Sleep-wake effects following the selective 5-HT(1A) receptor antagonist p-MPPI in the freely moving rat

The 5-HT(1A) receptors appear to play an important role in the serotonergic modulation of sleep and waking. Both presynaptic somatodendritic 5-HT(1A) autoreceptors and postsynaptic 5-HT(1A) heteroreceptors may be involved. The present study addressed the question of whether the selective 5-HT(1A) receptor antagonist 4-(2'-methoxy-phenyl)-1-[2'-(n-2"-pyridinyl)-p-iodobenzamido]-ethy l-p iperazine (p-MPPI) affected sleep and waking and whether such an effect would be dose-related. Polygraphic recording of sleep and waking in freely moving rats was employed following control injection and three doses of p-MPPI (1, 5 and 10 mg/kg i.p. in a balanced order design. Waking was increased and deep slow wave sleep decreased, while rapid eye movement (REM) sleep was suppressed over the first 6 h following injection, compared to after control injection. REM sleep was also suppressed following 10 mg/kg i.p. of p-MPPI as compared to following 1 mg/kg i.p. of p-MPPI. The interpretation of the effects is complex and the effects are not easily compatible with a simple model for serotonergic sleep-waking modulation. However, the REM sleep reduction probably reflects p-MPPIs ability to block the presynaptic 5-HT(1A) autoreceptors, increasing the firing activity in the serotonergic neurones and possibly inhibiting serotonin sensitive REM sleep active neurones.