Subchronic treatment with anxiolytic doses of the 5-HT1A receptor agonist ipsapirone does not affect 5-HT2 receptor sensitivity in the rat.

Acute stimulation of 5-HT1A receptors has been reported to diminish some 5-HT2 receptor-mediated responses in the rat, but there is controversy as to whether repeated stimulation of 5-HT1A receptors leads to identical changes. In this study, we tested the influence of repeated treatment with the 5-HT1A receptor agonist ipsapirone (0.5 g/l in drinking water for 21 days) on some 5-HT2 receptor-mediated responses elicited by the acute injection of the 5-HT1C/5-HT2 receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI). These responses included hyperglycemia, corticosterone release, and head shakes; cortical 5-HT2 receptor number and DOI-induced prolactin release (a 5-HT1C/5-HT2 receptor-mediated event) were also analyzed. In a first series of experiments, ipsapirone administration for 1, 8, 15, and 20 days reduced the duration fo shock-induced ultrasonic vocalization. Ipsapirone administration for 21 days reduced fluid intake and decreased body weight, but did not affect baseline plasma glucose, corticosterone, and prolactin levels or cortical 5-HT2 receptor number. The increases in plasma glucose levels elicited by acute injection of either DOI (0.1-1 mg/kg i.v.) or clonidine (an alpha 2-adrenoceptor agonist; 0.05 mg/kg i.v.) were reduced in ipsapirone-pretreated rats. The maximal effects of DOI and clonidine on plasma corticosterone or prolactin levels were not affected by ipsapirone pretreatment. Ipsapirone decreased the area under the corticosterone curve in both DOI- and clonidine-treated rats. Lastly, the head-shake response to DOI (0.5-2 mg/kg s.c.) was similar in vehicle- and ipsapirone-pretreated rats. These data indicate that a 3-week treatment with anxiolytic doses of the 5-HT1A receptor agonist ipsapirone does not desensitize 5-HT2 receptors.