title: μ-opioid receptors in the stimulation of mesolimbic dopamine activity by ethanol and morphine in Long-Evans rats: a delayed effect of ethanol.
abstract: BACKGROUND
  Naltrexone, a non-selective opioid antagonist, decreases the euphoria and positive subjective responses to alcohol in heavy drinkers. It has been proposed that the μ-opioid receptor plays a role in ethanol reinforcement through modulation of ethanol-stimulated mesolimbic dopamine release.
  
  
  OBJECTIVE
  To investigate the ability of naltrexone and β-funaltrexamine, an irreversible μ-opioid specific antagonist, to inhibit ethanol-stimulated and morphine-stimulated mesolimbic dopamine release, and to determine whether opioid receptors on mesolimbic neurons contribute to these mechanisms.
  
  
  METHODS
  Ethanol-naïve male Long Evans rats were given opioid receptor antagonists either intravenously, subcutaneously, or intracranially into the ventral tegmental area (VTA), followed by intravenous administration of ethanol or morphine. We measured extracellular dopamine in vivo using microdialysis probes inserted into the nucleus accumbens shell (n = 114).
  
  
  RESULTS
  Administration of naltrexone (intravenously) and β-funaltrexamine (subcutaneously), as well as intracranial injection of naltrexone into the VTA did not prevent the initiation of dopamine release by intravenous ethanol administration, but prevented it from being as prolonged. In contrast, morphine-stimulated mesolimbic dopamine release was effectively suppressed.
  
  
  CONCLUSIONS
  Our results provide novel evidence that there are two distinct mechanisms that mediate ethanol-stimulated mesolimbic dopamine release (an initial phase and a delayed phase), and that opioid receptor activation is required to maintain the delayed-phase dopamine release. Moreover, μ-opioid receptors account for this delayed-phase dopamine response, and the VTA is potentially the site of action of this mechanism. We conclude that μ-opioid receptors play different roles in the mechanisms of stimulation of mesolimbic dopamine activity by ethanol and morphine.
authors.affiliation: College of Pharmacy, Department of Pharmacology, University of Texas at Austin, 2409 University Avenue, Stop A1900, Austin, TX 78712-1113, USA.
authors.forename: John P
authors.initials: JP
authors.lastname: Valenta
authors.forename: Martin O
authors.initials: MO
authors.lastname: Job
authors.forename: Regina A
authors.initials: RA
authors.lastname: Mangieri
authors.forename: Christina J
authors.initials: CJ
authors.lastname: Schier
authors.forename: Elaina C
authors.initials: EC
authors.lastname: Howard
authors.forename: Rueben A
authors.initials: RA
authors.lastname: Gonzales
mesh_terms: D000818:Animals; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000008:administration & dosage / Q000494:pharmacology*; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D008297:Male; D017551:Microdialysis; D008845:Microinjections; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology*; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D051381:Rats; D020318:Rats, Long-Evans; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors*; D013997:Time Factors; D017557:Ventral Tegmental Area / Q000187:drug effects* / Q000378:metabolism
chemical_list: D009292:Narcotic Antagonists; D017450:Receptors, Opioid, mu; D000431:Ethanol; D009271:Naltrexone; C024524:beta-funaltrexamine; D009020:Morphine; D004298:Dopamine