The 5-HT2C receptor agonist Ro60-0175 reduces cocaine self-administration and reinstatement induced by the stressor yohimbine, and contextual cues

Neuropsychopharmacology. 2008 May;33(6):1402-12. doi: 10.1038/sj.npp.1301509. Epub 2007 Jul 25.

Abstract

Previously, we showed that the 5-HT2C receptor agonist Ro60-0175 reduces cocaine self-administration, and the ability of cocaine to reinstate responding after extinction of drug-seeking behavior. The present experiments extended these findings further by determining whether the effects of Ro60-0175 on self-administration were sustained with repeated treatment, and whether Ro60-0175 altered reinstatement induced by the pharmacological stressor yohimbine, or by the context in which self-administration occurred. In Experiment 1, Ro60-0175 (1 mg/kg, s.c.) reduced cocaine (0.25 mg/infusion) self-administration maintained by a progressive ratio schedule. This reduction was sustained over eight daily injections. In Experiment 2, rats self-administered cocaine in daily 2 h sessions for 15 days on a FR1 schedule. Following extinction, yohimbine (1 mg/kg, i.p.) reinstated responding, and this effect was reduced dose dependently by Ro60-0175 (0.3-3 mg/kg, s.c.). In Experiment 3, rats were trained to respond for cocaine on a FR1 schedule in a distinct environmental context (A); responding was then extinguished in a different context (B). Reinstatement tests occurred in either context A or B. Responding was reinstated only when rats were tested in the original self-administration context (A). This reinstatement was reduced dose dependently by Ro60-0175. All effects of Ro60-0175 were blocked by the 5-HT2C receptor antagonist SB242084. Thus, Ro60-0175, acting via 5-HT2C receptors, reduces cocaine self-administration and cocaine-seeking triggered by a stressor and by drug-associated cues. The effects of Ro60-0175 do not exhibit tolerance within the 8-day test period. These results indicate that selective 5-HT2C receptor agonists may be a useful pharmacological strategy for treatment of drug abuse.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic alpha-Antagonists / pharmacology*
  • Animals
  • Behavior, Animal / drug effects
  • Cocaine / administration & dosage*
  • Conditioning, Operant / drug effects
  • Cues*
  • Dopamine Uptake Inhibitors / administration & dosage*
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Ethylamines / pharmacology*
  • Extinction, Psychological / drug effects
  • Indoles / pharmacology*
  • Male
  • Rats
  • Rats, Sprague-Dawley
  • Reinforcement, Psychology*
  • Self Administration
  • Serotonin Receptor Agonists / pharmacology*
  • Yohimbine / pharmacology*

Substances

  • Adrenergic alpha-Antagonists
  • Dopamine Uptake Inhibitors
  • Ethylamines
  • Indoles
  • Ro 60-0175
  • Serotonin Receptor Agonists
  • Yohimbine
  • Cocaine