Effects of the putative 5-hydroxytryptamine(1A) antagonists BMY 7378, NAN 190 and (-)-propranolol on serotonergic dorsal raphe unit activity in behaving cats

Recent evidence from our laboratory has demonstrated that blockade of somatodendritic 5-hydroxytryptamine (5-HT)(1A) autoreceptors by systemic administration of spiperone increases the firing rate of central serotonergic neurons in awake cats. The present study examines the effects of three other putative 5-HT(1A) antagonists (BMY 7378 {8-[2-[4-(2-methoxyphenyl)-1- piperazinyl]ethyl]-8-azaspiro[4,5]decane-7,9-dione}, NAN 190 {1-(2- methoxyphenyl)-4-[4-(2-phthalimido)butyl]piperazine} and (-)-propranolol) on the single-unit activity of serotonergic neurons recorded in the dorsal raphe nucleus of free-moving cats. Systemic administration of the phenylpiperazine derivatives BMY 7378 (5-100 μg/kg i.v.) and NAN 190 (5-250 μg/kg i.v.) produced a rapid, dose-dependent inhibition of neuronal activity with BMY 7378 being approximately twice as potent as NAN 190 (ED₅₀ = 15.3 μg/kg vs. 34.2 μg/kg). The suppression of neuronal activity produced by both compounds was greatly attenuated by spiperone (1 mg/kg i.v.). Systemic administration of (-)-propranolol (2 and 4 mg/kg i.v.) produced a modest suppression of serotonergic neuronal activity which did not appear to be dose-related. The ability of BMY 7378, NAN 190 and (-)-propranolol to block the suppression of neuronal activity produced by 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH- DPAT), a selective 5-HT(1A) agonist, was also examined. Pretreatment with these compounds had no significant effect on the inhibitory response of serotonergic neurons to 8-OH-DPAT challenge. These results indicate that BMY 7378 and NAN 190 act as agonists rather than antagonists at the somatodendritic 5-HT(1A) autoreceptor. Furthermore, (-)-propranolol, unlike spiperone, does not appear to be an effective 5-HT(1A) autoreceptor antagonist, because it did not block the action of 8-OH-DPAT or increase basal serotonergic neuronal activity in awake animals.