title: Levodopa-induced dyskinesias are associated with transient down-regulation of cAMP and cGMP in the caudate-putamen of hemiparkinsonian rats: reduced synthesis or increased catabolism?
abstract: Second messenger cAMP and cGMP represent a key step in the action of dopamine that modulates directly or indirectly their synthesis. We aimed to verify whether levodopa-induced dyskinesias are associated with changes of the time course of levodopa/dopamine stimulated cAMP and cGMP levels, and/or with changes of their catabolism by phosphodiesterase activity in rats with experimental hemiparkinsonism. Microdialysis and tissue homogenates of the striatal tissues demonstrated that extracellular and intracellular cAMP/cGMP levels were lower in dyskinetic animals during the increasing phase of dyskinesias compared to eukinetic animals, but cAMP/cGMP levels increased in dyskinetic animals during the phase of decreasing and extinction of dyskinesias. Dyskinesias and the abnormal lowering of striatal cGMP and cAMP after levodopa were prevented by pretreatment with the multipotent drug amantadine, outlining the inverse relationship of cAMP/cGMP to dyskinesias. Moreover, dyskinetic animals showed higher striatal hydrolyzing cGMP-phosphodiesterase but not hydrolyzing cAMP-phosphodiesterase activity, suggesting that low cGMP but not cAMP levels could be due to increased catabolism. However, expressions of isozyme phosphodiesterase-1B and -10A highly and specifically located in the basal ganglia were not changed after levodopa in dyskinetic and eukinetic animals: accordingly, selective inhibitors of phosphodiesterase-1B and -10A were ineffective on levodopa dyskinesias. Therefore, the isozyme(s) expressing higher cGMP-phosphodiesterase activity in the striatum of dyskinetic animal should be determined. These observations suggest that dopamine-mediated processes of synthesis and/or degradation of cAMP/cGMP could be acutely impaired in levodopa dyskinesias, opening new ways to understanding physiopathology and treatment.
authors.affiliation: Department of Systems Medicine, Tor Vergata University of Rome, Italy; Santa Lucia Foundation, Rome, Italy. Electronic address: sancesario@med.uniroma2.it.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Sancesario
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Italy.
authors.forename: Luigi Antonio
authors.initials: LA
authors.lastname: Morrone
authors.affiliation: Department of Systems Medicine, Tor Vergata University of Rome, Italy.
authors.forename: Vincenza
authors.initials: V
authors.lastname: D'Angelo
authors.affiliation: Department of Biology and Biotechnology "Charles Darwin", Sapienza University of Rome, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Castelli
authors.affiliation: Department of Systems Medicine, Tor Vergata University of Rome, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Ferrazzoli
authors.affiliation: Department of Systems Medicine, Tor Vergata University of Rome, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Sica
authors.affiliation: Department of Systems Medicine, Tor Vergata University of Rome, Italy; Santa Lucia Foundation, Rome, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Martorana
authors.affiliation: Department of Systems Medicine, Tor Vergata University of Rome, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Sorge
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Cavaliere
authors.affiliation: Santa Lucia Foundation, Rome, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Bernardi
authors.affiliation: Department of Biology and Biotechnology "Charles Darwin", Sapienza University of Rome, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Giorgi
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects*; D002421:Caudate Nucleus / Q000187:drug effects* / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism*; D006152:Cyclic GMP / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D004409:Dyskinesia, Drug-Induced / Q000378:metabolism* / Q000503:physiopathology*; D007980:Levodopa / Q000009:adverse effects*; D008297:Male; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D011699:Putamen / Q000187:drug effects* / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000978:Antiparkinson Agents; D010726:Phosphodiesterase Inhibitors; D007980:Levodopa; D000242:Cyclic AMP; D010727:Phosphoric Diester Hydrolases; D006152:Cyclic GMP
keywords: Amantadine; Levodopa dyskinesia; Parkinson disease; Phopsphodiesterase; cAMP; cGMP