Adenosine A2A Receptor Antagonists Do Not Disrupt Rodent Prepulse Inhibition: An Improved Side Effect Profile in the Treatment of Parkinson's Disease

Department of In Vivo Pharmacology, Neuroscience, Merck Research Laboratories, 2015 Galloping Hill Road, K-15-1600, Kenilworth, NJ 07033, USA.
Parkinson's disease 01/2012; 2012(4):591094. DOI: 10.1155/2012/591094
Source: PubMed


Parkinson's disease (PD) is characterized by loss of dopaminergic neurons in the substantia nigra. Current treatments for PD focus on dopaminergic therapies, including L-dopa and dopamine receptor agonists. However, these treatments induce neuropsychiatric side effects. Psychosis, characterized by delusions and hallucinations, is one of the most serious such side effects. Adenosine A(2A) receptor antagonism is a nondopaminergic treatment for PD with clinical and preclinical efficacy. The present studies assessed A(2A) antagonists SCH 412348 and istradefylline in rodent prepulse inhibition (PPI), a model of psychosis. Dopamine receptor agonists pramipexole (0.3-3 mg/kg), pergolide (0.3-3 mg/kg), and apomorphine (0.3-3 mg/kg) significantly disrupted PPI; ropinirole (1-30 mg/kg) had no effect; L-dopa (100-300 mg/kg) disrupted rat but not mouse PPI. SCH 412348 (0.3-3 mg/kg) did not disrupt rodent PPI; istradefylline (0.1-1 mg/kg) marginally disrupted mouse but not rat PPI. These results suggest that A(2A) antagonists, unlike dopamine agonists, have an improved neuropsychiatric side effect profile.

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    • "In non-lesioned rodents, higher doses of L-DOPA (100 or 300 mg/kg), acutely, reduced PPI response in rats but not in mice [4]. In the same work, authors found that the acute administration of L-DOPA 30 mg/kg, the same dose used in the present study, 1 h before PPI test, did not cause any PPI change in the non-lesioned rats [4]. Our results demonstrated that chronic L-DOPA (30 mg/kg) did not induce significant changes of PPI response in sham-operated rats. "
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    • "This possibility is highlighted by the observation that this conditional gene deletion is sufficient to enhance the animals' reaction to cocaine – a dopamine releaser [19], and to modify the transition from goal-directed to habit-based instrumental behavior [36]. To our knowledge, no study has yet specifically examined the involvement of striatal A 2A R in LI, whilst its role in the regulation of PPI remains ambiguous due to inconsistent findings [37] [38] [39] [40]. "
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    ABSTRACT: Introduction: Recent experimental and clinical research has shown that A2A adenosine receptor antagonism can bring about an improvement in the motor behavior of patients with Parkinson's disease. Istradefylline , a xanthine derivative, has the longest half-life of all the currently available A2A adenosine receptor antagonists; it can successfully permeate through the blood-brain barrier and has a high human A2A adenosine receptor affinity. Areas covered: In this article, the author discusses the potential role of A2A adenosine receptor antagonists in the treatment of Parkinson's disease through the evaluation of istradefylline. Specifically, the article reviews the clinical and pharmacokinetic information available to elucidate its therapeutic potential. Expert opinion: A2A adenosine receptor antagonists are efficacious in combination with l-dopa. l-dopa has a complex pharmacokinetic behavior and causes long-term behavioral and metabolic side effects. Future research on A2A adenosine receptor antagonism should consider compounds like istradefylline as l-dopa and/or dopamine agonist-sparing treatment alternatives, since their clinical handling, safety and side-effect profile are superior to l-dopa and/or dopamine agonists. The current focus to demonstrate a specific dyskinesia-ameliorating efficacy of A2A adenosine receptor antagonism in clinical trials is risky, since the presentation of dyskinesia varies on a day-to-day basis and is considerably influenced by peripheral l-dopa metabolism. The demonstration of an antidyskinetic effect may convince authorities, but this is far less relevant in clinical practice as patients generally better tolerate dyskinesia than other phenomena and dopaminergic side effects.
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