Motor effects induced by a blockade of adenosine A2A receptors in the caudate-putamen

Abstract

Motor effects mediated through adenosine A2A receptors within the caudate-putamen were investigated in rats using bilateral microinfusions of MSX-3 (9 microg in 1 microl per side), a water-soluble phosphate prodrug of the selective A2A receptor antagonist MSX-2. Blockade of striatal A2A receptors produced a significant motor stimulation measured by an enhanced sniffing activity. Furthermore, catalepsy induced by systemic dopamine D1 (0.75 mg/kg SCH23390, i.p.) or dopamine D2 receptor blockade (1.5 mg/kg raclopride, i.p.) was potently reversed. These findings suggest that A2A receptors within the caudate-putamen are tonically activated by endogenous adenosine and that a striatal A2A receptor blockade produces motor stimulant effects, in particular in animals with dopamine hypofunction. The present results support the view that A2A receptor antagonists may be potentially useful therapeutics for the treatment of Parkinson's disease.

Injections of the selective adenosine A2A antagonist MSX-3 into the nucleus accumbens core attenuate the locomotor suppression induced by haloperidol in rats

“…The present results are consistent with previous studies demonstrating that systemic administration of adenosine A 2A antagonists can reverse the deficits in locomotion that were induced by reserpine [73], D 2 receptor deficiency [3], and haloperidol [18]. In addition, these results involving locomotion are consistent with those of studies that employed other measures of motor dysfunction, including haloperidol-induced rigidity [79], catalepsy [30,32,40], and drug-induced tremulous jaw movements, which are used as an animal model of parkinsonian tremor [18,74]. Taken together, these results provide additional support for the hypothesis that adenosine A 2A antagonism can reverse motor impairments induced by interference with DA transmission in animals.…”

“…Additional studies should investigate the role of factors such as dose, placement, age, degree of habituation, and behavioral conditions in modulating the locomotor effects of MSX-3 when administered alone. Furthermore, in view of data indicating that medial caudateputamen is involved in the effects of adenosine A2A receptor agonists and antagonists on catalepsy [30][31][32], it is possible that this striatal region also is involved in locomotor effects of these drugs. For that reason, future mapping studies should explore the effects of drug injections into various placement sites within the region extending from the nucleus accumbens core to the anteromedial regions of caudate-putamen.…”

“…The dose of haloperidol used (0.5 mg/kg), and the 14 day repeated administration procedures, were selected based upon previous studies [18,81]. The doses of MSX-3 were chosen based upon pilot experiments, as well as the results of previously published studies [30,59].…”

“…[18]), and to produce motor side effects in humans [8,53]. MSX-3 is a water-soluble pro-drug that is rapidly cleaved by phosphatases in vivo into MSX-2, which is the active antagonist of A 2A receptors [30,34,57,71]. Experiments 1 and 2 studied the ability of systemic injections of MSX-3 to reverse the suppression of locomotion induced by acute or repeated subchronic administration of 0.5 mg/kg haloperidol.…”

Simultaneous Blockade of Adenosine A2A and Metabotropic Glutamate mGlu5 Receptors Increase their Efficacy in Reversing Parkinsonian Deficits in Rats

“…Conversely, A 2A receptor agonists prevented the rotational behavior produced by apomorphine (Morelli et al, 1994). Recent evidence suggest that the antagonism of striatal A 2A receptors may represent an alternative therapeutic approach to PD and systemic or intrastriatal infusions of selective A 2A receptor antagonists, CSC or MSX-3, respectively, were found to reverse the cataleptic response induced by DA receptors blockade (Hauber et al, 1998(Hauber et al, , 2001. When tested in monkeys treated with 1-methyl-4-phenyl-1,2,5,6,-tetrahydropyridin (MPTP), the A 2A antagonist KW-6002 produced a significant improvement in motor disability (Kanda et al, 1998) and potentiated L-DOPA-mediated effects (Grondin et al, 1999).…”