Central-type benzodiazepine receptors mediate the antidopaminergic effect of clonazepam and melatonin in 6-hydroxydopamine lesioned rats: involvement of a GABAergic mechanism.
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In this study, we examined the effect of the central-type benzodiazepine agonist, clonazepam, and the indoleamine hormone, melatonin, on central dopaminergic function using the 6-hydroxydopamine model of dopamine receptor supersensitivity. Unilateral lesioning of the nigrostriatal pathway with 6-hydroxydopamine was carried out in Sprague-Dawley rats. Two weeks after surgery, the animals were examined for the presence of dopaminergic supersensitivity by their response to the dopamine receptor agonist, apomorphine. Clonazepam, melatonin and its analogs, 6-chloromelatonin and 2-iodomelatonin, significantly inhibited apomorphine-induced turning behavior (P < .01). Pretreatment with a central-type benzodiazepine antagonist, flumazenil, significantly reduced the effect of melatonin and clonazepam (P < .01). The peripheral-type benzodiazepine antagonist, PK 11195, caused some attenuation of melatonin's effect (P < .05), but it was significantly less potent than flumazenil. Bicuculline, a GABAA 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 clonazepam and melatonin is mediated predominantly by central-type benzodiazepine receptors in the central nervous system, via a GABAergic mechanism.
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