The 5-HT2C receptor agonist Ro60-0175 reduces cocaine self-administration and reinstatement induced by the stressor yohimbine, and contextual cues.
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.
Fletcher
Paul J
PJ
Section of Biopsychology, Centre for Addiction and Mental Health, Toronto, ON, Canada. Paul_Fletcher@camh.net
Rizos
Zoë
Z
Sinyard
Judy
J
Tampakeras
Maria
M
Higgins
Guy A
GA
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003042:Cocaine / Q000008:administration & dosage*; D003216:Conditioning, Operant / Q000187:drug effects; D003463:Cues; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005021:Ethylamines / Q000494:pharmacology*; D005108:Extinction, Psychological / Q000187:drug effects; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012054:Reinforcement, Psychology; D012646:Self Administration; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D015016:Yohimbine / Q000494:pharmacology*
D000317:Adrenergic alpha-Antagonists; D018765:Dopamine Uptake Inhibitors; D005021:Ethylamines; D007211:Indoles; C103848:Ro 60-0175; D017366:Serotonin Receptor Agonists; D015016:Yohimbine; D003042:Cocaine