title: Decreased sensitivity to the effects of dopamine D1-like, but not D2-like, receptor antagonism in the posterior hypothalamic region/anterior ventral tegmental area on brain reward function during chronic exposure to nicotine in rats.
abstract: Chronic administration of nicotine induces adaptations in central nervous system function to counteract nicotine's acute effects. When nicotine administration ceases, these adaptations remain unopposed and may lead to drug withdrawal. The present studies were conducted to assess the effects of chronic nicotine administration on dopamine D1- and D2-like receptor activity in the posterior hypothalamus/anterior ventral tegmental area (VTA). An intracranial self-stimulation discrete trial procedure that provides current intensity thresholds was used to provide a measure of brain reward function in rats. Previous studies showed that systemic administration of dopamine D1- or D2-like receptor antagonists induced elevations in brain reward thresholds in drug-free rats, indicative of a decrease in brain reward function. We show here that injections of the D1-like receptor antagonist SCH 23390 (1-4 microg total bilateral dose) into the posterior hypothalamus/anterior VTA differentially elevated brain reward thresholds in rats chronically treated with nicotine (9 mg/kg/day, salt) versus saline-treated rats. The nicotine-treated rats were less sensitive to the threshold elevating effects of D1-like receptor antagonism. By contrast, the D2-like receptor antagonist eticlopride (1-4 microg total bilateral dose) injected into the posterior hypothalamus/anterior VTA significantly elevated brain reward thresholds in saline- and nicotine-treated rats. No differential effect of eticlopride on brain reward thresholds in saline- and nicotine-treated rats was observed. Decreased sensitivity to D1-like receptor antagonism in the posterior hypothalamus/anterior VTA may partly mediate the development of tolerance to the reinforcing effects of nicotine and the manifestation of negative affective signs associated with cessation of nicotine administration.
authors.affiliation: Molecular and Integrative Neuroscience Department, CVN-7, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Adrie W
authors.initials: AW
authors.lastname: Bruijnzeel
authors.forename: Athina
authors.initials: A
authors.lastname: Markou
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D065127:Dopamine D2 Receptor Antagonists; D004334:Drug Administration Schedule; D004361:Drug Tolerance / Q000502:physiology*; D007034:Hypothalamus, Posterior / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D012201:Reward; D013375:Substance Withdrawal Syndrome / Q000378:metabolism / Q000503:physiopathology; D014029:Tobacco Use Disorder / Q000378:metabolism / Q000503:physiopathology; D017557:Ventral Tegmental Area / Q000187:drug effects* / Q000378:metabolism
chemical_list: D065127:Dopamine D2 Receptor Antagonists; D018722:Nicotinic Agonists; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D009538:Nicotine