title: Attenuation of cocaine-induced reinstatement of drug seeking in squirrel monkeys by direct and indirect activation of 5-HT2C receptors.
abstract: BACKGROUND
  5-Hydroxytryptamine (5-HT) transport inhibitors can attenuate the abuse-related effects of cocaine, and the mechanisms underlying this attenuation may involve activation of 5-HT2C receptors.
  
  
  OBJECTIVE
  The objective of this study was to investigate the consequences of direct and indirect pharmacological activation of 5-HT2C receptors on reinstatement of cocaine-seeking behavior induced by cocaine priming and a cocaine-paired stimulus.
  
  
  METHODS
  Monkeys were trained to self-administer cocaine under a second-order schedule in which responding was maintained by i.v. cocaine injections and a cocaine-paired stimulus. Drug seeking was extinguished by replacing cocaine with vehicle and eliminating the cocaine-paired stimulus. During reinstatement tests, the animals received a priming injection of cocaine along with restoration of the cocaine-paired stimulus, but only vehicle was available for self administration.
  
  
  RESULTS
  Pretreatment with either the 5-HT transport inhibitor fluoxetine (5.6 mg/kg) or the 5-HT2C receptor agonist Ro 60-0175 (1 mg/kg) attenuated reinstatement of drug seeking by cocaine priming. The reinstatement-attenuating effects of both drugs were reversed by the 5-HT2C receptor antagonist SB 242084 (0.03-0.56 mg/kg). Ro 60-0175 (1 mg/kg) attenuated cocaine-induced reinstatement of drug seeking regardless of whether priming injections were or were not accompanied by restoration of the cocaine-paired stimulus. Ro 60-0175 (0.56 mg/kg) was equally effective whether it was administered acutely or chronically. Finally, Ro 60-0175 (0.3-1 mg/kg) had observable behavioral effects suggestive of anxiolytic-like properties.
  
  
  CONCLUSIONS
  5-HT2C receptor mechanisms play a key role in the modulation of cocaine-induced reinstatement by fluoxetine and Ro 60-0175. Direct activation of 5-HT2C receptors may offer a novel, tolerance-free therapeutic strategy for the prevention of cocaine relapse.
authors: Harvard Medical School, New England Primate Research Center, Southborough, MA, USA.
authors: Daniela
authors: D
authors: Rüedi-Bettschen
authors: Roger D
authors: RD
authors: Spealman
authors: Donna M
authors: DM
authors: Platt
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology; D000818:Animals; D003042:Cocaine / Q000008:administration & dosage*; D019970:Cocaine-Related Disorders / Q000188:drug therapy; D003463:Cues; D058999:Drug-Seeking Behavior / Q000187:drug effects*; D005021:Ethylamines / Q000494:pharmacology; D005473:Fluoxetine / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D012453:Saimiri; D012646:Self Administration; D058826:Serotonin 5-HT2 Receptor Agonists / Q000494:pharmacology*
chemical_list: C107820:6-chloro-5-methyl-1-((2-(2-methylpyrid-3-yloxy)pyrid-5-yl)carbamoyl)indoline; D000631:Aminopyridines; D005021:Ethylamines; D007211:Indoles; C103848:Ro 60-0175; D058826:Serotonin 5-HT2 Receptor Agonists; D005473:Fluoxetine; D003042:Cocaine