title: Diminished role of dopamine D1-receptor signaling with the development of an addicted phenotype in rats.
abstract: BACKGROUND
  Although considerable evidence implicates dopamine D1-receptor signaling in the nucleus accumbens in motivation for cocaine during early stages of addiction, less is known with regard to its role after the development of addiction. Here, we examined its role in the development of an addicted phenotype in intact male and female rats, and in female rats that were either resistant or vulnerable to developing this phenotype.
  
  
  METHODS
  Intact males, females, and ovariectomized (OVX) females with and without estradiol (vulnerable, OVX+E; resistant, OVX+Veh) were given either short access (ShA) (three fixed-ratio 1 sessions, maximum of 20 infusions) or 24-hour extended access (ExA) to cocaine for 10 days (4 trials/hour). Motivation for cocaine was assessed after a 14-day abstinence period with a progressive-ratio schedule. Once responding stabilized, the effects of intra-accumbens infusion of the D1-receptor antagonist, SCH-23390 (0, .3, 1.0, 3.0 µg), were examined.
  
  
  RESULTS
  Motivation for cocaine was markedly higher after abstinence from ExA versus ShA self-administration in intact males and females, indicating the development of an addicted phenotype in these groups. Motivation for cocaine was also higher than ShA control subjects in OVX+E but not OVX+Veh females after ExA self-administration, confirming the categorization of these groups as vulnerable versus resistant. After ExA self-administration, intact males and females and OVX+E but not OVX+Veh females were less sensitive to the effects of D1-receptor antagonism as compared with their ShA counterparts.
  
  
  CONCLUSIONS
  These results suggest that the role of D1-receptor signaling, although critical in "nonaddicted" stages, becomes diminished once addiction has developed.
authors.affiliation: Department of Psychiatry and Neurobehavioral Sciences, University of Virginia, Charlottesville, VA 22911.
authors.forename: Carolina P
authors.initials: CP
authors.lastname: Ramôa
authors.affiliation: Department of Psychiatry and Neurobehavioral Sciences, University of Virginia, Charlottesville, VA 22911.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Doyle
authors.affiliation: Department of Psychiatry and Neurobehavioral Sciences, University of Virginia, Charlottesville, VA 22911.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Lycas
authors.affiliation: Department of Psychiatry and Neurobehavioral Sciences, University of Virginia, Charlottesville, VA 22911.
authors.forename: Andrea K
authors.initials: AK
authors.lastname: Chernau
authors.affiliation: Department of Psychiatry and Neurobehavioral Sciences, University of Virginia, Charlottesville, VA 22911.
authors.forename: Wendy J
authors.initials: WJ
authors.lastname: Lynch
mesh_terms: D000818:Animals; D016739:Behavior, Addictive / Q000503:physiopathology*; D001552:Benzazepines / Q000008:administration & dosage / Q000494:pharmacology; D003042:Cocaine / Q000008:administration & dosage; D019970:Cocaine-Related Disorders / Q000503:physiopathology*; D003216:Conditioning, Operant / Q000187:drug effects; D018492:Dopamine Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D008297:Male; D008845:Microinjections; D009714:Nucleus Accumbens / Q000187:drug effects / Q000502:physiology*; D010052:Ovariectomy; D010641:Phenotype; D051381:Rats; D017447:Receptors, Dopamine D1 / Q000502:physiology*; D012055:Reinforcement Schedule; D012646:Self Administration
chemical_list: D001552:Benzazepines; D018492:Dopamine Antagonists; D017447:Receptors, Dopamine D1; C534628:SCH 23390; D004958:Estradiol; D003042:Cocaine
keywords: Cocaine; SCH-23390; estradiol; extended access; nucleus accumbens; self-administration