title: Effects of selective D1- or D2-like dopamine receptor antagonists with acute "binge" pattern cocaine on corticotropin-releasing hormone and proopiomelanocortin mRNA levels in the hypothalamus.
abstract: We have previously demonstrated that there are stimulatory effects of acute (1 day) "binge" cocaine on corticotropin-releasing hormone (CRH) gene expression in the rat hypothalamus and on the stress responsive hypothalamic-pituitary-adrenal (HPA) activity. The first aim of the present study was to investigate the possible role of dopamine (DA) D1- or D2-like receptors (D1R or D2R) in modulating these acute effects. Administration of acute "binge" cocaine (3x15 mg/kg, i.p.) was preceded by injections of either the selective D1R antagonist (SCH23390, 2 mg/kg) or D2R antagonist (sulpiride, 50 mg/kg). The D1R or D2R blockade by SCH23390 or sulpiride, respectively, did not alter the mRNA levels of CRH in the hypothalamus, CRH-R1 or proopiomelanocortin (POMC) in the anterior pituitary. However, the acute "binge" cocaine-induced increase in hypothalamic CRH mRNA levels was not found in the rats that received either D1R or D2R antagonist pretreatment. In the anterior pituitary, acute "binge" cocaine or its combinations with either DA antagonist did not alter CRH-R1 receptor or POMC mRNA levels. Both the D1R and D2R antagonists attenuated the elevation of plasma corticosterone levels induced by acute "binge" cocaine. These results suggest that both D1R and D2R mediate acute cocaine's stimulatory effect on HPA axis at the hypothalamic CRH level. Neurobiological evidence has demonstrated functional interactions between dopaminergic and opioidergic systems that regulate preproenkephalin and preprodynorphin gene expression in the striatum. The second aim of our study was to investigate the roles that D1R or D2R could play in regulation of POMC mRNA levels in the hypothalamus in response to acute "binge" cocaine. The D2R blockade by sulpiride increased POMC mRNA levels in the hypothalamus, indicating that D2R exerts a tonic inhibitory effect on hypothalamic POMC gene expression. The POMC mRNA increases induced by the D2R blockade were attenuated by acute "binge" cocaine. Neither the D2R blockade nor acute "binge" cocaine altered POMC mRNA levels in the amygdala, anterior pituitary or neurointermediate lobe of the pituitary. In contrast to the D2R, the D1R blockade by SCH23390, acute "binge" cocaine or their combination had no effect on hypothalamic POMC mRNA levels. These results support a specific role for D2R in acute cocaine's effects on hypothalamic POMC gene expression.
authors.affiliation: Laboratory of the Biology of Addictive Diseases, Box 171, The Rockefeller University, New York, NY 10021, USA. zhouya@mail.rockefeller.edu
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhou
authors.forename: Rudolph
authors.initials: R
authors.lastname: Spangler
authors.forename: Vadim P
authors.initials: VP
authors.lastname: Yuferov
authors.forename: Stefan D
authors.initials: SD
authors.lastname: Schlussmann
authors.forename: Ann
authors.initials: A
authors.lastname: Ho
authors.forename: Mary Jeanne
authors.initials: MJ
authors.lastname: Kreek
mesh_terms: D000679:Amygdala / Q000187:drug effects; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D003042:Cocaine / Q000494:pharmacology*; D003345:Corticosterone / Q000097:blood; D003346:Corticotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism*; D018492:Dopamine Antagonists / Q000494:pharmacology*; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology*; D004347:Drug Interactions; D024202:Electrophoretic Mobility Shift Assay / Q000379:methods; D007031:Hypothalamus / Q000033:anatomy & histology / Q000187:drug effects*; D008297:Male; D010902:Pituitary Gland / Q000187:drug effects; D011333:Pro-Opiomelanocortin / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D011863:Radioimmunoassay / Q000379:methods; D051381:Rats; D011916:Rats, Inbred F344; D013469:Sulpiride / Q000494:pharmacology
chemical_list: D001552:Benzazepines; D018492:Dopamine Antagonists; D018765:Dopamine Uptake Inhibitors; D012333:RNA, Messenger; D011333:Pro-Opiomelanocortin; D013469:Sulpiride; D003346:Corticotropin-Releasing Hormone; D003042:Cocaine; D003345:Corticosterone