Effects of the putative 5-hydroxytryptamine1A 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-HT1A 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 micrograms/kg i.v.) and NAN 190 (5-250 micrograms/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 micrograms/kg vs. 34.2 micrograms/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-HT1A 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-HT1A autoreceptor.(ABSTRACT TRUNCATED AT 250 WORDS)
Fornal
C A
CA
Department of Psychology, Princeton University, New Jersey.
Marrosu
F
F
Metzler
C W
CW
Tada
K
K
Jacobs
B L
BL
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002415:Cats; D005260:Female; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D010879:Piperazines / Q000494:pharmacology*; D011433:Propranolol / Q000494:pharmacology*; D011903:Raphe Nuclei / Q000187:drug effects* / Q000502:physiology; D012701:Serotonin / Q000502:physiology; D012702:Serotonin Antagonists / Q000494:pharmacology*
D010879:Piperazines; D012702:Serotonin Antagonists; C058895:1-(2-methoxyphenyl)-4-(4-(2-phthalimido)butyl)piperazine; D012701:Serotonin; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D011433:Propranolol; C053428:BMY 7378