Estradiol in the Preoptic Area Regulates the Dopaminergic Response to Cocaine in the Nucleus Accumbens

Neuropsychopharmacology. 2016 Jun;41(7):1897-906. doi: 10.1038/npp.2015.360. Epub 2015 Dec 9.


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.

MeSH terms

  • Analysis of Variance
  • Anesthetics, Local / pharmacology*
  • Animals
  • Cocaine / pharmacology*
  • Dopamine / metabolism*
  • Estradiol / metabolism*
  • Excitatory Amino Acid Agonists / toxicity
  • Female
  • Microdialysis
  • N-Methylaspartate / toxicity
  • Nucleus Accumbens / drug effects*
  • Nucleus Accumbens / physiology
  • Ovariectomy
  • Phosphopyruvate Hydratase / metabolism
  • Preoptic Area / drug effects*
  • Preoptic Area / injuries
  • Preoptic Area / physiology
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Estrogen / metabolism
  • Receptors, G-Protein-Coupled / metabolism
  • Stilbamidines / pharmacokinetics
  • Time Factors
  • Tyrosine 3-Monooxygenase / metabolism


  • 2-hydroxy-4,4'-diamidinostilbene, methanesulfonate salt
  • Anesthetics, Local
  • Excitatory Amino Acid Agonists
  • GPER1 protein, human
  • Receptors, Estrogen
  • Receptors, G-Protein-Coupled
  • Stilbamidines
  • Estradiol
  • N-Methylaspartate
  • Tyrosine 3-Monooxygenase
  • Phosphopyruvate Hydratase
  • Cocaine
  • Dopamine