BIMT 17, a 5-HT1A receptor agonist/5-HT2A receptor antagonist, directly activates postsynaptic 5-HT inhibitory responses in the rat cerebral cortex.
BIMT 17 (1-[2-[4-(3-trifluoromethyl phenyl) piperazin-1-yl] ethyl] benzimidazol- [1H]-2-one), a 5-HT1A receptor agonist/5-HT2A receptor antagonist (see Borsini et al., accompanying paper), in a dose range of 1-10 mg/kg i.v., dose-dependently inhibited the electrical activity of rat medial prefronto-cortical neurons, whereas buspirone, in a dose range of 0.1-1000 micrograms/kg, increased it. 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) and 1-[2-(2-thenoylamino)ethyl]-4-[1-(7-methoxynaphthyl)] piperazine (S 14671) presented biphasic patterns of response; they increased electrical activity at doses in the range of 0.1-10 micrograms/kg and 0.1-3 micrograms/kg i.v. respectively, and reduced it at high doses, 30-300 micrograms/kg and 10-30 micrograms/kg i.v., respectively. The inhibitory effect of BIMT 17 on the firing rate of neurons in the frontal cortex was antagonized by the 5-HT1A antagonists tertatolol and WAY 100135, and was still present after destruction of serotonin (5-HT) containing neuronal endings by the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT; 150 micrograms/rat, given intraventricularly), which reduced the cortical 5-HT content by 85%. This destruction of 5-HT neurons, while suppressing the ability of 8-OH-DPAT to inhibit the firing rate at high doses, did not change the excitatory action of this compound at low doses. The addition of ritanserin, a 5-HT2A receptor antagonist, potentiated both the excitatory and inhibitory effects of 8-OH-DPAT on neuronal electrical activity. Direct microiontophoretic application (100 nA/20 s) of 5-HT and BIMT 17, but not that of 8-OH-DPAT, onto medial prefronto-cortical neurons, decreased the firing rate of these neurons.(ABSTRACT TRUNCATED AT 250 WORDS)
Borsini
F
F
Research Division, Boehringer Ingelheim Italia, Milano, Italy.
Ceci
A
A
Bietti
G
G
Donetti
A
A
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000378:metabolism / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000378:metabolism / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001562:Benzimidazoles / Q000378:metabolism / Q000494:pharmacology*; D001667:Binding, Competitive; D002065:Buspirone / Q000378:metabolism / Q000494:pharmacology; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D007478:Iontophoresis; D008297:Male; D008839:Microelectrodes; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D010879:Piperazines / Q000378:metabolism / Q000494:pharmacology; D011224:Prazosin / Q000378:metabolism / Q000494:pharmacology; D011412:Propanolamines / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000187:drug effects*; D016713:Ritanserin / Q000378:metabolism / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000378:metabolism / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000378:metabolism / Q000494:pharmacology*; D013876:Thiophenes / Q000378:metabolism / Q000494:pharmacology
D000319:Adrenergic beta-Antagonists; D000928:Antidepressive Agents; D001562:Benzimidazoles; D010879:Piperazines; D011412:Propanolamines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D013876:Thiophenes; C081293:WAY 100135; C073650:S 14671; D016713:Ritanserin; C098107:flibanserin; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; C005632:tertatolol; D002065:Buspirone; D011224:Prazosin