Catalepsy induced by a blockade of dopamine D₁ or D₂ receptors was reversed by a concomitant blockade of adenosine A_2A receptors in the caudate‐putamen of rats

Abstract

The present study sought to determine, in more detail, the effects of an unselective and a selective adenosine A(2A) receptor blockade on catalepsy induced by a blockade of dopamine D1 or D2 receptors in rats. The results demonstrated that systemic administration of the unselective A1/A2 receptor antagonist, theophylline and the selective A(2A) receptor antagonist, CSC potently reversed catalepsy induced by a systemic D2 receptor blockade with raclopride or by a bilateral blockade of D2 receptors in the caudate-putamen (CPu) with S(-)sulpiride. Likewise, systemic administration of theophylline and CSC reversed catalepsy induced by a systemic D1 receptor blockade with SCH23390; theophylline also counteracted catalepsy after an intra-CPu D1 receptor blockade with SCH23390. Intracerebral co-microinfusions of the selective A(2A) receptor antagonist, MSX-3 together with a D1 (SCH23390) or D2 receptor [S(-) sulpiride] antagonist revealed that catalepsy due to intra-CPu D1 or D2 receptor blockade can be potently reversed by an intra-CPu A2A receptor blockade. In conclusion, our results with systemic and intra-CPu drug administration demonstrate that D1 and D2 receptor-mediated catalepsy can both be reversed by a concomitant blockade of A(2A) receptors. Our results implicate that the CPu is a critical neural substrate for antagonistic interactions of a D1/D2 receptor blockade and an A(2A) receptor blockade in control of motor activity. The present results provide further support for the view that A(2A) receptor antagonists may be potential therapeutics for the treatment of Parkinson's disease.

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

“…As shown by in situ hybridization and binding studies (Martinez-Mir et al, 1991;Schiffmann et al, 1991;Svenningsson et al, 1998), the A 2A receptor is coexpressed with DA D 2 receptors in the striatopallidal GABAergic neurons, which contain enkephalin and originate in the so-called striatal efferent indirect pathway (Fink et al, 1992). Behavioral data support the strong A 2A -D 2 receptor interactions to explain the enhancement of the antiParkinsonian effects of DA agonists in rodent models of PD (Pinna et al, 1996;Fenu et al, 1997;Koga et al, 2000;Hauber et al, 2001).…”

“…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).…”

“…Electrophysiological studies have reported that adenosine A 2A receptors may control the GABA-evoked overflow in striatum and globus pallidus (Corsi et al, 1999;Kirk and Richardson, 1994;Mayfield et al, 1993), and synergistically increase the pallidal GABA levels when agonists acting at both A 2A /mGlu 5 receptors are coinjected (Diaz-Cabiale et al, 2002). The systemic injection of CSC is known to reverse the catalepsy produced by the bilateral blockade of D 2 DA receptors in the striatum with sulpiride (Hauber et al, 2001) and to decrease contralateral rotation induced by intrastriatal and intrasubthalamic nucleus administration of a nonselective groups I and II mGlu receptors agonist, 1S,3R-ACPD (Feeley-Kearney and Albin, 1995). Furthermore, intrastriatal administration of selective antagonists of group I mGlu receptors (AIDA) inhibited the haloperidol-induced muscle rigidity (Wolfarth et al, 2000).…”

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

“…In these striatal areas, there is considerable evidence of a functional interaction between dopamine D 2 and adenosine A 2A receptors (Fink et al 1992;Ferré 1997;Hillion et al 2002;Fuxe et al 2003). 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).…”

“…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).…”