"Serotonin Receptors and Parkinson's Disease"

Meharry Medical College, Nashville TN

Investigators

Linked publications & trials

Abstract

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