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The novel adenosine A2A antagonist prodrug MSX-4 is effective in animal models related to motivational and motor functions

Santerre, Jessica L.; Nunes, Eric J.; Kovner, Rotem; Leser, Chelsea E.; Randall, Patrick A.; Collins-Praino, Lyndsey E.; Lopez-Cruz, Laura; Correa, Merce; Baqi, Younis; Müller, Christa E. and Salamone, John D. (2012). The novel adenosine A2A antagonist prodrug MSX-4 is effective in animal models related to motivational and motor functions. Pharmacology Biochemistry and Behavior, 102(4) pp. 477–487.

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Adenosine A2A and dopamine D2 receptors interact to regulate diverse aspects of ventral and dorsal striatal functions related to motivational and motor processes, and it has been suggested that adenosine A2A antagonists could be useful for the treatment of depression, parkinsonism and other disorders. The present experiments were performed to characterize the effects of MSX-4, which is an amino acid ester prodrug of the potent and selective adenosine A2A receptor antagonist MSX-2, by assessing its ability to reverse pharmacologically induced motivational and motor impairments. In the first group of studies, MSX-4 reversed the effects of the D2 antagonist eticlopride on a concurrent lever pressing/chow feeding task that is used as a measure of effort-related choice behavior. MSX-4 was less potent after intraperitoneal administration than the comparison compound, MSX-3, though both were equally efficacious. With this task, MSX-4 was orally active in the same dose range as MSX-3. MSX-4 also reversed the locomotor suppression induced by eticlopride in the open field, but did not induce anxiogenic effects as measured by the relative amount of interior activity. Behaviorally active doses of MSX-4 also attenuated the increase in c-Fos and pDARPP-32(Thr34) expression in nucleus accumbens core that was induced by injections of eticlopride. In addition, MSX-4 suppressed the oral tremor induced by the anticholinesterase galantamine, which is consistent with an antiparkinsonian profile. These actions of MSX-4 indicate that this compound could have potential utility as a treatment for parkinsonism, as well as some of the motivational symptoms of depression and other disorders.

Item Type: Journal Item
Copyright Holders: 2012 Elsevier Inc.
ISSN: 0091-3057
Keywords: Depression; Effort-related choice behavior; Parkinson's disease; Drug-induced parkinsonism; Locomotion; Tremulous jaw movements; c-Fos; DARPP-32
Academic Unit/School: Faculty of Science, Technology, Engineering and Mathematics (STEM) > Life, Health and Chemical Sciences
Faculty of Science, Technology, Engineering and Mathematics (STEM)
Item ID: 66603
Depositing User: Laura Lopez-Cruz
Date Deposited: 27 Sep 2019 11:03
Last Modified: 11 Jul 2020 11:55
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