Title

Dopamine-adenosine interactions in animal models of parkinsonism

Date of Completion

January 2006

Keywords

Biology, Neuroscience|Psychology, Psychobiology|Health Sciences, Pathology|Psychology, Physiological

Degree

Ph.D.

Abstract

A series of 15 experiments was conducted to investigate functional interactions between dopamine D2 and adenosine A2A receptors in rat models of parkinsonism, in which the selective A2A antagonist MSX-3 was assessed for its ability to reverse the motor effects of the D2 antagonist haloperidol. Experiment 1 (Chapter 1) investigated the effects of systemic MSX-3 on tremulous jaw movements induced by repeated administration of haloperidol. MSX-3 attenuated haloperidol-induced jaw movements. Experiments 2-9 (Chapter 2) examined the effects of MSX-3 on haloperidol-induced suppression of locomotion. First, the effects of systemic MSX-3 on haloperidol-induced locomotor suppression were assessed with acute (experiment 2) or 14-day repeated (experiment 3) administration of haloperidol. MSX-3 increased locomotion in haloperidol-treated animals in both experiments. Next, MSX-3 was intracranially injected to determine the brain site at which the compound could reverse the locomotor suppression induced by haloperidol administered acutely (experiments 4-6) or repeatedly for 14 days (experiments 7-9). The effects of MSX-3 for increasing locomotion in haloperidol-treated rats were more potent when the drug was injected into the nucleus accumbens core than when injected into the nucleus accumbens shell or the ventrolateral neostriatum. In experiment 10 (Chapter 3), patterns of Fos-like immunoreactivity were analyzed in the nucleus accumbens and the ventrolateral neostriatum in animals treated acutely with haloperidol and/or MSX-3. It was found that haloperidol induced strong Fos-like immunoreactivity in both regions, and that MSX-3 showed non-significant tendencies to reduce haloperidol-induced c-fos expression. In experiments 11-15 (Chapter 4), in vivo microdialysis methods were employed to examine how acute systemic haloperidol would affect extracellular GABA levels in the globus pallidus and ventral pallidum. It was expected that haloperidol would increase GABA levels in those pallidal areas. However, haloperidol did not significantly increase GABA levels in either the globus pallidus or the ventral pallidum, although there was a non-significant tendency to increase GABA in the ventral pallidum when the concentration of calcium was doubled in the perfusion medium. Taken together, the present studies elucidate the brain mechanisms through which adenosine A2A antagonists exert their antiparkinsonian effects and foster the development of new drugs for the treatment of parkinsonism. ^

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