Replacement therapy with the dopamine (DA) precursor L-DOPA is a highly effective treatment for the motor symptoms of Parkinson's disease (PD). Unfortunately, chronic L- DOPA administration induces abnormal involuntary movements termed L-DOPA- induced dyskinesia (LID), which severely impacts the quality of life for the individual. Given that L-DOPA will continue to be the primary treatment for PD, the long-term objective of the present application is to elucidate novel mechanisms that will improve pharmacotherapy for the reduction of LID. While the pathogenesis of LID is not well understood, excessive L-DOPA-induced corticostriatal glutamate release and post- synaptic striatal DA D1 receptors (D1R) appear essential. Unfortunately, effective anti- dyskinetic glutamate and DA receptor pharmacotherapies have proven elusive and/or far from clinical use. Recent evidence indicates that 5-HT1A receptors (5-HT1AR) constitute a viable pharmacological target for the control of LID. Despite these initial findings, the mechanism(s) by which 5-HT1AR exert their effects is largely unknown. Preliminary results from our laboratory have identified a novel striatal 5-HT1AR mechanism that appears integral to the anti-dykinetic effects of 5-HT1AR agonists. Therefore, the central hypothesis of the proposed research is that 5-HT1AR stimulation reduces LID by squelching corticostriatal glutamate release and D1R signaling in the DA-depleted striatum. This assertion will be tested using well-characterized behavioral, neurochemical and cellular techniques. The objective of this application will be accomplished by addressing 3 specific aims testing the following hypotheses: 1. Striatal 5-HT1AR stimulation attenuates LID. 2. 5-HT1AR stimulation ameliorates LID by lowering excessive corticostriatal glutamate release. 3. 5-HT1AR stimulation reduces LID by lessening overactive D1R signaling mechanisms that promote LID. Completion of these studies will enhance the field's understanding of 5-HT1A receptor regulation of movement and in so doing, advocate the use and improvement of 5-HT1AR agonists for LID treatment.
The movement disorder Parkinson's disease (PD) is effectively treated with the drug L-DOPA. Unfortunately chronic administration of L-DOPA leads to debilitating side effects known as dyskinesia. Studies of this application will investigate a novel pharmacologic target that shows promise in reducing dyskinesia, prolonging L-DOPA's benefit and improving the quality of life for the PD patient.
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|Conti, Melissa M; Ostock, Corinne Y; Lindenbach, David et al. (2014) Effects of prolonged selective serotonin reuptake inhibition on the development and expression of L-DOPA-induced dyskinesia in hemi-parkinsonian rats. Neuropharmacology 77:1-8|
|Lindenbach, David; Bishop, Christopher (2013) Critical involvement of the motor cortex in the pathophysiology and treatment of Parkinson's disease. Neurosci Biobehav Rev 37:2737-50|
|Lindenbach, David; Dupre, Kristin B; Eskow Jaunarajs, Karen L et al. (2013) Effects of 5-HT1A receptor stimulation on striatal and cortical M1 pERK induction by L-DOPA and a D1 receptor agonist in a rat model of Parkinson's disease. Brain Res 1537:327-39|
|Bhide, Nirmal; Lindenbach, David; Surrena, Margaret A et al. (2013) The effects of BMY-14802 against L-DOPA- and dopamine agonist-induced dyskinesia in the hemiparkinsonian rat. Psychopharmacology (Berl) 227:533-44|
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