Serotonin 1A receptor (5-HT1AR) agonists reduce dyskinesia in experimental and clinical models of Parkinson's disease. In order to improve and hasten the use of these compounds, the current proposal will investigate their interactions with dopamine (DA) D1 (D1R) and glutamate NMDA (NMDAR) receptors.
Specific Aim 1 will test the hypothesis that 5-HT1AR stimulation diminishes D1R- mediated dyskinesia by reducing aberrant striatal NMDAR subunit expression and signaling. To do so, chronic and acutely treated hemiparkinsonian rats will be pretreated with vehicle or a 5-HT1 AR agonist prior to D1R agonist treatment and abnormal involuntary movements (AIMs), a measure of dyskinesia, will be monitored. To test this, RT-PCR, Western blots, and immunohistochemistry will be employed. It is predicted that 5-HT1AR stimulation will reduce DIR-mediated dyskinesia while diminishing NR2B subunit mRNA and protein expression, as well as overactive mitogen-activated protein kinase signaling, within the DA-depleted striatum.
Specific Aim 2 will use in vivo microdialysis to test the hypothesis that striatal 5-HT1 AR stimulation reduces DIR-mediated dyskinesia by diminishing striatonigral GABA release. DIR-primed rats will receive striatal pretreatment of vehicle or a 5-HT1AR agonist followed by systemic D1R agonist treatment.
AIMs ratings and substantia nigra pars reticulata sampling of GABA will follow. Striatal 5-HT1 AR stimulation is predicted to decrease D1R agonist-mediated dyskinesia while simultaneously lessening nigral GABA levels. Together, these experiments are expected to reveal a novel mechanism of 5-HT1AR agonists with significant implications for PD treatment. Relevance to public health: Parkinson's disease (PD) is the second most frequent neurodegenerative disease in the world, affecting 1.5 million people in the United States. Treatment for PD consists of L-DOPA therapy, which unfortunately over time loses its efficacy and deleterious side effects appear, such as L- DOPA-induced dyskinesia. The proposed experiments are meant to ultimately improve the use of 5-HT1AR agonists for the treatment of PD patients experiencing L-DOPA-induced dyskinesia by understanding how this class of compounds works.
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| Dupre, Kristin B; Ostock, Corinne Y; George, Jessica A et al. (2013) Effects of 5-HT1A receptor stimulation on D1 receptor agonist-induced striatonigral activity and dyskinesia in hemiparkinsonian rats. ACS Chem Neurosci 4:747-60 |
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