Chronic alnespirone-induced desensitization of somatodendritic 5-HT1A autoreceptors in the rat dorsal raphe nucleus

The effects of long-term (7, 14, or 21 days) administration of the 5-HT1A receptor agonist alnespirone [5 mg/(kg day), i.p.] on the binding characteristics of 5-HT1A,5-HT2A and 5-HT3 receptors, and the functional status of 5-HT1A autoreceptors were assessed using biochemical and electrophysiological approaches in rats. Whatever the treatment duration, the specific binding of [H-3]8 hydroxy-2-(di-n-propylamino)tetralin ([H-3]8-OH-DPAT), [H-3]trans,4-[(3Z)3-(2-dimethylaminoethyl) oxyimino-3(2-fluorophenyl) propen-1-yl] phenol hemifumarate ([H-3]SR 46349B), and [H-3]S-zacopride to 5-HT1A, 5-HT2A and 5-HT3 receptors, respectively, were unaltered in all the brain areas examined. In contrast, in vitro electrophysiological recordings performed 24 h after the last injection of alnespirone showed that the potency of the 5-HT1A receptor agonist, 8-OH-DPAT, to depress the firing of serotoninergic neurons in the dorsal raphe nucleus, was significantly reduced after a 21-day treatment with alnespirone. However, no changes were noted after a 7-day or 14-day treatment. These data indicate that desensitization of somatodendritic 5-HT1A autoreceptors is a selective but slowly developing adaptive phenomenon in response to their chronic stimulation in rats. (C) 1999 Elsevier Science B.V. All rights reserved.