Abstract
Convergent evidence suggests that serotonin 5-HT1A receptor (5-HT1AR) agonists reduce l-DOPA-induced dyskinesia by auto-regulating aberrant release of l-DOPA-derived dopamine (DA) from raphestriatal neurons. However, recent findings indicate that 5-HT1AR stimulation also modifies D1 receptor (D1R)-mediated dyskinesia and rotations implicating a previously unexplored extra-raphe mechanism. In order to characterize the contribution of the striatum to these effects, rats with medial forebrain bundle DA lesions were tested for abnormal involuntary movements (AIMs) and rotations following striatal microinfusions of the 5-HT1AR agonist +/-8-OH-DPAT and systemic D1R agonist treatment with SKF81297. Additional rats with multi-site striatal DA lesions were tested for motor disability following systemic or intrastriatal +/-8-OH-DPAT with or without systemic SKF81297. In rats with medial forebrain bundle lesions, striatal infusions of +/-8-OH-DPAT dose-dependently reduced AIMs while conversely increasing rotations. In rats with striatal lesions, +/-8-OH-DPAT alone, both systemic and intrastriatal administration, optimally reversed motor disability. Collectively, these results support an important functional interaction between 5-HT1AR and D1R in the striatum with implications for the improved treatment of Parkinson's disease.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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8-Hydroxy-2-(di-n-propylamino)tetralin / pharmacology
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Adrenergic Agents / toxicity
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Animals
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Benzazepines / pharmacology
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Biogenic Monoamines / metabolism
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Brain Chemistry / drug effects
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Chromatography, High Pressure Liquid / methods
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Corpus Striatum / drug effects
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Corpus Striatum / metabolism*
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Desipramine / pharmacology
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Disease Models, Animal
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Dopamine Agonists / pharmacology
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Dyskinesia, Drug-Induced / metabolism*
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Enzyme Inhibitors / pharmacology
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Functional Laterality / drug effects
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Functional Laterality / physiology*
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Male
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Movement Disorders / drug therapy
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Movement Disorders / etiology
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Movement Disorders / metabolism*
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Oxidopamine / toxicity
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Parkinson Disease* / complications
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Parkinson Disease* / drug therapy
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Parkinson Disease* / pathology
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Piperazines / pharmacology
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Psychomotor Performance / drug effects
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Pyridines / pharmacology
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Rats
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Rats, Sprague-Dawley
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Receptor, Serotonin, 5-HT1A / metabolism*
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Receptors, Dopamine D1 / metabolism*
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Serotonin Antagonists / pharmacology
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Serotonin Receptor Agonists / pharmacology
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Time Factors
Substances
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Adrenergic Agents
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Benzazepines
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Biogenic Monoamines
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Dopamine Agonists
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Enzyme Inhibitors
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Piperazines
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Pyridines
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Receptors, Dopamine D1
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Serotonin Antagonists
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Serotonin Receptor Agonists
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Receptor, Serotonin, 5-HT1A
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SK&F 81297
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N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide
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8-Hydroxy-2-(di-n-propylamino)tetralin
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Oxidopamine
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Desipramine