Effect of neurokinin-I receptor antagonists on the function of 5-HT and noradrenaline neurons.
Substance P antagonists have been proposed to be a new class of antidepressants. The present study aimed to determine the effect of the selective non-peptide rat neurokinin-1 (NK1) receptor antagonists WIN 51,708 and CP-96,345 on the firing activity of rat dorsal raphe serotonin (5-HT) and locus coeruleus noradrenaline (NA) neurons. While WIN51,708 (2mg/kg, i.v.) and CP-96,345 (0.15 mg/kg, i.v.) did not modify the firing activity of 5-HT and NA neurons, both antagonists attenuated the suppressant effect of the alpha2-adrenoceptor agonist clonidine on the firing activity of both types of neurons. In contrast, the responsiveness of 5-HT neurons to the i.v. administration of the 5-HT autoreceptor agonist LSD and the 5-HT1A receptor agonist 8-OH-DPAT remained unchanged. These findings suggest that NK1 receptor antagonists affect markedly the NA system via an attenuation of the function of alpha2-adrenoceptors on the cell body of NA neurons and, consequently, may also modulate 5-HT neurotransmission.
Haddjeri
N
N
Neurobiological Psychiatry Unit, McGill University, Montréal, Québec, Canada.
Blier
P
P
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000008:administration & dosage; D000316:Adrenergic alpha-Agonists / Q000008:administration & dosage; D000317:Adrenergic alpha-Antagonists / Q000008:administration & dosage; D000731:Androstanes / Q000008:administration & dosage; D000818:Animals; D001562:Benzimidazoles / Q000008:administration & dosage; D001596:Benzylamines / Q000008:administration & dosage; D001713:Biphenyl Compounds / Q000008:administration & dosage; D003000:Clonidine / Q000008:administration & dosage / Q000037:antagonists & inhibitors; D004305:Dose-Response Relationship, Drug; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D008125:Locus Coeruleus / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008238:Lysergic Acid Diethylamide / Q000008:administration & dosage; D008297:Male; D064729:Neurokinin-1 Receptor Antagonists; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011903:Raphe Nuclei / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000008:administration & dosage; D017366:Serotonin Receptor Agonists / Q000008:administration & dosage
D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D000731:Androstanes; D001562:Benzimidazoles; D001596:Benzylamines; D001713:Biphenyl Compounds; D064729:Neurokinin-1 Receptor Antagonists; D010879:Piperazines; D011725:Pyridines; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; C086111:WIN 51708; D012701:Serotonin; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D008238:Lysergic Acid Diethylamide; D003000:Clonidine; C012102:DSP 4; C066892:CP 96345; D009638:Norepinephrine