Involvement of central serotonergic systems in dextromethorphan-induced behavioural syndrome in rats

Abstract

Dextromethorphan, a noncompetitive blocker of the N-methyl-D-aspartate (NMDA) type of glutamate receptor, at 45, 60 and 75 mg/kg,<i> </i>ip doses induced a behavioural syndrome characterised by reciprocal forepaw treading, lateral head-weaving, hind-limb abduction and flat body posture. Such type of behavioural syndrome is induced by 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) by directly stimulating the central postsynaptic 5-hydroxytryptamine (5-HT, serotonin) receptors of the 5-HT_1A type. Pretreatment with buspirone (5, 10 mg/kg, ip) and l-propranolol (10, 20 mg/kg,<i> </i>ip) antagonised the behavioural syndrome induced by 8-OH-DPAT and dextromethorphan. Pretreatment with <i>p</i>-chlorophenylalanine (100 mg/kg/day×4 days) antagonised the behavioural syndrome induced by dextromethorphan and dexfenfluramine but had no significant effect on 8-OH-DPAT induced behavioural syndrome. This indicates that dextromethorphan induces the behavioural syndrome by releasing 5-HT from serotonergic neurons with resultant activation of the postsynaptic 5-HT_1A receptors by the released 5-HT. Pretreatment with fluoxetine (10 mg/kg,<i> </i>ip) significantly potentiated the behavioural syndrome induced by dextromethorphan and 5-hydroxytryptophan but significantly antagonised dexfenfluramine induced behavioural syndrome. This indicates that dextromethorphan releases 5-HT by a mechanism which differs from that of dexfenfluramine. Dextromethorphan may be releasing 5-HT by blocking the NMDA receptors and thereby counteracting the inhibitory influence of 1-glutamate on 5-HT release.