MECHANISMS UNDERLYING THE ANTIDOPAMINERGIC EFFECT OF CLONAZEPAM AND MELATONIN IN STRIATUM

Intrastriatal injection of the GABA(A) antagonist, bicuculline, caused about a 75% decrease in the inhibitory effect of the central-type ben zodiazepine (BZ) agonist, clonazepam or the indoleamine hormone, melat onin, on apomorphine-induced rotation in a 6-hydroxydopamine model of dopaminergic supersensitivity. Pretreatment with the peripheral-type B Z antagonist, PK 11195 (intrastriatally or intraperitoneally), also at tenuated the antidopaminergic effect of these drugs but with much less potency than bicuculline. However, the combination of both bicucullin e and PK 11195, injected directly into the striatum, completely blocke d the antidopaminergic action of clonazepam or melatonin. These result s indicate that the antidopaminergic action of clonazepam and melatoni n in the striatum involves two distinct mechanisms: (1) a predominant GABAergic activation via the BZ/GABA(A) receptor complex, and (2) a se condary mechanism linked to a PK 11195 sensitive BZ receptor pathway. Recent studies indicate that PK 11195 blocks BZ-induced inhibition of the adenylyl cyclase-cyclic AMP pathway in the striatum. Since cyclic AMP has been implicated in the rotational behaviour of 6-hydroxydopami ne-lesioned animals, it is possible that the antidopaminergic action o f clonazepam and melatonin also involves suppression of this second me ssenger. (C) 1998 Elsevier Science Ltd. All rights reserved.