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 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.
Tenn
C C
CC
Department of Biomedical Sciences, McMaster University, Hamilton Ontario, Canada.
Niles
L P
LP
D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D001640:Bicuculline / Q000494:pharmacology; D002998:Clonazepam / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D018491:Dopamine Agonists / Q000494:pharmacology; D005442:Flumazenil / Q000494:pharmacology; D005445:Flunitrazepam / Q000378:metabolism; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D008550:Melatonin / Q000031:analogs & derivatives / Q000494:pharmacology*; D016627:Oxidopamine / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
D018491:Dopamine Agonists; D007546:Isoquinolines; D011963:Receptors, GABA-A; D005442:Flumazenil; D005680:gamma-Aminobutyric Acid; D002998:Clonazepam; D005445:Flunitrazepam; D016627:Oxidopamine; D008550:Melatonin; D001058:Apomorphine; D001640:Bicuculline; C037850:PK 11195