Effects of the novel 5-HT1A receptor antagonist, (+)-WAY 100135, on stereotyped behaviour induced by the NMDA receptor antagonist dizocilpine in rats.

We have recently shown that the stereotyped behaviour induced by the uncompetitive NMDA receptor antagonist dizocilpine (MK-801) can be attenuated or blocked by partial agonists at 5-HT receptors of the 5HT1A subtype, indicating that 5-HT (5-hydroxytryptamine, serotonin) is involved in the stereotyped behaviour produced by dizocilpine. In the present experiment, a selective, silent 5-HT1A receptor antagonist, (+)-WAY 100135 (N-tert-butyl 3-4(2-methoxyphenyl) piperazin 1-yl-2-phenylpropanamide dihydrochloride), was used to further study the role of 5-HT activation in dizocilpine-induced behaviours. At a dose of 10 mg/kg, (+)-WAY 100135 significantly reduced the intensity of head weaving induced by dizocilpine, but this effect was lost by increasing the dose to 20 mg/kg. At this higher dose, (+)-WAY 100135 induced marked but short-lasting increases in skeletal muscle tone and hindlimb abduction, resembling components of the '5-HT behavioural syndrome', which would explain its biphasic effects on dizocilpine induced behaviours. The data substantiate that, in addition to the well known activation of dopaminergic transmission, activation of the 5-HT system might be involved in the behavioural effects of NMDA receptor antagonists such as dizocilpine.