title: 5-HT1A autoreceptor-mediated effects of the amperozide congeners, FG5865 and FG5893, on rat brain 5-hydroxytryptamine neurochemistry in vivo.
abstract: The two diphenylbutylpiperazinepyridinyl derivatives, FG5865 and FG5893, have a unique receptor binding profile in that they show very high and essentially equipotent affinities for both 5-HT1A and 5-HT2 receptors. The present report describes the acute effects of FG5865 and FG5893 on presynaptic 5-hydroxytryptamine (5-HT) neuronal function in the rat CNS, using established ex vivo and in vivo neurochemical techniques. Post-mortem measurements of tissue levels of 5-HT, its metabolite, 5-hydroxyindoleacetic acid (5-HIAA), and of the formation of 5-hydroxytryptophan (5-HTP; after inhibition of aromatic amino acid decarboxylase by NSD 1015) showed that FG5865 (0.1-20 mg/kg, s.c.) and FG5893 (0.1-20 mg/kg, s.c.) dose dependently decreased the synthesis and the metabolism/turnover of 5-HT--this to an extent comparable to the reference 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin. Reserpine (5 mg/kg, s.c.) pretreatment did not prevent the FG5893-induced decrease of 5-HT synthesis rate. In contrast, about 25-50 times higher doses of FG5865 were required to produce a comparable decrease in brain 5-HT synthesis in reserpinized vs. non-pretreated rats. In in vivo microdialysis experiments, both FG5865 (0.1-3.0 mg/kg, s.c.) and FG5893 (0.03-1.0 mg/kg, s.c.) caused a marked and dose-dependent decrease of 5-HT release in the ventral hippocampus. Pretreatment with the 5-HT1A receptor antagonist, (+/-)-pindolol (8 mg/kg, s.c.), abolished the FG5865 (0.3 mg/kg, s.c.)-induced reduction of 5-HT release, and (-)-pindolol (8 mg/kg, s.c.) similarly reversed the FG5893 (0.3 mg/kg, s.c.)-induced decrease. Local infusion of FG5865 into the ventral hippocampus (10 microM, 20-min pulse) resulted in a rapid and transient elevation of the 5-HT output, an effect that was independent of extracellular Ca2+. FG5893, on the other hand, did not affect the 5-HT release upon local administration. The results demonstrate that FG5865 and FG5893 potently affect a range of neurochemical indices of rat brain 5-HT neuronal activity in vivo, in a way consistent with indirect (FG5865) and direct (FG5865 and FG5893) stimulation of the 5-HT1A autoreceptors in the raphe nuclei.
authors.affiliation: Department of Pharmacology, University of Göteborg, Sweden.
authors.forename: S
authors.initials: S
authors.lastname: Hjorth
authors.forename: G
authors.initials: G
authors.lastname: Pettersson
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002118:Calcium / Q000494:pharmacology; D015283:Citalopram / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009539:Nicotinic Acids / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D011903:Raphe Nuclei / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism*; D012110:Reserpine / Q000494:pharmacology; D012701:Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*
chemical_list: D009539:Nicotinic Acids; D010879:Piperazines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D015283:Citalopram; C049058:amperozide; C083635:FG 5865; C081594:FG 5893; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; D012110:Reserpine; D002118:Calcium