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.

Figure 1

Behavioral experiment schedules. Evaluation of the effects of different pharmacological treatments on the behavioral deficits induced by the 6-OHDA lesion. The behavioral studies began 3 weeks after surgery and tests were carried out in opposite orders for groups A and B. FST, forced-swim test; 6-OHDA, 6-hydroxydopamine.

Figure 2

Bilateral partial lesions of the SNc result in a partial DA denervation of the dorsal striatum. (a, b) Photographs of coronal sections stained for TH at mesencephalic (a, anteriority −5.2 mm from bregma) and striatal (b, anteriority +1.2 mm from bregma) levels, according to Paxinos and Watson (2005). (c) Quantifications of the loss of TH staining in the NAc and the dorsal striatum for each treatment, independently of the dose used, expressed as the percentage of the mean value obtained for sham-operated animals. Scale bar, 1 mm. DA, dopamine; NAc, nucleus accumbens; 6-OHDA, 6-hydroxydopamine; SNc, substantia nigra pars compacta; TH, tyrosine hydroxylase; VTA, ventral tegmental area. ***P<0.001 (n=13–22 per group).

Figure 3

Effects of dopaminergic agonists on affective-related deficits induced by 6-OHDA SNc lesions. Evaluation of the effects of subchronic administration of SKF-38193 (2.5 and 3.5 mg kg⁻¹), sumanirole (0.1 and 0.15 mg kg⁻¹) and PD-128907 (0.1 and 0.15 mg kg⁻¹) in the elevated-plus maze (a–e) and the forced-swim test (f), in sham-operated (white histograms) and 6-OHDA SNc-lesioned (black histograms) animals. Indexes of anxiety-related behaviors evaluated here were the percentage of time spent in the open arms (a), the time spent specifically at the end of the open arms (b), the number of head dips when animals are exploring the open arms (c), the number of stretched attend episodes toward the open arms (d) and the time spent in the central area (e). Overall, DA agonists reversed the anxiety-like behaviors induced by 6-OHDA SNc lesions, as well as the increase in the time spent immobile in the forced-swim test. Dot lines represented the mean of the behavioral performances of vehicle-treated sham animals. *P<0.05; **P<0.01, ***P<0.01 sham-operated versus lesioned within the same treatment and ^#P<0.05, ^##P<0.01 between the treatments for sham-operated and lesioned conditions, respectively (n=8–21 per group). 6-OHDA, 6-hydroxydopamine; PD, Parkinson's disease; SNc, substantia nigra pars compacta.

Figure 4

Only the preferential D₃R agonist, PD-128907, reverses the instrumental deficit induced by 6-OHDA SNc lesions. Evolution of operant sucrose (2% in water) self-administration performances, under a fixed ratio 1 (FR1) schedule of reinforcement, in sham-operated (white chips) and lesioned (black chips) animals, during the eight instrumental sessions. Subchronic administration of PD-128907 (0.1 and 0.15 mg kg⁻¹), but not of SKF-38393 (2.5 and 3.5 mg kg⁻¹) or sumanirole (0.1 and 0.15 mg kg⁻¹), improved the instrumental performances of 6-OHDA-lesioned rats. Dot lines represented the mean of the instrumental performances of the three last FR1 sessions of vehicle-treated sham animals. *P<0.05; **P<0.01; ***P<0.001, sham-operated versus lesioned within the same treatment (n=8–21 per group). 6-OHDA, 6-hydroxydopamine; PD, Parkinson's disease; SNc, substantia nigra pars compacta.

Figure 5

Reversion of the motivational deficits induced by 6-OHDA SNc lesions by the D3R agonist PD-128907 was blocked by the D₃R antagonist SB-277011A, but not by the D₂R antagonist L-741626. (a) Representation of the mean number of sucrose deliveries of the three last fixed ratio 1 (FR1) sessions in sham-operated (white histograms) and lesioned (black histograms) animals. Subchronic administration of PD-128907 (0.1 and 0.15 mg kg⁻¹), but not of SKF-38393 (2.5 and 3.5 mg kg⁻¹) or sumanirole (0.1 and 0.15 mg kg⁻¹), improved instrumental performances of the 6-OHDA-lesioned rats. (b) SB-277011A (10 mg kg⁻¹) but not L-741626 (1.5 mg kg⁻¹) blocked specifically this reversal effect of PD-128907 (0.15 mg kg⁻¹) in lesioned rats. (c) PD-128907, but not SKF-38393 or sumanirole enhanced the breakpoint (that is, last ratio completed) of 6-OHDA-lesioned rats after 8 days of sucrose self-administration. (d) A similar effect of PD-128907 (0.15 mg kg⁻¹) was observed after 18 days of sucrose self-administration. Dot lines represented the mean of the instrumental performances of the three last FR1 sessions of vehicle-treated sham animals (a), the mean of the number of sucrose deliveries of vehicle-treated 6-OHDA-lesioned animals during antagonists tests (b) or the mean of the breakpoint of vehicle-treated 6-OHDA-lesioned animals (c–d). *P<0.05; **P<0.01; ***P<0.001, sham-operated versus lesioned within the same treatment and ^#P<0.05, ^##P<0.01, ^###P<0.001 between the treatments for sham-operated and lesioned conditions, respectively (n=8–21 per group). 6-OHDA, 6-hydroxydopamine; PD, Parkinson's disease; SNc, substantia nigra pars compacta.