WAY-100635, a potent and selective 5-hydroxytryptamine_1A antagonist, increases serotonergic neuronal activity in behaving cats: Comparison with (S)-WAY-100135

We reported previously that pharmacological blockade of somatodendritic 5-hydroxytryptamine (5-HT)_1A autoreceptors with spiperone, a nonselective 5-HT_1A antagonist, increases the spontaneous firing rate of central serotonergic neurons in awake cats. The present study examined the effects of systemic administration of two reportedly selective 5-HT_1A receptor antagonists, (S)-WAY-100135 {N-fert-butyl-3-[4-(2-methoxyphenyl)piperazin-1-yl]-2-phenylpropanamide} and its more potent analog WAY-100635 {N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexanecarboxamide}, on the single-unit activity of serotonergic neurons in the dorsal raphe nucleus of freely moving cats. In addition, we assessed the antagonist action of these compounds at the 5-HT_1A autoreceptor by examining their ability to block the inhibition of serotonergic neuronal activity produced by systemic administration of 8-hydroxy-2-(di-n-propylamino)tetralin, a highly selective 5-HT_1A agonist. Administration of (S)-WAY-100135 (0.025-1.0 mg/kg i.v.) moderately depressed neuronal activity at all doses tested. In contrast, administration of WAY-100635 (0.025-0.5 mg/kg i.v.) significantly increased neuronal activity. The stimulatory action of WAY-100635, like that of spiperone, was evident during wakefulness (when serotonergic neurons typically display a relatively high level of activity) but not during sleep (when serotonergic neurons display little or no spontaneous activity). Pretreatment with (S)-WAY-100135 (0.5 mg/kg i.v.) weakly attenuated the inhibitory action of 8-hydroxy-2-(di-n-propylamino)tetralin. In contrast, WAY-100635 at doses as low as 0.1 mg/kg i.v. completely blocked the action of 8-hydroxy-2-(di-n-propylamino)tetralin. The antagonist action of WAY-100635 at 5-HT_1A autoreceptors closely paralleled its ability to increase neuronal activity. Overall, WAY-100635 appears to act as a selective 5-HT_1A antagonist, whereas (S)-WAY-100135 does not. The results obtained with WAY-100635 confirm our previous findings obtained with spiperone and further support the hypothesis that 5-HT_1A autoreceptor-mediated feedback inhibition operates under physiological conditions.