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)