Parkinson's disease (PD) is a progressive neurologic disorder characterized by rigidity, bradykinesia and tremor. The mainstay of treatment is dopamine (DA) replacement therapy with L-dopa. Disabling side effects siich as dyskinesia and motor fluctuations often undermine L-dopa treatment and have prompted the need to identify non-dopaminergic drug targets. In the basal ganglia, DA neuronal loss leads to hyperactivity of the subthalamic nucleus, which provides an increased glutamatergic excitatory drive onto the internal part of the globus pallidus and substantia nigra pars reticulata. Strategies to counteract glutamatergic hyperactivity can provide alternatives to conventional dopaminergic therapies. It has been observed that typical antipsychotic drugs (APD), which are potent DA D2 antagonists, have parkinsdnism side effect whereas atypical APD that exhibit a high 5-HT2A:DA D2 receptor affinities ratio, are less prone to induce parkinsonism. Animal studies showed that haloperidol-induced catalepsy was reduced by 5-HT2A receptor antagonists. Limited success of clinical trials involving 5-HT2 antagonists could be attributed to the relatively nonspecific 5-HT effects of the agents used or lack of information on the serotonergic drug targets impacted in PD. Cortieo-striatal and pallido-striatal neurons are a major source of 5-HT2A receptor binding in the striatum. This proposal will test the hypothesis that 5-HT2A receptor antagonists acting at cortico-striatal terminals may be beneficial in restoring motor function in parkinsonism by decreasing glutamate release from cortico-striatal neurons.
The specific aims proposed are 1)To determine the impact of 1-methyl-4- phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced hypokinesia on serotonergic markers in mice: 2) To examine the effect of treatment with 5-HT2A, 5-HT2C and mixed 5-HT2A/2C receptor antagonists on MPTPinduced motor deficits 3)To determine if treatment with 5-HT2A receptor antagonists will decrease striatal extracellular glutamate levels and alter the functional activity of striatal neurons of MPTP-treated mice.
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