Abstract
Previously, we have shown that systemic administration of the 5-HT2C 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-HT2C 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 μg, 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 μg 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 μg) on responding for cocaine was prevented by pretreatment with the selective 5-HT2C 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-HT2C 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-HT2C receptors localized within the VTA modulate the activity of mesolimbic DA neurons.
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This work was supported by a grant from the Canadian Institutes of Health Research to PJF.
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Fletcher, P., Chintoh, A., Sinyard, J. et al. Injection of the 5-HT2C Receptor Agonist Ro60-0175 into the Ventral Tegmental Area Reduces Cocaine-Induced Locomotor Activity and Cocaine Self-Administration. Neuropsychopharmacol 29, 308–318 (2004). https://doi.org/10.1038/sj.npp.1300319
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DOI: https://doi.org/10.1038/sj.npp.1300319
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