Long lasting attenuation of 8-OH-DPAT-induced corticosterone secretion after a single injection of a 5-HT1A receptor agonist.

The effects of 8-hydroxy-2-(di-n-propyl-amino)tetralin (8-OH-DPAT) and some other 5-hydroxytryptamine1A (5-HT1A) receptor agonists (buspirone, ipsapirone and flesinoxan) on corticosterone secretion in rats were studied. The 5-HT1A receptors mediating the corticosterone secretion appear to be postsynaptic to the 5-HT neurons, since the response to 8-OH-DPAT was not decreased but potentiated by depletion of 5-HT with p-chlorophenylalanine pretreatment of the animals. Rapid attenuation of the response was developed after a single dose of a 5-HT1A receptor agonist. Thus, 1 mg/kg s.c. of 8-OH-DPAT attenuated the response of a challenge dose (0.1 mg/kg s.c.) of this compound within 4 h lasting between 7 and 14 d. The development of the subsensitivity was antagonized by pretreatment of the rats with the 5-HT1A receptor antagonist S-5-fluoro-8-hydroxy-2-(di-n-propylamino)tetralin ((-)-UH 301). This compound also antagonized the acute effect of 8-OH-DPAT in increasing serum corticosterone. The subsensitivity development was specific for the 5-HT1A receptor-mediated corticosterone secretion, since the increase in serum corticosterone produced by stimulation of other receptor systems, e.g. alpha 2-adrenoreceptors (clonidine) or 5-HT2 receptors [1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane, (DOI)] was not affected.