title: Modafinil prevents the MPTP-induced increase in GABAA receptor binding in the internal globus pallidus of MPTP-treated common marmosets.
abstract: The psychostimulant drug modafinil induces a reversal of motor deficits in MPTP treated primates and prevents MPTP toxicity to substantia nigra but its mechanism of action is not clear. In common marmosets acutely treated with MPTP in the presence or absence of modafinil, we have studied changes in GABA(A) receptor binding in the basal ganglia. MPTP treatment had no effect on [(3)H]-flunitrazepam (FNZ) binding density in the striatum or external globus pallidus (GPe) but increased [(3)H]-FNZ binding density in the internal globus pallidus (GPi). Administration of modafinil (10-100 mg/kg) with MPTP did not alter [(3)H]-FNZ binding density in the striatum or GPe. Low doses of modafinil (10 and 30 mg/kg) had no effect on the increased [(3)H]-FNZ binding density in the GPi but high dose modafinil (100 mg/kg) significantly decreased [(3)H]-FNZ binding density in GPi. These findings suggest that modafinil can selectively alter GABA binding density in the GPi either by preventing MPTP-induced toxicity or through an action on striatal output pathway related to its antiparkinsonian activity and its ability to inhibit MPTP toxicity.
authors.affiliation: Neurodegenerative Disease Research Centre, Guy's, King's and St Thomas' School of Biomedical Sciences, King's College, London SE1 1UL, UK.
authors.forename: B-Y
authors.initials: BY
authors.lastname: Zeng
authors.forename: L A
authors.initials: LA
authors.lastname: Smith
authors.forename: R K B
authors.initials: RK
authors.lastname: Pearce
authors.forename: B
authors.initials: B
authors.lastname: Tel
authors.forename: L
authors.initials: L
authors.lastname: Chancharme
authors.forename: G
authors.initials: G
authors.lastname: Moachon
authors.forename: P
authors.initials: P
authors.lastname: Jenner
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D000818:Animals; D001559:Benzhydryl Compounds / Q000494:pharmacology*; D002144:Callithrix; D015259:Dopamine Agents / Q000494:pharmacology; D005260:Female; D005445:Flunitrazepam / Q000378:metabolism / Q000494:pharmacology; D018757:GABA Modulators / Q000378:metabolism / Q000494:pharmacology; D005917:Globus Pallidus / Q000187:drug effects / Q000378:metabolism*; D020267:MPTP Poisoning / Q000188:drug therapy*; D008297:Male; D000077408:Modafinil; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011963:Receptors, GABA-A / Q000378:metabolism*; D014316:Tritium
chemical_list: D001559:Benzhydryl Compounds; D015259:Dopamine Agents; D018757:GABA Modulators; D018696:Neuroprotective Agents; D011963:Receptors, GABA-A; D014316:Tritium; D005445:Flunitrazepam; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000077408:Modafinil