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

Neurobiol Dis. 2011 Jan;41(1):51-61. doi: 10.1016/j.nbd.2010.08.018. Epub 2010 Aug 22.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenylyl Cyclases / biosynthesis*
  • Animals
  • Dyskinesia, Drug-Induced / enzymology
  • Dyskinesia, Drug-Induced / metabolism*
  • Dyskinesia, Drug-Induced / pathology
  • Enzyme Inhibitors / pharmacology
  • Levodopa / toxicity*
  • Male
  • Oxidopamine / toxicity
  • Parkinsonian Disorders / drug therapy
  • Parkinsonian Disorders / enzymology*
  • Parkinsonian Disorders / pathology
  • Rats
  • Rats, Wistar
  • Severity of Illness Index
  • Substantia Nigra / drug effects*
  • Substantia Nigra / enzymology
  • Substantia Nigra / metabolism
  • Up-Regulation / drug effects
  • Up-Regulation / physiology*
  • gamma-Aminobutyric Acid / metabolism*


  • Enzyme Inhibitors
  • Levodopa
  • gamma-Aminobutyric Acid
  • Oxidopamine
  • Adenylyl Cyclases
  • adenylyl cyclase 6
  • adenylyl cyclase type V