L-DOPA-induced dyskinesia in hemiparkinsonian rats is associated with up-regulation of adenylyl cyclase type V/VI and increased GABA release in the substantia nigra reticulata.
L-DOPA treatment induces abnormal involuntary movements (AIMs) in Parkinson's patients and experimental animals. We examined the relationship between the development of AIMs (dyskinesia) and changes in [(3)H]-GABA release and cAMP signaling in striatonigral terminals of rats with unilateral 6-OHDA lesions. Analysis of AIMs scores in hemiparkinsonian rats treated with L-DOPA for 20 days was fitted by the sum of two Gaussian distributions showing the presence of two populations: one with mild and the other with severe dyskinesia. cAMP signaling was evaluated in the two populations by determining changes in cAMP formation, Gα(olf) and adenylyl cyclase type V/VI levels. In animals that were not treated with L-DOPA, all the parameters were significantly increased in the denervated side. In the animals that had mild dyskinesia, L-DOPA treatment normalized these parameters. In contrast, in the animals in which l-DOPA treatment induced severe dyskinesia all the parameters, except for Gα(olf) levels, were significantly higher in the denervated side. Similarly, D1-stimulated [(3)H]-GABA release was not elevated in L-DOPA-treated animals with mild dyskinesia but was increased in animals with severe dyskinesia. Changes in Gα(olf) and adenylyl cyclase type V/VI levels in the striatum paralleled the response in the SNr. The linkage between the changes in [(3)H]-GABA release and cAMP activity was further evaluated with the selective adenylyl cyclase V/VI antagonist NKY80. This inhibitor blocked the increases of both [(3)H]-GABA release and cAMP production. These results indicate that increased expression of adenylyl cyclase V/VI is a major determinant of increased GABAergic transmission in the substantia nigra pars reticulata of animals in which L-DOPA induces severe dyskinesia.
Rangel-Barajas
Claudia
C
Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, D.F. México.
Silva
Isaac
I
Lopéz-Santiago
Luz María
LM
Aceves
Jorge
J
Erlij
David
D
Florán
Benjamín
B
D000262:Adenylyl Cyclases / Q000096:biosynthesis*; D000818:Animals; D004409:Dyskinesia, Drug-Induced / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007980:Levodopa / Q000633:toxicity*; D008297:Male; D016627:Oxidopamine / Q000633:toxicity; D020734:Parkinsonian Disorders / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D012720:Severity of Illness Index; D013378:Substantia Nigra / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D004791:Enzyme Inhibitors; D007980:Levodopa; D005680:gamma-Aminobutyric Acid; D016627:Oxidopamine; D000262:Adenylyl Cyclases; C121100:adenylyl cyclase 6; C419510:adenylyl cyclase type V