Emerging pharmacotherapies for Parkinson's Disease: Experimental studies in the rat

Abstract: Parkinson´s disease (PD) is a neurodegenerative disorder characterized by the typical motor symptoms, akinesia/bradykinesia, rigidity and resting tremor. These symptoms are caused by a deficiency of dopamine (DA) in the brain, which depends on degeneration of DA neurons in the substantia nigra. The most effective treatment for PD is the DA precursor, L-DOPA. Unfortunately, within a few years, L-DOPA causes dyskinesias (abnormal involuntary movements) that are debilitating and treatment-limiting. In experimental models of PD, L-DOPA-induced dyskinesia (LID) can be improved through pharmacological modulation of glutamate or serotonin (5-HT) transmission. However, the applicability of either approach, and the underlying mechanisms, have remained unclear. This thesis work has examined the effects of novel glutamate- and 5-HT modulators in animal models of PD and LID. In a first study, we evaluated Fenobam, a clinically approved antagonist of metabotropic glutamate receptor type 5 (mGluR5) in parkinsonian rats and monkeys. Compared with animals treated with L-DOPA, rats cotreated with Fenobam and L-DOPA exhibited a reduced peak severity of LID but a maintained an antiparkinsonian-like motor response. Similar results were obtained in the monkey model of PD. In a second study, we examined the antiakinetic and antidyskinetic potential of novel ligands of metabotropic glutamate receptor type 4 (mGluR4), which is highly expressed in the basal ganglia. We show that neither a positive allosteric modulator (PAM) nor an orthosteric agonist of mGluR4 ameliorate LID. However, the mGluR4 PAM potentiated the antiakinetic effect of low doses of L-DOPA in certain behavioral tests. In a third study, we investigated the effects of novel, potent and selective agonists of the 5-HT1A receptor, which has emerged as an important modulator of DA release in parkinsonian subjects treated with L-DOPA. The 5-HT1A agonists examined here had superior antidyskinetic efficacy to previously used compounds. Intriguingly, one agonist completely abolished LID and only slightly interfered with the antiakinetic effect of L-DOPA. This compound was shown to markedly reduce the activity of 5-HT neurons, assessed by measuring 5-HT release in the striatum. In the fourth study, we addressed the hypothesis that mGluR5 antagonists and 5-HT1A/B agonists have distinct mechanisms of action, by examining the effects of the two drug categories on involuntary movements induced by either L-DOPA or a D1 receptor agonist. D1 agonist-induced dyskinesia was responsive to mGluR5 but not 5-HT1A/B modulation. Combined mGluR5 antagonism and 5-HT1A/B agonism exerted greater-than-additive antidyskinetic effects in L-DOPA-treated rats. However, there was no advantage in combining the two drugs when dyskinesias were elicited by the D1 receptor agonist. These results prompted the interesting hypothesis that different types of PD dyskinesias may respond differently to putative antidyskinetic interventions, depending on their main underlying mechanism. To systematically address the above hypothesis, we performed a fifth study to characterize dyskinesia induced by different classes of DA receptor agonists, and examine their response to treatment. Interestingly, the phenomenology of dyskinesias was found to depend on the inducing agent. In particular, combination of D1- and D2- receptor agonists produced involuntary movements with more pronounced dystonic features. The antidyskinetic response to mGluR5 antagonism was also conditional on the inducing treatment. Only dyskinesias induced by a D1 receptor agonist, but not those induced by a D2 agonist, were significantly improved by mGluR5 antagonism. Taken together, the results of this thesis provide a robust experimental and theoretical basis for developing antidyskinetic treatments that modulate mGluR5 and 5-HT1A/B receptors.