Date of Completion

Spring 5-6-2012

Thesis Advisor(s)

John Salamone

Department

Psychology

Disciplines

Biological Psychology | Psychology

Abstract

Nucleus accumbens dopamine (DA) is an important regulator of locomotion. The neuromodulator adenosine also has a role in regulating locomotion. The adenosine A2A receptor subtype is colocalized with DA D2 receptors on medium spiny neurons in the striatum and nucleus accumbens. Interactions between adenosine A2A and DA D2 receptor antagonists are significant for regulating various aspects of motor and motivational function. The adenosine A2A antagonist MSX-3 has been shown to reverse the suppression of locomotion induced by the DA D2 antagonist eticlopride. The structure of MSX-3 was modified to produce the prodrug MSX-4 which has high oral bioavailability. The present studies sought to elucidate the interactions between eticlopride and MSX-4 by determining if MSX-4 could reverse eticlopride-induced locomotion suppression. Moreover, the induction of anxiety was measured by recording the relative amount of activity in the inner portion of the open field arena. Rats were injected with eticlopride, MSX-4, saline, or both drugs. The animal’s locomotion and anxiety-like behaviors were measured. To provide a neural marker of the interaction between eticlopride and MSX-4, histological studies measured the expression of c-Fos. Eticlopride significantly suppressed locomotion and increased c-Fos expression in the nucleus accumbens as compared to vehicle animals. MSX-4 reversed the locomotion suppression induced by eticlopride, and decreased the eticlopride-induced expression of c-Fos in the nucleus accumbens. MSX-4 produced no significant increase in the anxiety index. MSX-4 fits the general antiparkinsonian profile of adenosine A2A antagonists. This research may be relevant for the development of novel drug therapies for the treatment of parkinsonism and psychomotor dysfunctions in depression.