[Frontiers in Bioscience 13, 3594-3605, May 1, 2008]

Tremorolytic effects of adenosine A2A antagonists: implications for parkinsonism

John D. Salamone1, Adrienne J. Betz1, Keita Ishiwari1, Jennifer Felsted1, Lisa Madson1, Brian Mirante1, Karen Clark1 , Laura Font1,4, Samantha Korbey1, Thomas N. Sager2, Jorg Hockemeyer3, Christa E. Muller 3

1Department of Psychology, University of Connecticut, Storrs, CT 06269-1020, 2 Department of Pharmacology Target Research, H. Lundbeck A/S, 9 Ottiliavej, Valby 2500,  Denmark, 3Universitat Bonn, Pharmazeutisches Institut, Pharmazeutische Chemie, Bonn, Germany, 4Area de Psicobiologia, Universitat Jaume I, Castello, Spain

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Materials and methods
3.1. Animals
3.2. Drugs
3.3. Selection of Doses and Treatment Procedures
3.4. Behavioral procedures
3.4.1. Overview
3.4.2. Tremulous jaw movements (TJMs)
3.4.3. Behavioral procedures: catalepsy
3.4.4. Behavioral procedures: locomotor activity
3.4.5. Surgical and intracranial injection procedures
3.5. Experiments
3.5.1. Experiment 1: Effects of pimozide on TJMs, catalepsy and locomotion
3.5.2. Experiment 2: Effects of KW 6002 on pimozide-induced TJMs, catalepsy and suppression of locomotion
3.5.3. Experiment 3: Effects of MSX-3 on pimozide-induced TJMs, catalepsy and suppression of locomotion
3.5.4. Experiment 4: Effects of MSX-3 on haloperidol-induced TJMs
3.5.5. Experiment 5: Effects of MSX-3 on reserpine-induced TJMs
3.5.6. Experiment 6: Effects of ventrolateral neostriatal injections of MSX-3 on pimozide-induced TJMs
3.6. Data Analyses
4. Results
4.1. Experiment 1: Effects of Pimozide on TJMs, catalepsy and locomotion
4.2. Experiment 2: Effects of KW 6002 on pimozide-induced TJMs, catalepsy and suppression of locomotion
4.3. Experiment 3: Effects of MSX-3 on pimozide-induced TJMs, catalepsy and suppression of locomotion
4.4. Experiments 4 and 5: Effects of MSX-3 on haloperidol and reserpine-induced TJMs
4.5. Experiment 6: Effects of ventrolateral neostriatal injections of MSX-3 on pimozide-induced TJMs
5. Discussion
6. Acknowledgements
7. References

1. ABSTRACT

Drug-induced tremulous jaw movements in rats have been used as a model of parkinsonian tremor. Because adenosine A2A antagonists have antiparkinsonian effects, the present experiments were conducted to study the ability of adenosine A2A antagonism to reverse the tremulous jaw movements produced by the antipsychotic drugs pimozide, haloperidol and reserpine. In one group of studies, rats received daily injections of the dopamine antagonist pimozide, and on day 8 they received injections of pimozide plus various doses of the A2A antagonists KW 6002 or MSX-3. KW 6002 and MSX-3 suppressed pimozide-induced tremulous jaw movements, reduced catalepsy, and increased locomotion. MSX-3 also suppressed the jaw movements induced by haloperidol and reserpine. In addition, local injections of MSX-3 into the ventrolateral neostriatum suppressed pimozide-induced tremulous jaw movements. Thus, adenosine A2A antagonism can reverse the tremulous movements induced by antipsychotic drugs, which is consistent with the hypothesis that antagonism of adenosine A2A receptors can result in antiparkinsonian effects. Adenosine A2A antagonists may be useful for their tremorolytic effects, and may help in treating both idiopathic and antipsychotic-induced parkinsonian symptoms.