
authors.initials: YM
authors.lastname: Torres-Díaz
authors.affiliation: Biology Department, Rio Piedras Campus, P.O. Box 23360, San Juan 00931, Puerto Rico.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Silva
authors.affiliation: University of Puerto Rico, Physiology Department, Medical Sciences Campus, P.O. Box 365067, San Juan 00936-5067, Puerto Rico.
authors.forename: Anabel
authors.initials: A
authors.lastname: Puig-Ramos
authors.affiliation: University of Puerto Rico, Physiology Department, Medical Sciences Campus, P.O. Box 365067, San Juan 00936-5067, Puerto Rico.
authors.forename: Raissa
authors.initials: R
authors.lastname: Menéndez-Delmestre
authors.affiliation: Biology Department, Rio Piedras Campus, P.O. Box 23360, San Juan 00931, Puerto Rico.
authors.forename: José G
authors.initials: JG
authors.lastname: Rivera-Bermúdez
authors.affiliation: University of Puerto Rico, Physiology Department, Medical Sciences Campus, P.O. Box 365067, San Juan 00936-5067, Puerto Rico.
authors.forename: Waldo
authors.initials: W
authors.lastname: Amadeo
authors.affiliation: Biology Department, Rio Piedras Campus, P.O. Box 23360, San Juan 00931, Puerto Rico.
authors.forename: José L
authors.initials: JL
authors.lastname: Agosto-Rivera
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003042:Cocaine / Q000494:pharmacology*; D003216:Conditioning, Operant / Q000187:drug effects* / Q000502:physiology; D003463:Cues; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004958:Estradiol / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*; D004965:Estrogen Antagonists / Q000494:pharmacology*; D005260:Female; D000077267:Fulvestrant; D009043:Motor Activity / Q000187:drug effects; D010052:Ovariectomy; D051381:Rats; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D018765:Dopamine Uptake Inhibitors; D004965:Estrogen Antagonists; D011960:Receptors, Estrogen; D000077267:Fulvestrant; D004958:Estradiol; D003042:Cocaine
keywords: Behavioral sensitization; Cocaine; Conditioned place preference; Context dependent learning; Drugs of abuse; Estradiol; Estrogen receptors; Females; ICI 182,780; Ovariectomized