title: Cannabinoid CB1 antagonists possess antiparkinsonian efficacy only in rats with very severe nigral lesion in experimental parkinsonism.
abstract: We have observed that systemic administration of cannabinoid CB1 antagonists exerts antiparkinsonian effects in rats with very severe nigral lesion (>95% cell loss), but not in rats with less severe lesion (85-95% cell loss). Local injections into denervated striatum and corresponding globus pallidus reduced parkinsonian asymmetry. Infusions into lesioned substantia nigra enhanced motor asymmetries, but this effect was absent after very severe nigral lesion. At the striatal level, CB1 antagonists act enhancing dopamine D1 receptor function and reducing D2 receptor function. Striatal dopaminergic denervation did not affect cannabinoid CB1 receptor coupling to G proteins. These results suggest that (i) systemic administration of CB1 antagonists in rats with severe nigral degeneration is ineffective because striatopallidal-mediated motor effects are antagonized by nigra-mediated activity, and (ii) CB1 antagonists exert antiparkinsonian effects after very severe nigral degeneration because nigra-mediated inhibition disappears. CB1 receptor antagonists that lack psychoactive effects might be of therapeutic value in the control of very advanced stage of Parkinson's disease in humans.
authors.affiliation: Facultad de Medicina, Departamento de Fisiologia Medica y Biofisica, Universidad de Sevilla, Av. Sanchez Pizjuan 4, E-41009 Sevilla, Spain. efespejo@us.es
authors.forename: Emilio
authors.initials: E
authors.lastname: Fernandez-Espejo
authors.forename: Isabel
authors.initials: I
authors.lastname: Caraballo
authors.forename: Fernando Rodriguez
authors.initials: FR
authors.lastname: de Fonseca
authors.forename: Fadwa
authors.initials: F
authors.lastname: El Banoua
authors.forename: Belen
authors.initials: B
authors.lastname: Ferrer
authors.forename: Juan A
authors.initials: JA
authors.lastname: Flores
authors.forename: Beatriz
authors.initials: B
authors.lastname: Galan-Rodriguez
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000627:therapeutic use*; D002186:Cannabinoids / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D008297:Male; D020734:Parkinsonian Disorders / Q000188:drug therapy* / Q000503:physiopathology; D010880:Piperidines / Q000627:therapeutic use; D011720:Pyrazoles / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors* / Q000502:physiology; D000077285:Rimonabant; D013378:Substantia Nigra / Q000187:drug effects* / Q000502:physiology
chemical_list: D000978:Antiparkinson Agents; D002186:Cannabinoids; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D000077285:Rimonabant