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

Abstract

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.

Impact of Fluoxetine on Behavioral Invigoration of Appetitive and Aversively Motivated Responses: Interaction With Dopamine Depletion

“…These results obtained from animal studies are consistent with clinical data showing a reduced selection of high effort alternatives in depressed people tested on tasks of effort-based choice (Treadway et al, 2012;Chong et al, 2016). Administration of the vesicular monoamine transporter (VMAT-2) inhibitor tetrabenazine (TBZ), which blocks the monoamine storage and leads to a striatal DA depletion at low doses in primates (Pettibone et al, 1984), rats (Nunes et al, 2013;Podurgiel et al, 2015Podurgiel et al, , 2016Yohn et al, 2015b), and mice (López-Cruz et al, 2018;Carratalá-Ros et al, 2020) has been used to induce effort-related motivational impairments in rodents (Nunes et al, 2014;Yohn et al, 2015bYohn et al, , 2016bCorrea et al, 2018;López-Cruz et al, 2018;Rotolo et al, 2019;Carratalá-Ros et al, 2020). This drug is used in the treatment of Huntington's disease and has been reported to produce depressive symptoms including fatigue in people (Frank, 2009;Guay, 2010).…”

SLC6A4 Repeat and Single-Nucleotide Polymorphisms Are Associated With Depression and Rest Tremor in Parkinson's Disease: An Exploratory Study

“…But two duloxetine-treated PD patients showed an exacerbation of tremor in a multicenter randomized study (33), which however was not seen in another study of patients treated with duloxetine (34). Moreover, an animal study showed that administration of fluoxetine exacerbated oral tremor (35). Similar to 5-HTTLPR, rs25531 is also a functional polymorphism with the G allele leading to reduced efficiency of HTT transcription (9).…”

The cerebral basis of Parkinsonian tremor: A network perspective

“…To my knowledge, there is no convincing empirical evidence that shows the efficacy of serotonergic medication for treating resting tremor. On the contrary, in parkinsonian rodents, serotonin reuptake inhibitors worsen tremor by further depleting dopamine . Furthermore, postmortem studies have not found different patterns or degrees of serotonergic cell death between tremor‐dominant and nontremor PD patients .…”