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

Abstract

There is considerable evidence of interactions between adenosine A 2A receptors and dopamine D 2 receptors in striatal areas, and antagonists of the A 2A receptor have been shown to reverse the motor effects of DA antagonists in animal models. The D 2 antagonist haloperidol produces parkinsonism in humans, and also induces motor effects in rats, such as suppression of locomotion. The present experiments were conducted to study the ability of the adenosine A 2A antagonist MSX-3 to reverse the locomotor effects of acute or subchronic administration of haloperidol in rats. Systemic (i.p.) injections of MSX-3 (2.5-10.0 mg/kg) were capable of attenuating the suppression of locomotion induced by either acute or repeated (i.e., 14 day) administration of 0.5 mg/kg haloperidol. Bilateral infusions of MSX-3 directly into the nucleus accumbens core (2.5 µg or 5.0 µg in 0.5 µl per side) produced a dose-related increase in locomotor activity in rats treated with 0.5 mg/kg haloperidol either acutely or repeatedly. There were no overall significant effects of MSX-3 infused directly into the dorsomedial nucleus accumbens shell or the ventrolateral neostriatum. These results indicate that antagonism of adenosine A 2A receptors can attenuate the locomotor suppression produced by DA antagonism, and that this effect may be at least partially mediated by A 2A receptors in the nucleus accumbens core. These studies suggest that adenosine and dopamine systems interact to modulate the locomotor and behavioral activation functions of nucleus accumbens core.

Role of dopamine–adenosine interactions in the brain circuitry regulating effort-related decision making: insights into pathological aspects of motivation

“…Recently, it was demonstrated that either systemic or intra-accumbens injections of the adenosine A 2A receptor antagonist MSX-3 reversed the effects of intra-accumbens injections of the D 2 antagonist eticlopride on effort-related choice [84], demonstrating that nucleus accumbens is an important locus for this D 2 -A 2A interaction. Moreover, these results from studies of effort-related choice behavior are consistent with the large body of evidence demonstrating that A 2A antagonism can generally reverse the effects of D 2 antagonism across a wide range of behavioral contexts, including tasks that involve functions related to ventral and dorsal striatum [115,116,124,125]. The specificity of this interaction is possibly related to the pattern of cellular localization of adenosine A 1 and A 2A receptors in striatal areas, including the nucleus accumbens [103].…”

Intra-accumbens injections of the adenosine A2A agonist CGS 21680 affect effort-related choice behavior in rats

“…4). Recent data from our laboratory indicate that the locomotor effects of adenosine A 2A antagonists can differ depending upon whether they are injected into core or shell, with core placements being more effective (Ishiwari et al 2007). Thus, future research in this area should specifically target distinct core and shell placements, as was done previously with studies involving DA antagonists (e.g., Nowend et al 2001).…”

“…This interaction has typically been investigated in connection with neostriatal motor functions that are potentially related to parkinsonism Svenningsson et al 1999;Ferré et al 2001;Hauber et al 2001;Morelli and Pinna 2002;Jenner 2003Jenner , 2005Pinna et al 2005). In these studies, adenosine A 2A receptor antagonists have been shown to exert effects consistent with antiparkinsonian actions in animal models (Ferré et al , 2001Hauber et al 2001;Wardas et al 2001;Jenner 2003;Correa et al 2004;Pinna et al 2005;Ishiwari et al 2007), and adenosine A 2A receptor antagonists are being evaluated as antiparkinsonian agents in human clinical trials (Jenner 2005). More recently, researchers have begun to identify potential motivational functions of adenosine A 2A receptors (O'Neill and Brown 2006;Harper et al 2006;Cabeza de Vaca et al 2007;Farrar et al 2007).…”

Systemic administration of the adenosine A2A agonist CGS 21680 induces sedation at doses that suppress lever pressing and food intake

“…Considerable evidence indicates that there is a functional interaction between DA and adenosine A 2A receptors in both dorsal and ventral striatal areas (Chen et al, 2001;Hettinger et al, 2001;Svenningsson et al, 1999;Wang et al, 2000). This interaction often has been studied in the context of animal models related to parkinsonism, which typically focus on neostriatal motor functions (Ferré et al, , 2001Hauber et al, 2001;Ishiwari et al, 2007;Jenner, 2003Jenner, , 2005Morelli and Pinna, 2001;Pinna et al, 2005;Svenningsson et al, 1999). In these studies, adenosine A 2A receptor antagonists have been shown to exert effects consistent with antiparkinsonian actions in animal models (Correa et al, 2004;Ferré et al, 1997Ferré et al, , 2001Hauber et al, 2001;Pinna et al, 2005;Wardas et al, 2001).…”