What can rodent models tell us about apathy and associated neuropsychiatric symptoms in Parkinson's disease?

In addition to classical motor symptoms, Parkinson's disease (PD) patients display incapacitating neuropsychiatric manifestations, such as apathy, anhedonia, depression and anxiety. These hitherto generally neglected non-motor symptoms, have gained increasing interest in medical and scientific communities over the last decade because of the extent of their negative impact on PD patients' quality of life. Although recent clinical and functional imaging studies have provided useful information, the pathophysiology of apathy and associated affective impairments remains elusive. Our aim in this review is to summarize and discuss recent advances in the development of rodent models of PD-related neuropsychiatric symptoms using neurotoxin lesion-based approaches. The data collected suggest that bilateral and partial lesions of the nigrostriatal system aimed at inducing reliable neuropsychiatric-like deficits while avoiding severe motor impairments that may interfere with behavioral evaluation, is a more selective and efficient strategy than medial forebrain bundle lesions. Moreover, of all the different classes of pharmacological agents, D2/D3 receptor agonists such as pramipexole appear to be the most efficient treatment for the wide range of behavioral deficits induced by dopaminergic lesions. Lesion-based rodent models, therefore, appear to be relevant tools for studying the pathophysiology of the non-motor symptoms of PD. Data accumulated so far confirm the causative role of dopaminergic depletion, especially in the nigrostriatal system, in the development of behavioral impairments related to apathy, depression and anxiety. They also put forward D2/D3 receptors as potential targets for the treatment of such neuropsychiatric symptoms in PD.

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.

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.

Enhanced visual responses in the superior colliculus and subthalamic nucleus in an animal model of Parkinson's disease.

Striatal dopaminergic denervation leads to a change in afferent activity within the basal ganglia. Coupled with the effect of local dopaminergic denervation in the subthalamic nucleus, this is likely to affect the responsiveness of subthalamic neurons to their hyperdirect inputs in Parkinson's disease. Therefore, in this report, we investigated subthalamic nucleus responses to visual stimuli relayed by one such input - the superior colliculus - in 6-hydroxydopamine (6-OHDA)-lesioned rats. We used a protocol where the superior colliculus was selectively unlocked from the inhibitory effect of anesthesia with an injection of bicuculline, attenuating GABAergic inhibition in the colliculus, which arises predominantly from the substantia nigra pars reticulata. We found that visual responses in the superior colliculus were facilitated by partial or total lesions of dopaminergic neurons in the substantia nigra pars compacta, once the colliculus was disinhibited by bicuculline. Responses were faster, larger in amplitude and lasted longer compared to those in control rats. In the subthalamic nucleus, visual responses were also increased in amplitude and magnitude in partial or total lesioned groups. A classic hypothesis in Parkinson's disease suggests that following dopaminergic denervation, the discharge of cells in the substantia nigra pars reticulata increases, thereby intensifying the inhibitory influence that this structure exerts on its targets in the thalamus and brainstem. Our results suggest that neuroadaptations may have taken place within the superior colliculus in order to maintain normal function in the face of increased inhibitory tone coming from the substantia nigra pars reticulata, which once reduced, gave rise to facilitated responding. This facilitated responding in the superior colliculus then appears to lead to facilitated responding in the subthalamic nucleus.

Altered gravity downregulates aquaporin-1 protein expression in choroid plexus.

Aquaporin-1 (AQP1) is a water channel expressed abundantly at the apical pole of choroidal epithelial cells. The protein expression was quantified by immunocytochemistry and confocal microscopy in adult rats adapted to altered gravity. AQP1 expression was decreased by 64% at the apical pole of choroidal cells in rats dissected 5.5-8 h after a 14-day spaceflight. AQP1 was significantly overexpressed in rats readapted for 2 days to Earth's gravity after an 11-day flight (48% overshoot, when compared with the value measured in control rats). In a ground-based model that simulates some effects of weightlessness and alters choroidal structures and functions, apical AQP1 expression was reduced by 44% in choroid plexus from rats suspended head down for 14 days and by 69% in rats suspended for 28 days. Apical AQP1 was rapidly enhanced in choroid plexus of rats dissected 6 h after a 14-day suspension (57% overshoot, in comparison with control rats) and restored to the control level when rats were dissected 2 days after the end of a 14-day suspension. Decreases in the apical expression of choroidal AQP1 were also noted in rats adapted to hypergravity in the NASA 24-ft centrifuge: AQP1 expression was reduced by 47% and 85% in rats adapted for 14 days to 2 G and 3 G, respectively. AQP1 is downregulated in the apical membrane of choroidal cells in response to altered gravity and is rapidly restored after readaptation to normal gravity. This suggests that water transport, which is partly involved in the choroidal production of cerebrospinal fluid, might be decreased during spaceflight and after chronic hypergravity.

Hindlimb-suspension and spaceflight both alter cGMP levels in rat choroid plexus.

Effects of actual and simulated weightlessness on choroidal guanylate cyclase activity were evaluated by assaying the production of cyclic guanosine monophosphate (cGMP), a second messenger involved in mechanisms regulating the secretion of cerebrospinal fluid (CSF) in choroid plexus. Cyclic cGMP was measured, using radio-immunoassay, in choroidal extracts of hindlimb-suspended rats (HLS rats), adapted to an anti-orthostatic restraint for 30 min., or for 3, 9 or 14 days and after a 17-day spaceflight (Life and Microgravity SpaceLab experiment; LMS). Basal cGMP levels were slightly but significantly decreased in the first 30 min. of the HLS experiment, whereas they were significantly increased in rats adapted to longer anti-orthostatic restraints. LMS flight rats demonstrated a similar increase in the choroidal cGMP baseline. After natriuretic peptide stimulation, i.e. using ANP (atrial natriuretic peptide) or BNP (brain natriuretic peptide), choroidal cGMP contents were typically increased (by 1.5-2 times; p<0.05) in control rats (LMS and HLS experiments), but not significantly elevated in suspended rats, except for those adapted to HLS for 14 days. In these animals the ANP-dependent cGMP production was significantly increased (by about 3 times; p<0.005). The ANP- or BNP-dependent responses were similarly abolished in LMS flight rats, which were dissected 4-6 hours after return to Earth's gravity. The role of corticosteroids was also investigated during the LMS experiment. Results on choroidal functions revealed a lack of significant change of cGMP levels between adrenalectomized and sham-operated rats. For the first time, it is reported that both basal and ANP- stimulated cGMP levels are dramatically changed over the first 14 days of suspension, i.e. with experiments known to simulate some effects of weightlessness. Basal choroidal cGMP levels are also increased after 17 days in space, suggesting that space adaptation also impacts choroidal guanylate cyclase activities. However, the absence of ANP-dependent cGMP increase, observed in LMS flight animals, suggests that HLS could not simulate all the spaceflight effects. Thus, these preliminary results seem to show that a natriuretic peptides-independent s stem is involved in choroidal adaptation to spaceflight.