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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS059600-05
Application #
8247115
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Sieber, Beth-Anne
Project Start
2008-05-01
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2014-04-30
Support Year
5
Fiscal Year
2012
Total Cost
$262,395
Indirect Cost
$90,895
Name
State University of NY, Binghamton
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
090189965
City
Binghamton
State
NY
Country
United States
Zip Code
13902
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
Ostock, Corinne Y; Lindenbach, David; Goldenberg, Adam A et al. (2014) Effects of noradrenergic denervation by anti-DBH-saporin on behavioral responsivity to L-DOPA in the hemi-parkinsonian rat. Behav Brain Res 270:75-85
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
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
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
Barnum, Christopher J; Bhide, Nirmal; Lindenbach, David et al. (2012) Effects of noradrenergic denervation on L-DOPA-induced dyskinesia and its treatment by ?- and ?-adrenergic receptor antagonists in hemiparkinsonian rats. Pharmacol Biochem Behav 100:607-15
Eskow Jaunarajs, Karen L; Angoa-Perez, Mariana; Kuhn, Donald M et al. (2011) Potential mechanisms underlying anxiety and depression in Parkinson's disease: consequences of l-DOPA treatment. Neurosci Biobehav Rev 35:556-64
Ostock, Corinne Y; Dupre, Kristin B; Jaunarajs, Karen L Eskow et al. (2011) Role of the primary motor cortex in L-Dopa-induced dyskinesia and its modulation by 5-HT1A receptor stimulation. Neuropharmacology 61:753-60
Dupre, Kristin B; Ostock, Corinne Y; Eskow Jaunarajs, Karen L et al. (2011) Local modulation of striatal glutamate efflux by serotonin 1A receptor stimulation in dyskinetic, hemiparkinsonian rats. Exp Neurol 229:288-99
Lindenbach, David; Ostock, Corinne Y; Eskow Jaunarajs, Karen L et al. (2011) Behavioral and cellular modulation of L-DOPA-induced dyskinesia by beta-adrenoceptor blockade in the 6-hydroxydopamine-lesioned rat. J Pharmacol Exp Ther 337:755-65

Showing the most recent 10 out of 16 publications