Tremulous Jaw Movements Induced by the VMAT2 Inhibitor Tetrabenazine

Parkinsonism is a movement disorder characterized by several cardinal motor symptoms: resting tremor, akinesia, bradykinesia, rigidity, and postural instability. Parkinsonian resting tremor can be modeled in rodents using the tremulous jaw movement model. Tremulous jaw movements (TJMs) are defined as “rapid vertical deflections of the lower jaw that resemble chewing but are not directed at any particular stimulus.” TJMs occur in a frequency range of 3-7 Hz and are induced by a number of pharmacological manipulations that parallel those seen in human Parkinsonism including dopamine (DA) depleting agents, DA antagonists, and cholinomimetic administration. Additionally, TJMs can be attenuated using antiparkinsonian agents including L-DOPA, DA agonists, anticholinergics, and adenosine A2A antagonists. Tetrabenazine (TBZ) is a reversible VMAT2 inhibitor that is approved by the FDA for treatment of chorea associated with Huntington’s disease (HD). While TBZ inhibits storage of all monoamines into synaptic vesicles it has been shown to preferentially target DA. Therefore, patients being treated with TBZ often experience depression and Parkinsonism as side effects. The present studies demonstrate the ability of TBZ to induce Parkinsonian tremor using the tremulous jaw movement model. When administered to rats, tetrabenazine (0.25, 0.5, 1.0, 2.0 mg/kg IP) significantly induces tremulous jaw movements in a dose-dependent manner. Freeze frame video analysis reveals these TJMs primarily occur in the 3.0-7.5 Hz frequency range, which falls in the frequency range characteristic of parkinsonian resting tremor. Coadministration of the adenosine A2A antagonist MSX-3 (1.25, 2.5, 5.0, 10.0 mg/kg IP) significantly attenuates TJMs induced by 2.0 mg/kg TBZ in rats. Similarly, coadministration of MSX-3 (2.5, 5.0, 10.0 mg/kg IP) significantly reduces the number of TJMs induced by 10.0 mg/kg TBZ in mice. To provide a cellular marker of these pharmacological conditions, we examined c-Fos expression in the ventrolateral neostriatum (VLS), the region of the brain most closely associated with the production of TJMs. 2.0 mg/kg TBZ significantly increased the number of c-Fos positive cells in the VLS, while coadministration of 10.0 mg/kg MSX-3 significantly reduced the number of c-Fos positive cells. Taken together, the results indicate that TBZ induces tremor as measured in the tremulous jaw movement model. MSX-3 is capable of attenuating this behavior by blunting the cellular effects caused by TBZ administration, thus lending further support to the use of adenosine A2A antagonists as antiparkinsonian agents