Date of Completion
Merce Correa, James Chrobak
Field of Study
Master of Arts
Organisms frequently make effort-related decisions based upon assessments of motivational value and response costs. Dopamine (DA) and DA receptors (DA-Rs), particularly in nucleus accumbens (NAc), are known to regulate such effort-related choice behavior processes. For instance, DA-R antagonists as well as NAc DA depletion can decrease choice behavior. Moreover, previous studies have shown that systemic administration of adenosine A2A antagonists reverses the behavioral effects of DA-R D2 antagonists in rats responding on the concurrent choice task. MSX-3, a selective adenosine A2A antagonist, is a prodrug of MSX-2 with better water solubility. MSX-3 produces a substantial dose-related reversal of the effects of DA-R D2 antagonists on lever pressing and chow intake. MSX-4 is a novel A2A antagonist that is an amino acid ester prodrug of MSX-2, and is thought to have better oral bioavailability than MSX-3. In the present studies, we investigated the effects of MSX-4 on choice behavior using the commonly employed fixed ratio 5 (FR5)/chow feeding procedure. MSX-4 (2.0-8.0 mg/kg IP) produced a dose-related reversal of the effects of 0.08 mg/kg eticlopride on lever pressing and chow intake, with a similar time course as MSX-3. Following oral administration, both MSX-3 and MSX-4 showed a reversal of motivational impairments induced by eticlopride at comparable doses. Furthermore, eticlopride-induced increases in c-Fos expression in NAc were reversed by co-administration of MSX-3 and MSX-4. Overall, these data suggest that both adenosine A2A antagonist pro-drugs induce similar behavioral effects, and similar actions on cellular markers of neural activity in NAc. Additionally, this research further supports the hypothesis that DA and adenosine interact in the regulation of effort-related choice behavior. Further understanding this interaction between DA and adenosine and may have implications for understanding the energy-related motivational dysfunctions, such as psychomotor slowing, fatigue, and apathy, all of which are seen in patients with depression, Parkinson’s disease, and other central nervous system disorders.
Santerre, Jessica L., "Behavioral and Neurochemical Characterization of the Effects of the Novel Adenosine Antogonist MSX-4" (2011). Master's Theses. 190.