Comparative effects of chronic 8-OH-DPAT, gepirone and ipsapirone treatment on the sensitivity of somatodendritic 5-HT1A autoreceptors.

Chronic treatment with the full 5-hydroxytryptamine1A (5-HT1A) agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), either by twice daily subcutaneous injection (0.2 or 2.0 mg/kg) or continuous subcutaneous administration via osmotic minipumps (0.4 or 4.0 mg/kg/day), for 14 days, had no effect on the dose-response curves for inhibition of 5-hydroxytryptophan (5-HTP) accumulation in rat cortex or hippocampus by 8-OH-DPAT or the partial 5-HT1A agonist BMY 7378. In contrast, chronic treatment with the nonbenzodiazepine putative anxiolytic gepirone via osmotic minipumps (20 mg/kg/day) resulted in a small but significant rightward shift (1.8-fold) in the dose-response curve to 8-OH-DPAT challenge in the cortex and a slightly larger shift (2.4-fold) in the hippocampus. Similarly, chronic treatment with another putative anxiolytic, ipsapirone, administered via twice daily subcutaneous injections (20 mg/kg), also resulted in a rightward shift (2.6-fold) in the dose-response curve to 8-OH-DPAT in the cortex and a slightly smaller shift (2.3-fold) in the hippocampus. Neither drug, however, decreased the maximal response. The present results are consistent with the suggestion that the clinical anxiolytic effects of gepirone and ipsapirone, and not of 8-OH-DPAT, may be related to their ability to desensitize somatodendritic 5-HT1A autoreceptors; other potential mechanisms are discussed.