Injection of the 5-HT2C receptor agonist Ro60-0175 into the ventral tegmental area reduces cocaine-induced locomotor activity and cocaine self-administration.
Previously, we have shown that systemic administration of the 5-HT(2C) receptor agonist Ro60-0175 reduces cocaine-induced locomotor activity and cocaine self-administration. Ro60-0175 also alters the activity of midbrain dopamine (DA) neurons of the ventral tegmental area (VTA), a region where 5-HT(2C) receptors are expressed. The present experiments investigated whether microinjections of Ro60-0175 into the VTA would alter the locomotor stimulant effect of cocaine and cocaine self-administration. In the tests for locomotor activity injection of 3 and 10, but not 1 microg, Ro60-0175 into the VTA reduced the locomotor stimulation resulting from injection of 10 mg/kg cocaine. In tests of cocaine self-administration, rats were trained to lever press for intravenous infusions of 0.25 mg cocaine delivered on either a fixed ratio 5 (FR5) or a progressive ratio schedule. Intra-VTA injection of Ro60-0175 at doses of 3 and 10 microg reduced responding for cocaine on both schedules without significantly altering the latency to initiate responding or the rate of responding. A subsequent experiment determined that the suppressant effect of intra-VTA Ro60-0175 (3 microg) on responding for cocaine was prevented by pretreatment with the selective 5-HT(2C) receptor antagonist SB242,084 (0.5 mg/kg). In a final experiment, intra-VTA injection of Ro60-0175 reduced responding for food reinforcement on the same progressive ratio schedule as used for cocaine self-administration. These results demonstrate that stimulation of 5-HT(2C) receptors in the VTA is sufficient to attenuate the stimulant and reinforcing effects of cocaine. These effects complement electrophysiological and neurochemical findings, and indicate that 5-HT(2C) receptors localized within the VTA modulate the activity of mesolimbic DA neurons.
Fletcher
Paul J
PJ
Section of Biopsychology, Centre for Addiction and Mental Health, Toronto, Ontario, Canada. Paul_Fletcher@camh.net
Chintoh
Araba F
AF
Sinyard
Judy
J
Higgins
Guy A
GA
D000631:Aminopyridines / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal; D003042:Cocaine / Q000008:administration & dosage / Q000494:pharmacology*; D003216:Conditioning, Operant / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004338:Drug Combinations; D004347:Drug Interactions; D005021:Ethylamines / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D009043:Motor Activity / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D012055:Reinforcement Schedule; D012646:Self Administration; D058830:Serotonin 5-HT2 Receptor Antagonists; D013997:Time Factors; D017557:Ventral Tegmental Area / Q000033:anatomy & histology / Q000187:drug effects*
C107820:6-chloro-5-methyl-1-((2-(2-methylpyrid-3-yloxy)pyrid-5-yl)carbamoyl)indoline; D000631:Aminopyridines; D004338:Drug Combinations; D005021:Ethylamines; D007211:Indoles; C103848:Ro 60-0175; D058830:Serotonin 5-HT2 Receptor Antagonists; D003042:Cocaine