CENTRAL-TYPE BENZODIAZEPINE RECEPTORS MEDIATE THE ANTIDOPAMINERGIC EFFECT OF CLONAZEPAM AND MELATONIN IN 6-HYDROXYDOPAMINE LESIONED RATS - INVOLVEMENT OF A GABAERGIC MECHANISM

In this study, we examined the effect of the central-type benzodiazepi ne agonist, clonazepam, and the indoleamine hormone, melatonin, on cen tral dopaminergic function using the 6-hydroxydopamine model of dopami ne receptor supersensitivity. Unilateral lesioning of the nigrostriata l pathway with 6-hydroxydopamine was carried out in Sprague-Dawley rat s. Two weeks after surgery, the animals were examined for the presence of dopaminergic supersensitivity by their response to the dopamine re ceptor agonist, apomorphine. Clonazepam, melatonin and its analogs, 6- chloromelatonin and 2-iodomelatonin, significantly inhibited apomorphi ne-induced turning behavior (P <.01). Pretreatment with a central-type benzodiazepine antagonist, flumazenil, significantly reduced the effe ct of melatonin and clonazepam (P <.01). The peripheral-type benzodiaz epine antagonist, PK 11195, caused some attenuation of melatonin's eff ect (P <.05), but it was significantly less potent than flumazenil. Bi cuculline, a GABA(A) receptor antagonist, was also found to reduce the inhibitory effect of melatonin on the induced rotational response (P <.01). These results indicate that the antidopaminergic effect of clon azepam and melatonin is mediated predominantly by central-type benzodi azepine receptors in the central nervous system, via a GABAergic mecha nism.