title: Implication of dopamine D3 receptor activation in the reversion of Parkinson's disease-related motivational deficits.
abstract: In addition to the classical motor symptoms, motivational and affective deficits are core impairments of Parkinson's disease (PD). We recently demonstrated, by lesional approaches in rats, that degeneration of the substantia nigra pars compacta (SNc) dopaminergic (DA) neurons is likely to have a crucial role in the development of these neuropsychiatry symptoms. We have also shown that, as in clinical investigations, chronic treatment with levodopa or the DA D2/D3 receptor (D2/D3R) agonist ropinirole specifically reverses these PD-related motivational deficits. The roles of specific DA receptor subtypes in such reversal effects remain, however, unknown. We therefore investigated here the precise involvement of D1, D2 and D3R in the reversal of the motivational and affective deficits related to SNc DA neuronal loss. Three weeks after bilateral and partial 6-hydroxydopamine (6-OHDA) SNc lesions, rats received 14 daily intraperitoneal administrations of the selective D1R agonist SKF-38393 (2.5 or 3.5 mg kg(-1)), the selective D2R agonist sumanirole (0.1 or 0.15 mg kg(-1)), or the preferring D3R gonist PD-128907 (0.1 or 0.15 mg kg(-1)). Anxiety-, depressive-like and motivated behaviors were assessed in an elevated-plus maze, a forced-swim test, and an operant sucrose self-administration procedure, respectively. All DA agonists attenuated anxiety- and depressive-like behaviors. However, only PD-128907 reversed the motivational deficits induced by 6-OHDA SNc lesions. This effect was blocked by a selective D3R (SB-277011A, 10 mg kg(-1)), but not D2R (L-741,626, 1.5 mg kg(-1)), antagonist. These data provide strong evidence for the role of D3R in motivational processes and identify this receptor as a potentially valuable target for the treatment of PD-related neuropsychiatric symptoms.
authors.affiliation: 1] Institut National de la Santé et de la Recherche Médicale, Unité 836, Grenoble Institut des Neurosciences, Equipe 10, Dynamique et Physiopathologie des Ganglions de la Base, Grenoble, France [2] Grenoble University, Grenoble, France.
authors.forename: S
authors.initials: S
authors.lastname: Carnicella
authors.affiliation: 1] Institut National de la Santé et de la Recherche Médicale, Unité 836, Grenoble Institut des Neurosciences, Equipe 10, Dynamique et Physiopathologie des Ganglions de la Base, Grenoble, France [2] Grenoble University, Grenoble, France.
authors.forename: G
authors.initials: G
authors.lastname: Drui
authors.affiliation: 1] Institut National de la Santé et de la Recherche Médicale, Unité 836, Grenoble Institut des Neurosciences, Equipe 10, Dynamique et Physiopathologie des Ganglions de la Base, Grenoble, France [2] Grenoble University, Grenoble, France.
authors.forename: S
authors.initials: S
authors.lastname: Boulet
authors.affiliation: 1] Institut National de la Santé et de la Recherche Médicale, Unité 836, Grenoble Institut des Neurosciences, Equipe 10, Dynamique et Physiopathologie des Ganglions de la Base, Grenoble, France [2] Grenoble University, Grenoble, France.
authors.forename: C
authors.initials: C
authors.lastname: Carcenac
authors.affiliation: 1] Institut National de la Santé et de la Recherche Médicale, Unité 836, Grenoble Institut des Neurosciences, Equipe 10, Dynamique et Physiopathologie des Ganglions de la Base, Grenoble, France [2] Grenoble University, Grenoble, France.
authors.forename: M
authors.initials: M
authors.lastname: Favier
authors.affiliation: 1] Institut National de la Santé et de la Recherche Médicale, Unité 836, Grenoble Institut des Neurosciences, Equipe 10, Dynamique et Physiopathologie des Ganglions de la Base, Grenoble, France [2] Grenoble University, Grenoble, France.
authors.forename: T
authors.initials: T
authors.lastname: Duran
authors.affiliation: 1] Institut National de la Santé et de la Recherche Médicale, Unité 836, Grenoble Institut des Neurosciences, Equipe 10, Dynamique et Physiopathologie des Ganglions de la Base, Grenoble, France [2] Grenoble University, Grenoble, France [3] Department of Neurology and Psychiatry, Centre Hospitalier Universitaire de Grenoble, BP217, Grenoble, France.
authors.forename: M
authors.initials: M
authors.lastname: Savasta
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D004195:Disease Models, Animal; D018491:Dopamine Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D059290:Dopaminergic Neurons / Q000473:pathology*; D009042:Motivation / Q000187:drug effects*; D010300:Parkinson Disease / Q000188:drug therapy*; D051381:Rats; D017447:Receptors, Dopamine D1 / Q000819:agonists; D017448:Receptors, Dopamine D2 / Q000819:agonists; D050637:Receptors, Dopamine D3 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D013378:Substantia Nigra / Q000293:injuries*
chemical_list: D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3