Comparison of the behavioral effects of adenosine agonists and dopamine antagonists in mice

Abstract

The adenosine agonists 5'-N-ethylcarboxamideadenosine (NECA), 2-chloroadenosine (2-CLA), N6-cyclohexyladenosine (CHA), N6-cyclopentyladenosine (CPA), 2-(phenylamino)adenosine (CV-1808) and R and S isomers of N6-phenylisopropyladenosine (R-PIA and S-PIA) decreased spontaneous locomotor activity in mice and, except for CPA, did so at doses that did not impair motor coordination, a profile shared by dopamine antagonists. CV-1808, the only agent with higher affinity for A2 as compared with A1 adenosine receptors, displayed the largest separation between locomotor inhibitory and ataxic potency. Like dopamine antagonists, NECA and CV-1808 also decreased hyperactivity caused by d--amphetamine at doses that did not cause ataxia whereas A1-selective adenosine agonists reduced amphetamine's effects only at ataxic doses. Unlike dopamine antagonists, adenosine agonists inhibited apomorphine-induced cage climbing only at doses that caused ataxia. Involvement of central adenosine receptors in these effects was suggested by the significant correlation obtained between potency for locomotor inhibition after IP and ICV administration. Affinity for A1 but not A2 adenosine receptors was significantly correlated with potency for inducing ataxia. These results suggest that the behavioral profile of adenosine agonists in mice is related to their affinity for A1 and A2 adenosine receptors and indicate that adenosine agonists produce certain behavioral effects that are similar to those seen with dopamine antagonists.

2-[2-[4-[2-[2-[1,3-Dihydro-1,1-bis(4-hydroxyphenyl)-3-oxo-5-isobenzofuranthioureidyl]ethylaminocarbonyl]ethyl]phenyl] ethylamino]-5?-N-ethylcarboxamidoadenosine (FITC-APEC): A fluorescent ligand for A2a-adenosine receptors

“…FITC-APEC binding to bovine striatal membranes was saturable, with the estimated K D (57 ± 2 nM) similar to the K i value obtained in competition studies using pmol/mg protein) found by using A 2a -adenosine receptor radioligands [17,25,26] for similarly prepared tissues of various animal species (i.e., bovine, guinea pig, man, mouse, rabbit, and rat). Despite the moderate differences in B max obtained using fluorescent ligand and radioligand binding techniques, FITC-APEC binding was inhibited by compounds that recognize A 2a -adenosine receptors in a competitive manner, while agents that do not interact with A 2a -adenosine receptors did not inhibit FITC-APEC binding (Fig.…”

“…An association between A 2a -adenosine receptors and the postsynaptic dopaminergic system also has been proposed [17,18]. Moreover, A 2a -adenosine receptor agonists have shown antipsychotic-like effects [17].…”

“…Central A 2a -adenosine receptors are associated with CNS control of respiration, by modulating sensory inputs originating in carotid body chemoreceptors and controlling cardiovascular functions through the nucleus tractus solitarius [12]. An association between A 2a -adenosine receptors and the postsynaptic dopaminergic system also has been proposed [17,18]. Moreover, A 2a -adenosine receptor agonists have shown antipsychotic-like effects [17].…”

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

“…Consistent with these previous findings of an interaction between DA and adenosine receptors, adenosine A 2A agonists have been shown to induce effects that resemble those produced by DA antagonists or DA depletions (Heffner et al 1989;Barraco et al 1993;Ferré 1997;Rimondini et al 1997). Administration of the adenosine A 2A receptor agonist CGS 21680 into the ventricles inhibited acquisition and expression of wheel running behavior (Cabeza de Vaca et al 2007).…”

Adenosine A2A receptors in ventral striatum, hypothalamus and nociceptive circuitry

“…Nevertheless, we have also demonstrated A 2A -D 2 receptor interactions in the ventral striatum that are similar to interactions in the dorsal striatum (reviewed in Ferré, 1997). At the behavioral level, by acting on the ventral striatum, A 2A receptor agonists counteract and A 2A antagonists potentiate the motor, discriminative and rewarding effects of psychostimulants (Heffner et al, 1989;Popoli et al, 1994;Rimondini et al, 1997;Shimazoe et al, 2000;Knapp et al, 2001;Poleszak and Malec, 2002;Justinova et al, 2003;Filip et al, 2006). The non-selective A 1 and A 2A antagonist caffeine also potentiates these responses to psychostimulants (Misra et al, 1986;Logan et al, 1989;Gauvin et al, 1990;Horger et al, 1991;Comer and Carroll, 1996;Gasior et al, 2000;Munzar et al, 2002).…”