Serotonergic modulation of the behavioral effects of cocaine in the squirrel monkey.
The behavioral effects of cocaine (0.03-3.0 mg/kg) and several selective serotonin (5HT) uptake inhibitors, direct agonists and antagonists were determined in squirrel monkeys trained to respond under a fixed-interval (FI) schedule of stimulus termination and a second-order schedule of i.v. drug self-administration. Intermediate doses of cocaine increased fixed-interval response rate markedly, and higher doses decreased response rate below control (nondrug) values. The i.v. self-administration of cocaine (0.025-1.0 mg/injection) maintained schedule-appropriate responding over a range of doses, and response rate under the second-order schedule was a function of drug dose. In contrast, none of the 5HT uptake inhibitors (alaproclate, clomipramine and fluoxetine) or direct agonists ((+/-)-1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane, (+/-)-8-hydroxy-2-(di-N-propylamino) tetralin and quipazine) increased fixed-interval response rate, nor did the 5HT uptake inhibitors maintain self-administration. In drug interaction studies, the 5HT uptake inhibitors and quipazine produced an insurmountable attenuation of the behavioral-stimulant effects of cocaine, whereas the 5HT antagonists (ketanserin, mianserin and ritanserin) with high affinity for 5HT2 binding sites enhanced the behavioral-stimulant effects of low or intermediate doses of cocaine. Additionally, administration of ritanserin increased response rate for i.v. for self-administration of cocaine over a range of cocaine doses. The pharmacological profile of effects of selective 5HT uptake inhibitors and direct agonists indicates that the behavioral-stimulant and reinforcing effects of cocaine do not depend on inhibition of 5HT uptake, whereas the drug interactions suggest that the serotonergic system can modulate specific behavioral effects of cocaine.
Yerkes Regional Primate Research Center, Emory University, Atlanta, Georgia, USA.
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Howell
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Byrd
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D003042:Cocaine / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D008297:Male; D012453:Saimiri; D012646:Self Administration; D012702:Serotonin Antagonists / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*
D003042:Cocaine; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D017367:Selective Serotonin Reuptake Inhibitors