title: Amantadine attenuates levodopa-induced dyskinesia in mice and rats preventing the accompanying rise in nigral GABA levels.
abstract: Amantadine is the only drug marketed for treating levodopa-induced dyskinesia. However, its impact on basal ganglia circuitry in the dyskinetic brain, particularly on the activity of striatofugal pathways, has not been evaluated. We therefore used dual probe microdialysis to investigate the effect of amantadine on behavioral and neurochemical changes in the globus pallidus and substantia nigra reticulata of 6-hydroxydopamine hemi-lesioned dyskinetic mice and rats. Levodopa evoked abnormal involuntary movements (AIMs) in dyskinetic mice, and simultaneously elevated GABA release in substantia nigra reticulata (∼3-fold) but not globus pallidus. Glutamate levels were unaffected in both areas. Amantadine (40 mg/kg, i.p.), ineffective alone, attenuated (∼50%) AIMs expression and prevented the GABA rise. Moreover, it unraveled a facilitatory effect of levodopa on pallidal glutamate levels. Levodopa also evoked AIMs expression and a GABA surge (∼2-fold) selectively in the substantia nigra of dyskinetic rats. However, different from mice, glutamate levels rose simultaneously. Amantadine, ineffective alone, attenuated (∼50%) AIMs expression preventing amino acid increase and leaving unaffected pallidal glutamate. Overall, the data provide neurochemical evidence that levodopa-induced dyskinesia is accompanied by activation of the striato-nigral pathway in both mice and rats, and that the anti-dyskinetic effect of amantadine partly relies on the modulation of this pathway.
authors: Department of Experimental and Clinical Medicine, Section of Pharmacology, University of Ferrara, Ferrara, Italy.
authors: Simone
authors: S
authors: Bido
authors: Matteo
authors: M
authors: Marti
authors: Michele
authors: M
authors: Morari
mesh_terms: D000547:Amantadine / Q000494:pharmacology*; D000818:Animals; D000978:Antiparkinson Agents / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D003627:Data Interpretation, Statistical; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy*; D005917:Globus Pallidus / Q000187:drug effects / Q000378:metabolism; D005971:Glutamates / Q000378:metabolism; D006892:Hydroxydopamines / Q000633:toxicity; D007980:Levodopa / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D008297:Male; D051379:Mice; D017551:Microdialysis; D010302:Parkinson Disease, Secondary / Q000188:drug therapy; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism*; D013565:Sympatholytics / Q000633:toxicity; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D000978:Antiparkinson Agents; D005971:Glutamates; D006892:Hydroxydopamines; D013565:Sympatholytics; D007980:Levodopa; D005680:gamma-Aminobutyric Acid; D000547:Amantadine; D014446:Tyrosine 3-Monooxygenase