Bupropion Increases Selection of High Effort Activity in Rats Tested on a Progressive Ratio/Chow Feeding Choice Procedure: Implications for Treatment of Effort-Related Motivational Symptoms

Background: Depression and related disorders are characterized by deficits in behavioral activation, exertion of effort, and other psychomotor/motivational dysfunctions. Depressed patients show alterations in effort-related decision making and a bias towards selection of low effort activities. It has been suggested that animal tests of effort-related decision making could be useful as models of motivational dysfunctions seen in psychopathology. Methods: Because clinical studies have suggested that inhibition of catecholamine uptake may be a useful strategy for treatment of effort-related motivational symptoms, the present research assessed the ability of bupropion to increase work output in rats responding on a test of effort-related decision-making (ie, a progressive ratio/chow feeding choice task). With this task, rats can choose between working for a preferred food (high-carbohydrate pellets) by lever pressing on a progressive ratio schedule vs obtaining a less preferred laboratory chow that is freely available in the chamber. Results: Bupropion (10.0–40.0 mg/kg intraperitoneal) significantly increased all measures of progressive ratio lever pressing, but decreased chow intake. These effects were greatest in animals with low baseline levels of work output on the progressive ratio schedule. Because accumbens dopamine is implicated in effort-related processes, the effects of bupropion on markers of accumbens dopamine transmission were examined. Bupropion elevated extracellular dopamine levels in accumbens core as measured by microdialysis and increased phosphorylated dopamine and cyclic-AMP related phosphoprotein 32 kDaltons (pDARPP-32) immunoreactivity in a manner consistent with D1 and D2 receptor stimulation. Conclusion: The ability of bupropion to increase exertion of effort in instrumental behavior may have implications for the pathophysiology and treatment of effort-related motivational symptoms in humans

Extracellular GABA in globus pallidus increases during the induction of oral tremor by haloperidol but not by muscarinic receptor stimulation

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.Lyndsey E. Collins-Praino, Samantha J. Podurgiel, Rotem Kovner, Patrick A. Randall, John D. Salamon

Tremorolytic effects of safinamide in animal models of drug-induced parkinsonian tremor

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 A2A antagonists. In these present experiments, tremulous jaw movements were induced with the anticholinesterase galantamine (3.0mg/kg IP), the muscarinic agonist pilocarpine (0.5mg/kg IP), and the dopamine D2 antagonist pimozide (1.0mg/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 5.0-10.0mg/kg. The results of this study support the use of safinamide as a treatment for parkinsonian tremor.Samantha Podurgiel, Lyndsey E. Collins-Praino, Samantha Yohn, Patrick A. Randall, Arthur Roach, Christophe Lobianco, John D. Salamon

Oral tremor induced by galantamine in rats: a model of the parkinsonian side effects of cholinomimetics used to treat Alzheimer's disease

Anticholinesterases are the most common treatment for Alzheimer's disease, and, in recent years, a new group of cholinesterase inhibitors (i.e. rivastigmine, galantamine, and donepezil) has become available. Although these drugs improve cognitive symptoms, they also can induce or exacerbate parkinsonian symptoms, including tremor. The present studies were conducted to determine if galantamine induces tremulous jaw movements, a rodent model of parkinsonian tremor, and to investigate whether these oral motor impairments can be reversed by co-administration of adenosine A(2A) antagonists. The first experiment demonstrated that systemic injections of galantamine (0.75-6.0 mg/kg I.P.) induced a dose-related increase in tremulous jaw movements in rats. In a second study, co-administration of the muscarinic antagonist scopolamine (0.0156-0.25 mg/kg I.P.) produced a dose dependent suppression of tremulous jaw movements induced by a 3.0 mg/kg dose of galantamine, indicating that galantamine induces these tremulous oral movements through actions on muscarinic acetylcholine receptors. In two additional studies, analyses of freeze-frame video and electromyographic activity recorded from the lateral temporalis muscle indicated that the local frequency of these galantamine-induced jaw movements occurs in the 3-7 Hz frequency range that is characteristic of parkinsonian tremor. In the final experiment, the adenosine A(2A) antagonist MSX-3 significantly attenuated the tremulous jaw movements induced by the 3.0mg/kg dose of galantamine, which is consistent with the hypothesis that co-administration of adenosine A(2A) antagonists may be beneficial in reducing parkinsonian motor impairments induced by anticholinesterase treatment.Lyndsey E. Collins, Nicholas E. Paul, Shams F. Abbas, Chelsea E. Leser, Samantha J. Podurgiel, Daniel J. Galtieri, James J. Chrobak, Younis Baqi, Christa E. Müller, John D. Salamon

Deep brain stimulation of the subthalamic nucleus reverses oral tremor in pharmacological models of parkinsonism: interaction with the effects of adenosine A2A antagonism

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.Lyndsey E. Collins-Praino, Nicholas E. Paul, Felicia Ledgard, Samantha J. Podurgiel, Rotem Kovner, Younis Baqi, Christa E. Müller, Patrick B. Senatus, and John D. Salamon