CP-135,807, A SELECTIVE 5-HT1D AGONIST - EFFECTS IN DRUG DISCRIMINATION AND PUNISHMENT PROCEDURES IN THE PIGEON

CP-135,807 yrrolidin-2R-ylmethyl)-5-(3-nitropyrid-2-yl)amino- 1H-indol e] binds with high affinity to central 5-HT1D receptors, and in functi onal studies produces dose-dependent decreases in extracellular seroto nin. These and other findings have suggested that CP-135,807 may act a s a terminal 5-HT autoreceptor agonist. In an attempt to characterize the behavioral activity of selective 5-HT1D ligands, adult male Carnea u pigeons were trained to discriminate IM injections of 0.1 mg/kg CP-1 35,807 from saline under a two-key, fixed ratio schedule of food-reinf orced key pecking. CP-135,807 and the structurally unrelated 5-HT1D ag onist CP-286,601 fully and dose-dependently substituted for the traini ng dose. In contrast, little substitution was observed following admin istration of 8-OH-DPAT, a potent 5-HT1A agonist, the 5-HT1B agonist CP -94,253, or the serotonin reuptake inhibitor sertraline. In addition, the discriminative stimulus produced by CP-135,807 was not blocked by WAY 100,635, a selective 5-HT1A, antagonist, but was completely and do se-dependently antagonized by the selective 5-HT1D antagonist, GR12793 5. In subjects trained under a multiple schedule of punished and unpun ished responding, 8-OH-DPAT produced large increases in punished respo nding while having little effect on unpunished responding, In contrast , CP-135,807 and CP-94,253 produced no antipunishment effects, while G R127935 produced modest increases in punished responding. Collectively , these results suggest that CP-135,807 produces centrally mediated ps ychoactive effects that differ distinctly from those of 5-HT1A agonist s.