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.

Unilateral and Bilateral Subthalamic stimulation differently promote apathy: a translational approach

“…Furthermore, functional imaging studies suggest the implication of the dopaminergic degenerative process for apathy apparition in non-stimulated patient (23). In line with this assumption, we demonstrated in experimental approaches in rodents(24) the implication of the loss of substantia nigra pars compacta dopaminergic neurons for this loss of motivation in a rodent model of neuropsychiatric symptoms of PD (25), as well as the therapeutic contribution of dopaminergic agonists, especially those targeting the D2R and D3R (26,27). Thus, because STN-DBS classically permits to reduce the dopaminergic treatments(28), apathy following STN-DBS apathy was commonly attributed to the resurgence of pre-existing apathy revealed by the reduction or withdrawal of dopatherapy rather than to an effect of STN-DBS itself (29,30).…”

Emotional manifestations of PD: Neurobiological basis

“…As mentioned previously, diffuse DA lesions in MPTP monkey models lead to a reduction in goal‐directed behavior and behavioral activities that resembles apathy (see also reference ). In addition, partial and bilateral DA lesions of the nigrostriatal system of rats induce strong motivational deficits that can be reversed by DA agonists (Fig. ).…”

Efficacy and Safety of Adjunctive Cariprazine in Inadequate Responders to Antidepressants

“…Cariprazine differs from other antipsychotics by exhibiting a 10-fold greater in vitro affinity for D 3 versus D 2 receptors 10 and high and balanced in vivo occupancy of both D 2 and D 3 receptors at clinically relevant doses. 11,12 Since the D 3 receptor is preferentially expressed in areas of the brain associated with motivation and reward-related behavior, 13 it has been identified as a potential pharmacologic target for depression treatment. 14 Cariprazine also acts as a partial agonist at serotonin 5-HT 1A receptors, 10 which is a mechanism thought to enhance the neurochemical and behavioral effects of selective serotonin reuptake inhibitors (SSRIs).…”