[show abstract][hide abstract] ABSTRACT: Deep brain stimulation (DBS) of the subthalamic nucleus is increasingly being employed as a treatment for parkinsonian symptoms, including tremor. The present studies used tremulous jaw movements, a pharmacological model of tremor in rodents, to investigate the tremorolytic effects of subthalamic DBS in rats. Subthalamic DBS reduced the tremulous jaw movements induced by the dopamine D2 family antagonist pimozide and the D1 family antagonist ecopipam, as well as the cholinomimetics pilocarpine and galantamine. The ability of DBS to suppress tremulous jaw movements was dependent on the neuroanatomical locus being stimulated (subthalamic nucleus vs. a striatal control site), as well as the frequency and intensity of stimulation used. Importantly, administration of the adenosine A2A receptor antagonist MSX-3 reduced the frequency and intensity parameters needed to attenuate tremulous jaw movements. These results have implications for the clinical use of DBS, and future studies should determine whether adenosine A2A antagonism could be used to enhance the tremorolytic efficacy of subthalamic DBS at low frequencies and intensities in human patients.
European Journal of Neuroscience 04/2013; · 3.75 Impact Factor
[show abstract][hide abstract] ABSTRACT: Safinamide is an α-aminoamide derivative that is currently in Phase III clinical trial development as an add-on therapy to levodopa or dopamine agonists for patients with Parkinson's Disease. Safinamide is a monoamine oxidase B inhibitor with additional non-dopaminergic actions. The present experiments were performed to evaluate the ability of safinamide to attenuate parkinsonian motor impairments using the tremulous jaw movement model, an animal model of parkinsonian tremor. In rats, tremulous jaw movements can be induced with dopamine (DA) antagonists, DA depletion, and cholinomimetics, and can be reversed by various antiparkinsonian drugs, including L-DOPA, DA agonists, anticholinergics and adenosine A(2A) antagonists. In these present experiments, tremulous jaw movements were induced with the anticholinesterase galantamine (3.0 mg/kg IP), the muscarinic agonist pilocarpine (0.5 mg/kg IP), and the dopamine D2 antagonist pimozide (1.0 mg/kg IP). Safinamide significantly reduced the number of tremulous jaw movements induced by galantamine, pilocarpine, and pimozide, with consistent effects across all three drugs at a dose range of 5.0-10.0 mg/kg. The results of this study support the use of safinamide as a treatment for parkinsonian tremor.
Pharmacology Biochemistry and Behavior 01/2013; · 2.61 Impact Factor
[show abstract][hide abstract] ABSTRACT: Tremulous jaw movements are rapid vertical deflections of the lower jaw that resemble chewing but are not directed at any particular stimulus. In rats, tremulous jaw movements can be induced by a number of conditions that parallel those seen in human parkinsonism, including dopamine depletion, dopamine antagonism, and cholinomimetic drugs. Moreover, tremulous jaw movements in rats can be attenuated using antiparkinsonian agents such as L-DOPA, dopamine agonists, muscarinic antagonists, and adenosine A(2A) antagonists. In the present studies, a mouse model of tremulous jaw movements was established to investigate the effects of adenosine A(2A) antagonism, and a conditional neuronal knockout of adenosine A(2A) receptors, on cholinomimetic-induced tremulous jaw movements. The muscarinic agonist pilocarpine significantly induced tremulous jaw movements in a dose-dependent manner (0.25-1.0mg/kg IP). These movements occurred largely in the 3-7.5Hz local frequency range. Administration of the adenosine A(2A) antagonist MSX-3 (2.5-10.0mg/kg IP) significantly attenuated pilocarpine-induced tremulous jaw movements. Furthermore, adenosine A(2A) receptor knockout mice showed a significant reduction in pilocarpine-induced tremulous jaw movements compared to littermate controls. These results demonstrate the feasibility of using the tremulous jaw movement model in mice, and indicate that adenosine A(2A) receptor antagonism and deletion are capable of reducing cholinomimetic-induced tremulous jaw movements in mice. Future studies should investigate the effects of additional genetic manipulations using the mouse tremulous jaw movement model.
European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology 09/2012; · 3.68 Impact Factor
[show abstract][hide abstract] ABSTRACT: Tremulous jaw movements in rats can be induced by several conditions associated with parkinsonism and tremorogenesis, including dopamine depletion, dopamine antagonism, and cholinomimetic drugs. Previous research indicates that neostriatal mechanisms are involved in the generation of tremulous jaw movements, but the striatal output pathways involved in these movements remain uncertain. One important pathway for striatal output is the GABAergic striatopallidal system. The present studies were undertaken to determine if extracellular levels of GABA in globus pallidus are associated with the induction of tremulous jaw movements by either a dopamine D2 antagonist (haloperidol) or a cholinomimetic (the muscarinic agonist pilocarpine). The first experiment studied the effects of both acute and repeated (i.e. 8 days) administration of the D2 antagonist haloperidol. In the second experiment, the effect of acute administration of the muscarinic agonist pilocarpine on GABA levels in the globus pallidus was examined. In both experiments, behavioral observations of tremulous jaw movements were conducted in parallel with the collection of microdialysis samples. Acute and repeated haloperidol treatment induced tremulous jaw movements, and significantly elevated extracellular GABA in globus pallidus. Pooling across all treatment groups, there was a significant positive correlation between pallidal GABA levels and the number of tremulous jaw movements induced during the first three samples collected after injection. However, injection of 4.0mg/kg pilocarpine had no effect on pallidal GABA release, despite the robust induction of tremulous jaw movements. These results indicate that the tremulous jaw movements induced by dopamine D2 antagonism and those induced through muscarinic receptor stimulation may be generated via distinct mechanisms.
Behavioural brain research 06/2012; 234(1):129-35. · 3.22 Impact Factor
[show abstract][hide abstract] ABSTRACT: Adenosine A(2A) and dopamine D2 receptors interact to regulate diverse aspects of ventral and dorsal striatal functions related to motivational and motor processes, and it has been suggested that adenosine A(2A) antagonists could be useful for the treatment of depression, parkinsonism and other disorders. The present experiments were performed to characterize the effects of MSX-4, which is an amino acid ester prodrug of the potent and selective adenosine A(2A) receptor antagonist MSX-2, by assessing its ability to reverse pharmacologically induced motivational and motor impairments. In the first group of studies, MSX-4 reversed the effects of the D2 antagonist eticlopride on a concurrent lever pressing/chow feeding task that is used as a measure of effort-related choice behavior. MSX-4 was less potent after intraperitoneal administration than the comparison compound, MSX-3, though both were equally efficacious. With this task, MSX-4 was orally active in the same dose range as MSX-3. MSX-4 also reversed the locomotor suppression induced by eticlopride in the open field, but did not induce anxiogenic effects as measured by the relative amount of interior activity. Behaviorally active doses of MSX-4 also attenuated the increase in c-Fos and pDARPP-32(Thr34) expression in nucleus accumbens core that was induced by injections of eticlopride. In addition, MSX-4 suppressed the oral tremor induced by the anticholinesterase galantamine, which is consistent with an antiparkinsonian profile. These actions of MSX-4 indicate that this compound could have potential utility as a treatment for parkinsonism, as well as some of the motivational symptoms of depression and other disorders.
Pharmacology Biochemistry and Behavior 06/2012; 102(4):477-87. · 2.61 Impact Factor
[show abstract][hide abstract] ABSTRACT: Tremor is a cardinal symptom of parkinsonism, occurring early on in the disease course and affecting more than 70% of patients. Parkinsonian resting tremor occurs in a frequency range of 3-7 Hz and can be resistant to available pharmacotherapy. Despite its prevalence, and the significant decrease in quality of life associated with it, the pathophysiology of parkinsonian tremor is poorly understood. The tremulous jaw movement (TJM) model is an extensively validated rodent model of tremor. TJMs are induced by conditions that also lead to parkinsonism in humans (i.e., striatal DA depletion, DA antagonism, and cholinomimetic activity) and reversed by several antiparkinsonian drugs (i.e., DA precursors, DA agonists, anticholinergics, and adenosine A(2A) antagonists). TJMs occur in the same 3-7 Hz frequency range seen in parkinsonian resting tremor, a range distinct from that of dyskinesia (1-2 Hz), and postural tremor (8-14 Hz). Overall, these drug-induced TJMs share many characteristics with human parkinsonian tremor, but do not closely resemble tardive dyskinesia. The current review discusses recent advances in the validation of the TJM model, and illustrates how this model is being used to develop novel therapeutic strategies, both surgical and pharmacological, for the treatment of parkinsonian resting tremor.