The adenosine A2A antagonist MSX-3 reverses the effort-related effects of dopamine blockade: differential interaction with D1 and D2 family antagonists

Abstract

Rationale-Brain dopamine (DA) participates in the modulation of instrumental behavior, including aspects of behavioral activation and effort-related choice behavior. Rats with impaired DA transmission reallocate their behavior away from food-seeking behaviors that have high response requirements, and instead select less effortful alternatives. Although accumbens DA is considered a critical component of the brain circuitry regulating effort-related choice behavior, emerging evidence demonstrates a role for adenosine A 2A receptors.Objective-Adenosine A 2A receptor antagonism has been shown to reverse the effects of DA antagonism. The present experiments were conducted to determine if this effect was dependent upon the subtype of DA receptor that was antagonized to produce the changes in effort-related choice. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptMaterials and methods-The adenosine A 2A receptor antagonist MSX-3 (0.5-2.0 mg/kg IP) was assessed for its ability to reverse the effects of the D1 family antagonist SCH39166 (ecopipam; 0.2 mg/kg IP) and the D2 family antagonist eticlopride (0.08 mg/kg IP), using a concurrent lever pressing/ chow feeding procedure.Results-MSX-3 produced a substantial dose-related reversal of the effects of eticlopride on lever pressing and chow intake. At the highest dose of MSX-3, there was a complete reversal of the effects of eticlopride on lever pressing. In contrast, MSX-3 produced only a minimal attenuation of the effects of SCH39166, as measured by regression and effect size analyses.Conclusions-The greater ability of MSX-3 to reverse the effects of D2 vs. D1 blockade may be related to the colocalization of D2 and adenosine A 2A receptors on the same population of striatal neurons.

Effort-related motivational effects of the pro-inflammatory cytokine interleukin 1-beta: studies with the concurrent fixed ratio 5/ chow feeding choice task

“…Though previous work has shown that MSX-3 had no effect of FR5/chow feeding choice performance when administered on its own (Farrar et al 2007), co-administration of MSX-3 significantly reversed the behavioral effects of IL-1β injections, restoring the baseline behavioral pattern by increasing lever pressing and decreasing chow intake in IL-1β-treated rats. These results are consistent with previous research demonstrating that adenosine A 2A receptor blockade or genetic deletion can reverse the effort-related effects of DA antagonism and depletion (Farrar et al 2007, 2010; Worden et al 2009; Mott et al 2009; Salamone et al 2009; Nunes et al 2010; Pardo et al 2012). Furthermore, the present findings are consistent with reports showing that the adenosine A 2A antagonists can produce effects that are consistent with the behavioral profile of an antidepressant in rodents tested on the swim test or tail suspension task (El Yacoubi et al 2001; Hodgson et al 2009; Hanff et al 2010).…”

Wheel running alters patterns of uncontrollable stress-induced cfos mRNA expression in rat dorsal striatum direct and indirect pathways: A possible role for plasticity in adenosine receptors

“…Indeed, A 1 R and A 2A R are now recognized as major modulators of striatum function. Their relatively high degree of expression in the striatum, predominate post-synaptic location on medium spiny neurons, and antagonistic interaction with dopamine receptors are consistent with a role in motor control, instrumental learning, habit learning, working memory, reward, and motivation [76-85]. Thus, potential changes to A 1 R and A 2A R expression, related to reduced mRNA from running, may influence a number of striatum-involved cognitive modalities.…”

Adenosine A2A Receptors in the Nucleus Accumbens Bi-Directionally Alter Cocaine Seeking in Rats

“…For example, a recent study demonstrated that blocking A 2A receptors, and hence, removing the adenosine 'brake', produces wakefulness (Lazarus et al, 2011). Antagonism of A 2A receptors also restores deficits in effort-related behaviors induced by D 2 receptor blockade Worden et al, 2009), suggesting that A 2A receptors are a tonic modulator of D 2 receptor expressing neurons within the striatum (Harper et al, 2006;Nagel et al, 2003). Our data provide further support that A 2A receptors exert tonic regulation of D 2 receptors and suggests that A 2A receptors are an important modulator of DA-mediated behavior (Farrar et al, 2010;Hakansson et al, 2006;Harper et al, 2006;Nagel et al, 2003;Weber et al, 2010).…”