title: Estradiol in the Preoptic Area Regulates the Dopaminergic Response to Cocaine in the Nucleus Accumbens.
abstract: The sex-steroid hormone estradiol (E2) enhances the psychoactive effects of cocaine, as evidenced by clinical and preclinical studies. The medial preoptic area (mPOA), a region in the hypothalamus, is a primary neural locus for neuroendocrine integration, containing one of the richest concentrations of estrogen receptors in the CNS and also has a key role in the regulation of naturally rewarding behaviors. However, whether estradiol enhances the neurochemical response to cocaine by acting in the mPOA is still unclear. Using neurotoxic lesions and microdialysis, we examined whether the mPOA modulates cocaine-induced neurochemical activity in the nucleus accumbens. Tract tracing and immunohistochemical staining were used to determine whether projections from the mPOA to the ventral tegmental area (VTA) are sensitive to estrogen signaling. Finally, estradiol microinjections followed by microdialysis were used to determine whether estrogenic signaling in the mPOA modulates cocaine-induced changes of dopamine in the nucleus accumbens. Results showed that lesions of the mPOA or microinjections of estradiol directly into the mPOA increased cocaine-induced release of dopamine in the nucleus accumbens. Immunohistochemical analyses revealed that the mPOA modulates cocaine responsiveness via projections to both dopaminergic and GABAergic neurons in the VTA, and that these projections are sensitive to estrogenic stimulation. Taken together, these findings point to a novel estradiol-dependent pathway that modulates cocaine-induced neurochemical activity in the mesolimbic system.
authors.affiliation: Department of Psychology, The University of Texas at Austin, Austin, TX, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Tobiansky
authors.affiliation: Department of Psychology, The University of Texas at Austin, Austin, TX, USA.|Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin, Austin, TX, USA.
authors.forename: Ryan G
authors.initials: RG
authors.lastname: Will
authors.affiliation: Department of Psychology, The University of Texas at Austin, Austin, TX, USA.|Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin, Austin, TX, USA.
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Lominac
authors.affiliation: Institute for Neuroscience, The University of Texas at Austin, Austin, TX, USA.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Turner
authors.affiliation: Department of Psychology, The University of Texas at Austin, Austin, TX, USA.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Hattori
authors.affiliation: Department of Psychology, The University of Texas at Austin, Austin, TX, USA.
authors.forename: Krittika
authors.initials: K
authors.lastname: Krishnan
authors.affiliation: Department of Psychology, The University of Texas at Austin, Austin, TX, USA.
authors.forename: Julia R
authors.initials: JR
authors.lastname: Martz
authors.affiliation: Institute for Neuroscience, The University of Texas at Austin, Austin, TX, USA.
authors.forename: Victoria L
authors.initials: VL
authors.lastname: Nutsch
authors.affiliation: Department of Psychology, The University of Texas at Austin, Austin, TX, USA.|Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin, Austin, TX, USA.|Institute for Neuroscience, The University of Texas at Austin, Austin, TX, USA.
authors.forename: Juan M
authors.initials: JM
authors.lastname: Dominguez
mesh_terms: D000704:Analysis of Variance; D000779:Anesthetics, Local / Q000494:pharmacology*; D000818:Animals; D003042:Cocaine / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism*; D004958:Estradiol / Q000378:metabolism*; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D005260:Female; D017551:Microdialysis; D016202:N-Methylaspartate / Q000633:toxicity; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000502:physiology; D010052:Ovariectomy; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D011301:Preoptic Area / Q000187:drug effects* / Q000293:injuries / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D013266:Stilbamidines / Q000493:pharmacokinetics; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: C049774:2-hydroxy-4,4'-diamidinostilbene, methanesulfonate salt; D000779:Anesthetics, Local; D018690:Excitatory Amino Acid Agonists; C109584:GPER1 protein, human; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; D013266:Stilbamidines; D004958:Estradiol; D016202:N-Methylaspartate; D014446:Tyrosine 3-Monooxygenase; D010751:Phosphopyruvate Hydratase; D003042:Cocaine; D004298:Dopamine