Fluoxetine Administration Exacerbates Oral Tremor and Striatal Dopamine Depletion in a Rodent Pharmacological Model of Parkinsonism

The cardinal motor symptoms of Parkinson's disease (PD) include resting tremor, akinesia, bradykinesia, and rigidity, and these motor abnormalities can be modeled in rodents by administration of the VMAT-2 (type-2 vesicular monoamine transporter) inhibitor tetrabenazine (9,10-dimethoxy-3-(2-met...

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Published in:	Neuropsychopharmacology (New York, N.Y.) Vol. 40; no. 9; pp. 2240 - 2247
Main Authors:	Podurgiel, Samantha J, Milligan, Meredith N, Yohn, Samantha E, Purcell, Laura J, Contreras-Mora, Hector M, Correa, Mercè, Salamone, John D
Format:	Journal Article
Language:	English
Published:	England Nature Publishing Group 01-08-2015
Subjects:	Akinesia Analysis of Variance Animals Corpus Striatum - drug effects Corpus Striatum - metabolism Disease Models, Animal Dopamine Dopamine - metabolism Dose-Response Relationship, Drug Drug Synergism Fluoxetine - adverse effects Jaw - innervation Male Mental depression Original Parkinson Disease - complications Parkinson Disease - etiology Parkinson Disease - pathology Parkinson's disease Quality of life Rats Rats, Sprague-Dawley Rodents Selective Serotonin Reuptake Inhibitors - adverse effects Serotonin Systematic review Tetrabenazine - toxicity Tremor (Muscular contraction) Tremor - chemically induced Tremor - drug therapy United States > US
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Summary:	The cardinal motor symptoms of Parkinson's disease (PD) include resting tremor, akinesia, bradykinesia, and rigidity, and these motor abnormalities can be modeled in rodents by administration of the VMAT-2 (type-2 vesicular monoamine transporter) inhibitor tetrabenazine (9,10-dimethoxy-3-(2-methylpropyl)-1,3,4,6,7, 11b hexahydrobenzo[a]quinolizin-2-one; TBZ). Depression is also commonly associated with PD, and clinical data indicate that selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine ((±)-N-methyl-γ-[4-(trifluoromethyl)phenoxy]benzenepropanamine hydrochloride; FLX) are frequently used to treat depression in PD patients. The aim of the present study was to characterize the effect of FLX on the motor dysfunctions induced by a low dose of TBZ (0.75 mg/kg), and investigate the neural mechanisms involved. This low dose of TBZ was selected based on studies with rat models of depressive symptoms. In rats, coadministration of FLX (2.5, 5.0, and 10.0 mg/kg) increased TBZ-induced oral tremor (tremulous jaw movements), and decreased locomotor activity compared with administration of TBZ alone. Coadministration of the serotonin 5-HT2A/2C antagonist mianserin (2.5 and 5.0 mg/kg) attenuated the increase in oral tremor induced by coadministration of TBZ (0.75 mg/kg) with FLX (5.0 mg/kg). Consistent with these behavioral data, coadministration of TBZ and FLX decreased DA tissue levels in the rat ventrolateral neostriatum compared with TBZ alone, and coadministration of mianserin with TBZ and FLX attenuated this effect, increasing DA tissue levels compared with the TBZ/FLX condition. These data suggest that SSRI administration in PD patients may result in worsening of motor symptoms, at least in part, by exacerbating existing DA depletions through 5-HT2A/2C-mediated modulation of DA neurotransmission.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0893-133X 1740-634X
DOI:	10.1038/npp.2015.69