Pharmacological approaches to reduce and prevent L-Dopa-induced dyskinesias in a simian model of Parkinson's disease

The precise mechanisms of L-Dopa induced dyskinesias (LID), the most common problems in the management of Parkinson's disease (PD), are not well understood.; In the present study behavioral pharmacology approaches were used in MPTP-induced parkinsonian monkeys, in which the motor response is highly predictive of that observed in humans, to better understand the mechanisms involved in the development of LID and to find the treatments which could reduce or prevent these motor complications. These investigations can be divided in three parts: (1) Evaluation of the effect of the non-selective opioid antagonists and agonist, on the motor responses to dopaminergic agents in the primed and de novo MPTP monkeys, (2) Evaluation of the effect of docosahexaenoic acid (DHA) on the motor responses to L-Dopa in primed and de novo MPTP monkeys, and (3) Evaluation of the biochemical and behavioral effects Ro 61-8048, a novel potent inhibitor of kynurenine 3-hydroxylase which is known to raise kynurenic acid (KYNA) levels, on the motor responses to L-Dopa in primed MPTP monkeys.; Our results demonstrate that the blockade of opioid receptors by naloxone and naltrexone leads to a significant increase in the severity of LID in parkinsonian monkeys, while the opioid agonist morphine reduces these involuntary movements. Interestingly, in drug-naive MPTP parkinsonian monkeys, in addition to increase of dyskinesias, naltrexone in the short-term decreases antiparkinsonisn response to L-Dopa. These results are the first behavioral reports indicating that increased expression of opioid transmission in the striatum display an adaptive compensatory response that attempts to attenuate the short- and long-term changes that are responsible for the appearance of parkinsonism as well as the development of LID. Importantly, the observation indicating the occurance of dyskinesias with saline and naltrexone alone, after priming with dopaminergic agents and opioid antagonists, as a form of associative learning brings the first behavioral evidence suggesting the implication of a learning phenomenon in the induction of LID. The beneficial effect of DHA to reduce and/or prevent LID in primed and de novo MPTP parkinsonian monkeys suggests that DHA can be a novel and safe adjuvant in the treatment of motor complications in PD. The improvement of LID by administration of Ro 61-8048, also suggests that elevation of KYNA levels that may offset overactivity of glutamatergic transmission constitutes a promising novel approach for managing LID in PD.