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

Abstract

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.

G-protein coupled receptor 88knock-down in the associative striatum reduces the psychiatric symptoms in a translational model of Parkinson’s disease

“…We however did not replicate deficits relating to anhedonia and sensorimotor gating that had previously been reported in other 6OHDA models of the disease using the sucrose preference and prepulse inhibition (PPI) tests (39,52). Anhedonia is frequently reported in PD, but has however been associated with the mesolimbic dopamine pathway (53), which we did not affect in our study.…”

“…Indeed, while these symptoms have been linked to alterations in multiple neurotransmitter systems (26), clustering studies of de novo patients suggest that the loss of striatal dopamine in particular may play an important role in their emergence (66,67). This idea is further supported by studies in rodent models, which have consistently shown that inducing extensive DA loss throughout the striatum could induce representative behavioral deficits (52). Nevertheless, these models haven't necessarily accounted for the frequent pre-motor appearance of these symptoms, when the DA loss is mainly limited to sensorimotor areas of the striatum (25).…”

Evidence for an apathy phenotype in aged mice

“…Emotional blunting, defined as a diminished response to emotionally salient stimuli, is a core feature of apathy but is often overlooked in favour of effort-based paradigms, particularly in rodent models (Magnard et al, 2016). Methods commonly used to study anxiety or depression-related behaviours may provide an indication of relevant aspects of emotional behaviour in ageing although studies are limited.…”

PET imaging of the influence of physiological and pathological α‐synuclein on dopaminergic and serotonergic neurotransmission in mouse models

“…As the pathogenesis of human synucleinopathy remains unclear, animal genetic models are highly valuable for understanding the role of this protein in these neurodegenerative disorders . Several strategies were used to produce transgenic mice with α‐syn overexpression, sometimes considered rather simplistically as models of PD.…”

“…As the pathogenesis of human synucleinopathy remains unclear, animal genetic models are highly valuable for understanding the role of this protein in these neurodegenerative disorders. 21,22 Several strategies were used to produce transgenic mice with αsyn overexpression, sometimes considered rather simplistically as models of PD. Although mouse models do not fully reproduce the pathological changes seen in synucleinopathy patients (ie, dopaminergic cell loss, presence of typical Lewy bodies, etc.…”