Levodopa therapy - the gold standard in Parkinson's disease (PD) treatment - is associated with disabling motor complications (dyskinesias) that are largely resistant to available drugs. So far, studies on anti-dyskinetic therapies have paid little attention to the endocannabinoid neurotransmitter system, despite: (1) the striking abundance of cannabinoid receptors in the basal ganglia; (2) functional interactions between endocannabinoids and neurotransmitters that regulate basal ganglia circuitry, such as dopamine and glutamate; (3) clinical evidence suggesting anti-dyskinetic properties of cannabinergic drugs. No information is available as to whether current anti-dyskinetic agents (such as glutamate receptor antagonists) and dopamine replacement protocols producing lower incidence of dyskinesias (i.e. long-acting dopaminergic agonists), exert their therapeutic properties by modulating endocannabinoid transmission. This possibility is supported by our preliminary studies, showing that: (a) NMDA receptor antagonists and dopamine receptor agonists trigger the release of the endocannabinoid anandamide in the basal ganglia of normal rats; (b) in 6-hydroxydopamine (6-OHDA)-lesioned rats - an animal model of PD - levodopa does not elevate endocannabinoid levels, and induces motor complications that are suppressed by stimulation of cannabinoid receptors. Together, these observations suggest that current anti-dyskinetic therapies enhance endocannabinoid transmission, and that restoration of endocannabinoid tone alleviates levodopa-associated dyskinesias. Biochemical and behavioral approaches will be used to test this hypothesis.
The first aim will determine changes in endocannabinoid production, inactivation and cannabinoid receptor expression in the basal ganglia of intact and 6-OHDA-lesioned animals following administration of direct/indirect and short/long-acting dopaminergic agonists.
The second aim will address the effects of glutamate receptor antagonism on endocannabinoid transmission in the same brain areas.
The third aim will investigate the effects of endocannabinoid uptake and breakdown inhibitors on levodopa-induced dyskinesias, and how cannabinoid receptor antagonists affect the anti-dyskinetic properties of dopaminergic and glutamatergic agents. In conclusion, our study will elucidate the role of the endocannabinoid system in levodopa-associated dyskinesias and provide a rational to develop new treatments that act via the endocannabinoid system.
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