Striatal changes underlie MPEP-mediated suppression of the acquisition and expression of pramipexole-induced place preference in an alpha-synuclein rat model of Parkinson’s disease

Abstract

Impulsive-compulsive disorders in Parkinson's disease patients have been described as behavioural or substance addictions including pathological gambling or compulsive medication use of dopamine replacement therapy. A substantial gap remains in the understanding of these disorders. We previously demonstrated that the rewarding effect of the D2/D3 agonist pramipexole was enhanced after repeated exposure to L-dopa and alpha-synuclein mediated dopaminergic nigral loss with specific transcriptional signatures suggesting a key involvement of the glutamatergic pathway. Here, we further investigate the therapeutic potential of metabotropic glutamate receptor 5 antagonism in Parkinson's disease/dopamine replacement therapy related bias of reward-mediated associative learning. We identified protein changes underlying the striatal remodelling associated with the pramipexole-induced conditioned place preference. Acquisition and expression of the pramipexole-induced conditioned place preference were abolished by the metabotropic glutamate receptor 5 antagonist 2-methyl-6-phenylethynyl (pyridine) (conditioned place preference scores obtained with pramipexole conditioning were reduced by 12.5% and 125.8% when 2-methyl-6-phenylethynyl (pyridine) was co-administrated with pramipexole or after the pramipexole conditioning, respectively). Up-regulation of the metabotropic glutamate receptor 5 was found in the dorsomedial-striatum and nucleus accumbens core. Activation of these two brain sub-regions was also highlighted through FosB immunohistochemistry. Convergent molecular and pharmacological data further suggests metabotropic glutamate receptor 5 as a promising therapeutic target for the management of Parkinson's disease/dopamine replacement therapy related reward bias.

Implication of nigral dopaminergic lesion and repeated L-dopa exposure in neuropsychiatric symptoms of Parkinson’s disease

“…This finding diverges from previous studies highlighting decreased social interaction and anxiety-like behaviour in 6-OHDA-lesioned rats (Eskow Jaunarajs et al, 2010) or impaired cognitive function in healthy rats (Hernández et al, 2014) following chronic L-dopa. It is also contrasting with published data demonstrating important L-dopa-induced brain remodelling and behavioural changes in a parkinsonian context (Bordet et al, 1997(Bordet et al, , 2000Brown et al, 2005;Bychkov et al, 2007;Loiodice et al, 2017bLoiodice et al, , 2017aLoiodice et al, , 2018Sgambato-Faure et al, 2005;van Kampen and Stoessl, 2003). We believe that the key difference between the present study and the aforementioned reports relies on the degree of the nigral lesion (we report a DA cell loss of 48% in the SNc).…”

“…In agreement with this idea of a DRT-induced dysregulation of the DA system, animal studies have demonstrated that repeated exposure to DRT was associated with reward bias (Loiodice et al, 2017b(Loiodice et al, , 2017a and compulsive behaviour after nigrostriatal lesion (Dardou et al, 2017) in a parkinsonian context. In these experiments, the behavioural outcome (pramipexole-induced place preference and compulsive-like behaviour, respectively) was associated with an increase of Fos-like positive cells in the striatum (Dardou et al, 2017;Loiodice et al, 2017a) and the frontal cortex (Dardou et al, 2017), highlighting drug-induced changes in brain regions involved in cognitive/affective information processing. Other studies in 6-hydroxydopamine (6-OHDA)-lesioned rats have also reported that chronic L-dopa may worsen lesion-induced anxiety and depression (Eskow Jaunarajs et al, 2010, while it has been recently suggested that chronic L-dopa treatment per se could induce depression-like behaviour, anhedonia and cognitive dysfunction in unlesioned rats, with Fos induction and DA receptor dysregulation in the hippocampus (Hernández et al, 2014).…”

“…However, previous data reported that chronic exposure to DRT (especially L-dopa) was responsible for aberrant striatal neuroplasticities such as up-regulation of DA receptors, BDNF and FOSB (Bordet et al, 1997;Brown et al, 2005;Bychkov et al, 2007), which are believed to underlie (at least) motor complications (Bezard et al, 2001), and was also associated with PD-related neuropsychiatric disorders in patients (Beaulieu-Boire and Lang, 2015; Evans and Lees, 2004;Kuzuhara, 2001;Martínez-Fernández et al, 2016;Rascol et al, 2003). In agreement with this idea of a DRT-induced dysregulation of the DA system, animal studies have demonstrated that repeated exposure to DRT was associated with reward bias (Loiodice et al, 2017b(Loiodice et al, , 2017a and compulsive behaviour after nigrostriatal lesion (Dardou et al, 2017) in a parkinsonian context. In these experiments, the behavioural outcome (pramipexole-induced place preference and compulsive-like behaviour, respectively) was associated with an increase of Fos-like positive cells in the striatum (Dardou et al, 2017;Loiodice et al, 2017a) and the frontal cortex (Dardou et al, 2017), highlighting drug-induced changes in brain regions involved in cognitive/affective information processing.…”

“…1) received a daily subcutaneous injection of L-dopa methyl ester 20 mg/kg and benserazide 5 mg/kg for 12 consecutive days (between 2.00 and 3.00 PM). This dose was chosen based on previous studies demonstrating L-dopa-induced neuroplasticities in the striatum as well as behavioural changes and sensitization paradigms using a similar regimen (Bordet et al, 1997(Bordet et al, , 2000Brown et al, 2005;Bychkov et al, 2007;Loiodice et al, 2017bLoiodice et al, , 2017aLoiodice et al, , 2018Sgambato-Faure et al, 2005;van Kampen and Stoessl, 2003).…”

Effect of Levodopa on Reward and Impulsivity in a Rat Model of Parkinson’s Disease

“…These results seem to suggest that the rewarding effects of LD may depend on the dopaminergic degeneration profile caused by PD-mimicking lesions; however, more recent evidence reveals this may be insufficient to fully explain LD-induced reward. For instance, in relation to the study by Engeln et al ( 2013b ), in two studies employing a similar lesion approach and higher LD doses administered chronically, this drug failed to induce CPP (Loiodice et al, 2017a , b ).…”