Involvement of central serotonergic systems in dextromethorphan-induced behavioural syndrome in rats.
Dextromethorphan, a noncompetitive blocker of the N-methyl-D-aspartate (NMDA) type of glutamate receptor, at 45, 60 and 75 mg/kg, 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-HT1A type. Pretreatment with buspirone (5, 10 mg/kg, ip) and l-propranolol (10, 20 mg/kg, ip) antagonised the behavioural syndrome induced by 8-OH-DPAT and dextromethorphan. Pretreatment with p-chlorophenylalanine (100 mg/kg/day x 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-HT1A receptors by the released 5-HT. Pretreatment with fluoxetine (10 mg/kg, 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 l-glutamate on 5-HT release.
Gaikwad
R V
RV
Department of Pharmacology, Krishna Institute of Medical Sciences, Karad 415 110, India.
Gaonkar
R K
RK
Jadhav
S A
SA
Thorat
V M
VM
Jadhav
J H
JH
Balsara
J J
JJ
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000633:toxicity; D000818:Animals; D000996:Antitussive Agents / Q000633:toxicity; D001522:Behavior, Animal / Q000187:drug effects* / Q000502:physiology; D002065:Buspirone / Q000494:pharmacology; D002490:Central Nervous System / Q000187:drug effects* / Q000503:physiopathology; D020372:Dexfenfluramine / Q000633:toxicity; D003915:Dextromethorphan / Q000633:toxicity*; D005473:Fluoxetine / Q000494:pharmacology; D008297:Male; D011433:Propranolol / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000502:physiology; D017366:Serotonin Receptor Agonists / Q000633:toxicity; D013577:Syndrome
D000996:Antitussive Agents; D017366:Serotonin Receptor Agonists; D005473:Fluoxetine; D012701:Serotonin; D003915:Dextromethorphan; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D011433:Propranolol; D020372:Dexfenfluramine; D002065:Buspirone