cp-94253 and ipsapirone

The serotonergic cells of the dorsal raphé nucleus innervate much of the forebrain and are thought to be involved in the mechanism of action of antidepressants. Dysfunction of these cells might be involved in the neural mechanisms underlying depression and suicide. The traffic in pathways emanating from the dorsal raphé nucleus is controlled by 5-HT(1) autoreceptors. Until recently it was thought that the autoreceptors in the dorsal raphé nucleus were solely of the 5-HT(1A) subtype. In this article, we discuss evidence that the situation is more complex and that multiple 5-HT(1) subtypes govern different aspects of 5-HT function in the dorsal raphé nucleus presenting new therapeutic opportunities.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Animals; Antidepressive Agents, Second-Generation; Autoreceptors; Dimerization; Guinea Pigs; Humans; Ion Channels; Ion Transport; Mice; Nerve Tissue Proteins; Neurons; Oxadiazoles; Piperazines; Protein Isoforms; Pyridines; Pyrimidines; Raphe Nuclei; Rats; Receptor, Serotonin, 5-HT1B; Receptor, Serotonin, 5-HT1D; Receptors, Serotonin; Receptors, Serotonin, 5-HT1; Second Messenger Systems; Selective Serotonin Reuptake Inhibitors; Serotonin; Serotonin Receptor Agonists; Spiperone; Sumatriptan

The effects of serotonin (5-hydroxytryptamine, 5-HT)(1/2) receptor agonists for 5-HT(1) and 5-HT(2) receptors on dark-phase ingestive behavior were evaluated in 12-h food-deprived, female Wistar rats. The amount of food and water consumed after 1, 2, 6 and 12 h was measured. The following agonists were tested: ipsapirone [preferred 5-HT receptor(s) and dose range in mg/kg, IP: 5-HT(1A) and 3-30, respectively], CP-94,253 (5-HT(1B); 0.3-3), TFMPP (5-HT(1B/2C); 0. 3-10), m-CPP (5-HT(2C/1B); 0.3-10), ORG 37684 (5-HT(2C); 0.3-10), BW 723C86 (5-HT(2B); 3-30) and DOI (5-HT(2A/2C); 0.3-3). Ipsapirone induced hyperphagia during the first hour of food access and hypophagia during the last interval. All other compounds induced dose- and time-dependent hypophagia. m-CPP and TFMPP induced the most marked reduction of food intake and were the only drugs inducing rebound hyperphagia. Except for m-CPP and TFMPP, effects on food intake could generally be dissociated from effects on water intake. The receptor profile of the compounds tested suggests that stimulation of 5-HT(1B), 5-HT(2C), 5-HT(2A) or 5-HT(2B) receptors results in hypophagia. As the less selective agonists were the more potent anorexics, it is suggested that simultaneous activation of these receptors results in synergistic effects on ingestive behavior. Additional antagonism studies are required to ascertain the proposed role of particular 5-HT receptor subtypes in the hypophagic effects of the tested compounds.

Topics: Amphetamines; Animals; Darkness; Dose-Response Relationship, Drug; Drinking; Drinking Behavior; Eating; Feeding Behavior; Female; Indoles; Piperazines; Pyridines; Pyrimidines; Rats; Rats, Wistar; Receptors, Serotonin; Receptors, Serotonin, 5-HT1; Serotonin Receptor Agonists; Thiophenes; Time Factors