Attempts to develop new and effective treatments for movement disorders such as Parkinson's disease have been hampered by an insufficient knowledge of how basal ganglia receptor systems adapt to the consequences of dopamine depletion. This research focuses on determining the role of upregulated serotonin 2A receptors, which we hypothesize provide a mechanism for serotonin to exert greater control over basal ganglia transmission and locomotor function under conditions of dopamine depletion. Our preliminary studies indicate that the target of the serotonin 2A receptor mechanism is the DIRECT striatonigral pathway which utilizes tachykinin neuropeptides colocalized with GABA. New experiments of this application will test the central hypothesis that: upregulated serotonin 2A receptor signaling provides a mechanism for serotonin to enhance striatonigral transmission under conditions of dopamine depletion which influences basal ganglia function and animal behavior.
In Specific Aim 1, we will determine the functional consequences of an upregulated serotonin 2A receptor system on serotonin signal transduction within the dopamine depleted striatum by measuring serotonin 2A receptor binding, its linkage to phosphoinositol hydrolysis, its modulation of striatal membrane excitability, and its ability to trans-synaptically regulate striatal tachykinin and GABA expression.
In Specific Aim 2, we will determine if tachykinin striatonigral neurons react to the stimulation of upregulated serotonin 2A receptors in the dopamine depleted animal by increasing tachykinin and GABA transmission in the substantia nigra. We will also study the impact of this regulation on locomotor behavior. Finally, in Specific Aim 3, we will determine how an upregulated serotonin 2A receptor system influences the ability of the striatonigral system to regulate basal ganglia dopamine and GABA metabolism, and how these systems influence behavioral recovery of the dopamine depleted animal. Information obtained from these studies will contribute to a better understanding of basal ganglia function and may change how serotonin pathways are considered when designing new pharmacological strategies for diseases which affect dopamine transmission.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-BDCN-2 (01))
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Murphy, Diane
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Wayne State University
Anatomy/Cell Biology
Schools of Medicine
United States
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Bishop, Christopher; Krolewski, David M; Eskow, Karen L et al. (2009) Contribution of the striatum to the effects of 5-HT1A receptor stimulation in L-DOPA-treated hemiparkinsonian rats. J Neurosci Res 87:1645-58
Campbell, B M; Kreipke, C W; Walker, P D (2006) Failure of MK-801 to suppress D1 receptor-mediated induction of locomotor activity and striatal preprotachykinin mRNA expression in the dopamine-depleted rat. Neuroscience 137:505-17
Taylor, Jennifer L; Bishop, Christopher; Ullrich, Thomas et al. (2006) Serotonin 2A receptor antagonist treatment reduces dopamine D1 receptor-mediated rotational behavior but not L-DOPA-induced abnormal involuntary movements in the unilateral dopamine-depleted rat. Neuropharmacology 50:761-8
Bishop, Christopher; Taylor, Jennifer L; Kuhn, Donald M et al. (2006) MDMA and fenfluramine reduce L-DOPA-induced dyskinesia via indirect 5-HT1A receptor stimulation. Eur J Neurosci 23:2669-76
Bishop, Christopher; Daut, Gregory S; Walker, Paul D (2005) Serotonin 5-HT2A but not 5-HT2C receptor antagonism reduces hyperlocomotor activity induced in dopamine-depleted rats by striatal administration of the D1 agonist SKF 82958. Neuropharmacology 49:350-8
Taylor, Jennifer L; Bishop, Christopher; Walker, Paul D (2005) Dopamine D1 and D2 receptor contributions to L-DOPA-induced dyskinesia in the dopamine-depleted rat. Pharmacol Biochem Behav 81:887-93
Krolewski, David M; Bishop, Christopher; Walker, Paul D (2005) Intrastriatal dopamine D1 receptor agonist-mediated motor behavior is reduced by local neurokinin 1 receptor antagonism. Synapse 57:1-7
Kreipke, Christian W; Walker, Paul D (2004) NMDA receptor blockade attenuates locomotion elicited by intrastriatal dopamine D1-receptor stimulation. Synapse 53:28-35
Bishop, Christopher; Walker, Paul D (2004) Intranigral antagonism of neurokinin 1 and 3 receptors reduces intrastriatal dopamine D1 receptor-stimulated locomotion in the rat. Brain Res 1023:126-33
Bishop, Christopher; Tessmer, Jennifer L; Ullrich, Thomas et al. (2004) Serotonin 5-HT2A receptors underlie increased motor behaviors induced in dopamine-depleted rats by intrastriatal 5-HT2A/2C agonism. J Pharmacol Exp Ther 310:687-94

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