Loss of dopaminergic nigrostriatal neurons accounts for the motivational and affective deficits in Parkinson's disease.

Parkinson's disease (PD) involves the degeneration of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc) that is thought to cause the classical motor symptoms of this disease. However, motivational and affective impairments are also often observed in PD patients. These are usually attributed to a psychological reaction to the general motor impairment and to a loss of some of the neurons within the ventral tegmental area (VTA). We induced selective lesions of the VTA and SNc DA neurons that did not provoke motor deficits, and showed that bilateral dopamine loss within the SNc, but not within the VTA, induces motivational deficits and affective impairments that mimicked the symptoms of PD patients. Thus, motivational and affective deficits are a core impairment of PD, as they stem from the loss of the major group of neurons that degenerates in this disease (DA SNc neurons) and are independent of motor deficits.

Implication of dopamine D3 receptor activation in the reversion of Parkinson's disease-related motivational deficits.

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.