title: Genetic deletion of Rhes or pharmacological blockade of mTORC1 prevent striato-nigral neurons activation in levodopa-induced dyskinesia.
abstract: Ras homolog enriched in striatum (Rhes) is a small GTP-binding protein that modulates signal transduction at dopamine receptors, and also activates mammalian target of rapamycin complex 1 (mTORC1). Rhes binding to mTORC1 is hypothesized to play a role in motor disorders such as levodopa-induced dyskinesia. Here, we investigate the behavioral and in vivo neurocircuitry changes associated with genetic deletion of Rhes or inhibition of mTORC1 signaling in the mouse model of levodopa-induced dyskinesia. 6-Hydroxydopamine-hemilesioned Rhes knockout mice and wild-type littermates were chronically treated with levodopa. In parallel, 6-hydroxydopamine-hemilesioned naïve mice were chronically treated with levodopa or levodopa plus rapamycin, to block mTORC1 pathway activation. Dyskinetic movements were monitored during levodopa treatment along with motor activity on the rotarod. Finally, dyskinetic mice underwent microdialysis probe implantation in the dopamine-depleted striatum and ipsilateral substantia nigra reticulata, and GABA and glutamate levels were monitored upon acute challenge with levodopa. Both Rhes knockouts and rapamycin-treated mice developed less dyskinesia than controls, although only rapamycin-treated mice fully preserved rotarod performance on levodopa. Levodopa elevated nigral GABA and glutamate in controls but not in Rhes knockouts or rapamycin-treated mice. Levodopa also stimulated striatal glutamate in controls and Rhes knockouts but not in rapamycin-treated mice. We conclude that both genetic deletion of Rhes and pharmacological blockade of mTORC1 significantly attenuate dyskinesia development by reducing the sensitization of striato-nigral medium-sized spiny neurons to levodopa. However, mTORC1 blockade seems to provide a more favorable behavioral outcome and a wider effect on neurochemical correlates of dyskinesia.
authors.affiliation: Department of Medical Sciences, Section of Pharmacology, University of Ferrara and National Institute of Neuroscience, Ferrara, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Brugnoli
authors.affiliation: Laboratory of Behavioral Neuroscience, CEINGE Biotecnologie Avanzate, Naples, Italy; Department of Molecular Medicine and Medical Biotechnology, University of Naples "Federico II", Naples, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Napolitano
authors.affiliation: Laboratory of Behavioral Neuroscience, CEINGE Biotecnologie Avanzate, Naples, Italy; Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, The Second University of Naples (SUN), Caserta, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Usiello
authors.affiliation: Department of Medical Sciences, Section of Pharmacology, University of Ferrara and National Institute of Neuroscience, Ferrara, Italy. Electronic address: m.morari@unife.it.
authors.forename: Michele
authors.initials: M
authors.lastname: Morari
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000633:toxicity*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D005260:Female; D019204:GTP-Binding Proteins / Q000172:deficiency* / Q000235:genetics; D018698:Glutamic Acid / Q000378:metabolism; D007980:Levodopa / Q000633:toxicity*; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology; D020123:Sirolimus / Q000494:pharmacology; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000978:Antiparkinson Agents; D046912:Multiprotein Complexes; D018696:Neuroprotective Agents; D018698:Glutamic Acid; D007980:Levodopa; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D019204:GTP-Binding Proteins; C488189:Rasd2 protein, mouse; D020123:Sirolimus
keywords: 6-Hydroxydopamine; Dyskinesia; GABA; Glutamate; Levodopa; Microdialysis; Parkinson's disease; Rapamycin; Rhes; mTORC1