The 5-HT_1A receptor antagonist p-MPPI blocks 5-HT_1A autoreceptors and increases dorsal raphe unit activity in awake cats

The effects of the putative 5-HT_1A receptor antagonist 4-iodo-N-[2-[4-(methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinyl-benzamide (p-MPPI) were examined on the activity of serotonergic dorsal raphe nucleus neurons in freely moving cats. Systemic administration of p-MPPI produced a dose-dependent increase in firing rate. This stimulatory effect of p-MPPI was evident during wakefulness (when serotonergic neurons display a relatively high level of activity), but not during sleep (when serotonergic neurons display little or no spontaneous activity). p-MPPI also blocked the ability of the 5-HT_1A receptor agonist 8-hydroxy-(2-di-n-propylamino)tetralin (8-OH-DPAT) to inhibit serotonergic neuronal activity. This antagonism was evident both as a reversal of the neuronal inhibition produced by prior injection of 8-OH-DPAT and as a shift in the potency of 8-OH-DPAT following p-MPPI pretreatment. Overall, these results in behaving animals indicate that p-MPPI acts as an effective 5-HT_1A autoreceptor antagonist. The increase in firing rate produced by p-MPPI supports the hypothesis that autoreceptor-mediated feedback inhibition operates under physiological conditions.