title: CP-135,807, a selective 5-HT1D agonist: effects in drug discrimination and punishment procedures in the pigeon.
abstract: CP-135,807 [3-(N-methylpyrrolidin-2R-ylmethyl)-5-(3-nitropyrid-2- yl)amino-1H-indole] binds with high affinity to central 5-HT1D receptors, and in functional studies produces dose-dependent decreases in extracellular serotonin. These and other findings have suggested that CP-135,807 may act as a terminal 5-HT autoreceptor agonist. In an attempt to characterize the behavioral activity of selective 5-HT1D ligands, adult male Carneau pigeons were trained to discriminate IM injections of 0.1 mg/kg CP-135,807 from saline under a two-key, fixed ratio schedule of food-reinforced key pecking. CP-135,807 and the structurally unrelated 5-HT1D agonist CP-286,601 fully and dose-dependently substituted for the training dose. In contrast, little substitution was observed following administration 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 dose-dependently antagonized by the selective 5-HT1D antagonist, GR 127935. In subjects trained under a multiple schedule of punished and unpunished responding, 8-OH-DPAT produced large increases in punished responding while having little effect on unpunished responding. In contrast, CP-135,807 and CP-94,253 produced no antipunishment effects, while GR 127935 produced modest increases in punished responding. Collectively, these results suggest that CP-135,807 produces centrally mediated psychoactive effects that differ distinctly from those of 5-HT1A agonists.
authors.affiliation: Department of Neuroscience, Pfizer Central Research, Groton, CT 06340, USA.
authors.forename: R S
authors.initials: RS
authors.lastname: Mansbach
authors.forename: C C
authors.initials: CC
authors.lastname: Rovetti
authors.forename: J E
authors.initials: JE
authors.lastname: Macor
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D010856:Columbidae; D003216:Conditioning, Operant / Q000187:drug effects; D004193:Discrimination Learning / Q000187:drug effects; D004192:Discrimination, Psychological / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D007211:Indoles / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D008297:Male; D010069:Oxadiazoles / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011678:Punishment; D011725:Pyridines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D011985:Receptors, Serotonin / Q000502:physiology*; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*
chemical_list: D007211:Indoles; D010069:Oxadiazoles; D010879:Piperazines; D011725:Pyridines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; C101999:CP 135807; C090701:GR 127935; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin