Effect of the putative 5-HT1A receptor antagonist NAN-190 on rat brain serotonergic transmission.
Based on the fact that 1-(2-methoxyphenyl)-4(4-(2-phtalimido)butyl)piperazine (NAN-190), a high-affinity ligand for 5-HT1A and alpha 1-adrenoceptors, antagonizes the behavioural effects of the 5-HT1A receptor agonist 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin), it has been suggested that this drug behaves as a 5-HT1A receptor antagonist. In the present study we examined the effects of this putative 5-HT1A receptor antagonist on rat brain serotonergic neurotransmission. In hippocampal slices of immature rats, NAN-190 but not prazosin potently antagonized (IC50 = 29 nM) the inhibitory effect of 8-OH-DPAT (1 microM) on carbachol-stimulated phosphoinositide turnover but (up to 1 microM) failed to alter the carbachol response. Similarly, NAN-190 (0.1 microM) almost totally prevented the inhibition by 8-OH-DPAT (1 microM) of forskolin-stimulated adenylate cyclase activity in adult rat hippocampal slices but, per se, was without effect on the forskolin response. These results indicate that NAN-190 is a potent antagonist at postsynaptic 5-HT1A receptors in vitro. However, NAN-190 also potently antagonized (IC50 = 0.16 nM) the stimulation by norepinephrine of phosphoinositide turnover in rat cortical slices. In this respect NAN-190 was a 250-fold more potent antagonist than prazosin (IC50 = 49 nM). Thus, in addition to its 5-HT1A receptor antagonist properties, NAN-190 has potent alpha 1-adrenoceptor blocking properties.(ABSTRACT TRUNCATED AT 250 WORDS)
Claustre
Y
Y
Synthélabo Recherche (L.E.R.S.), Biology Department, Bagneux, France.
Rouquier
L
L
Serrano
A
A
Bénavidès
J
J
Scatton
B
B
D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000502:physiology; D002540:Cerebral Cortex / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D010716:Phosphatidylinositols / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects / Q000502:physiology; D011985:Receptors, Serotonin / Q000502:physiology; D012701:Serotonin / Q000502:physiology*; D012702:Serotonin Antagonists / Q000494:pharmacology*; D009435:Synaptic Transmission / Q000187:drug effects*
D010716:Phosphatidylinositols; D010879:Piperazines; D011942:Receptors, Adrenergic, alpha; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; C058895:1-(2-methoxyphenyl)-4-(4-(2-phthalimido)butyl)piperazine; D012701:Serotonin