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Pramipexole induced place preference promoted after L-dopa therapy and nigral dopaminergic loss: linking behavior to transcriptional modifications

ABSTRACT: Symptoms of the dopamine dysregulation syndrome in patients with Parkinson’s disease (PD) are close to those observed in psychostimulant addiction. This suggests that dopamine replacement therapy shares some properties with potentially addictive drugs. A remaining challenge is to understand the neuroadaptations leading to compulsive dopaminergic medication use. To this end, the reinforcing properties of the D2/D3 agonist pramipexole (PPX) were assessed after chronic exposure to L-dopa in an alpha-synuclein PD rat model.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE74382 | GEO | 2015/10/28

SECONDARY ACCESSION(S): PRJNA300207

REPOSITORIES: GEO

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Project description:Symptoms of the dopamine dysregulation syndrome in patients with Parkinsonâs disease (PD) are close to those observed in psychostimulant addiction. This suggests that dopamine replacement therapy shares some properties with potentially addictive drugs. A remaining challenge is to understand the neuroadaptations leading to compulsive dopaminergic medication use. To this end, the reinforcing properties of the D2/D3 agonist pramipexole (PPX) were assessed after chronic exposure to L-dopa in an alpha-synuclein PD rat model. Individual male rats underwent a bilateral nigral loss induced by AAV-mediated alpha-synuclein overexpression. Control sham animals received stereotaxic injection of the same AAV vector enabeling expresion of the GFP. Five weeks after lesion induction, animals received a subcutaneous daily administration of L-dopa methyl-ester (50mg/kg) plus benserazide (12,5mg/kg) or a saline solution. Following this 3 weeks period of chronic treatment, the reinforcing properties of the D2/D3 agonist pramipexole were assessed using a place conditioning paradigm. This procedure consists in pairing a drug with a specific environment and vehicle with another environment during a conditioning period. The first day, animals received an intraperitoneal injection of saline solution before a 20min habituation period that allowed exploration of the apparatus (pre-test). Time spent in each chamber was analyzed. The compartment less occupied by the animal was determined as the drug paired side. The following days, animals received either pramipexole 2mg/kg on days 1, 3, 5 and 7 or vehicle on days 2, 4, 6 and 8 and were placed in the paired-chamber for 40 minutes. Controls groups received saline solution during all conditioning sessions. The day following the last conditioning session, a probe test (post test) was performed with 20min free access to the apparatus after an ip injection of saline solution. Place preference scores were calculated as the difference in time spent in the drug-paired chamber between post-test and pre-test.

Project description:The therapeutic benefits of L–3,4–dihydroxyphenylalanine (L-DOPA) in Parkinson’s disease (PD) patients severely diminishes with the onset of L-DOPA-induced dyskinesia (LID), a debilitating motor side effect. LID is mainly due to altered dopaminergic signaling in the striatum, a brain region that controls motor and cognitive functions. However, the molecular mechanisms that promote LID remain unclear. Here, we have reported that increased striatal RasGRP1 (also known as CalDAG-GEF-II) is instrumentally linked to the development of LID in a 6-hydroxydopamine (6-OHDA) lesioned mouse model of PD. L-DOPA treatment rapidly upregulated RasGRP1 in the dopamine-1 receptor positive neurons in the dorsal striatum. RasGRP1 deleted mice (RasGRP1–/–) had drastically diminished LID, and RasGRP1–/– mice did not interfere with the therapeutic benefits of L-DOPA. In terms of its mechanism, RasGRP1 mediated L-DOPA-induced extracellular regulated kinase (ERK), the mammalian target of rapamycin kinase (mTOR) and the cAMP/PKA pathway. RasGRP1 bind directly with and acts 2 as a guanine nucleotide exchange (GEF) for Ras-homolog-enriched in the brain (Rheb), a potent activator of mTOR, both in vitro and in the intact striatum. High-resolution tandem mass tag mass spectrometry analysis of striatal tissue revealed significant targets, such as phosphodiesterase 10a (Pde10a), Pde2a, catechol-o-methyltransferase (Comt), and glutamate decarboxylase 1 and 2 (Gad1 and Gad2), as downstream regulators of RasGRP1 that are linked to LID vulnerability. Moreover, we found that RASGRP1 protein is also upregulated predominantly in the striatum of MPTP-lesioned macaque treated with L-DOPA, emphasizing the translational potential of this protein. Collectively, the findings of this study demonstrated that RasGRP1 is a major regulator of LID in the dorsal striatum. Pharmacological or gene-depletion strategies targeting RasGRP1 may offer novel therapeutic opportunities for preventing LID in PD patients.

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Pramipexole induced place preference promoted after L-dopa therapy and nigral dopaminergic loss: linking behavior to transcriptional modifications

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