Inactivation of Adenosine A2A Receptors Selectively Attenuates Amphetamine-Induced Behavioral Sensitization

Abstract

Repeated treatment with the psychostimulant amphetamine produces behavioral sensitization that may represent the neural adaptations underlying some features of psychosis and addiction in humans. In the present study we investigated the role of adenosine A 2A receptors in psychostimulant-induced locomotor sensitization using an A 2A receptor knockout (A 2A KO) model. Daily treatment with amphetamine for 1 week resulted in an enhanced motor response on day 8 (by two-fold compared to that on day 1), and remained enhanced at day 24 upon rechallenge with amphetamine. By contrast, locomotor sensitization to daily amphetamine did not develop in A 2A KO mice on day 8 or 24, and this absence was not the result of a nonspecific threshold effect. The absence of behavioral sensitization was selective for amphetamine since daily treatment with the D 1 agonist SKF81297 (2.5 mg/kg) or the D 2 agonist quinpirole (1.0 mg/kg) produced similar behavioral sensitization in both WT and A 2A KO mice. Furthermore, coinjection of SKF81297 and quinpirole also resulted in indistinguishable locomotor sensitization in A 2A KO and WT mice, suggesting normal D 1 and D 2 receptor responsiveness. Finally, at the cellular level A 2A receptor inactivation abolished the increase in striatal dynorphin mRNA induced by repeated amphetamine administration. The selective absence of amphetamine-induced behavioral sensitization in A 2A KO mice suggests a critical role of the A 2A receptor in the development of psychostimulant-induced behavioral sensitization, and supports the pharmacological potential of A 2A adenosinergic agents to modulate adaptive responses to repeated psychostimulant exposure.

A Critical Role of the Adenosine A2AReceptor in Extrastriatal Neurons in Modulating Psychomotor Activity as Revealed by Opposite Phenotypes of Striatum and Forebrain A2AReceptor Knock-Outs

“…Comparative analysis revealed strikingly opposite behavioral phenotypes of st-A 2A R KO and fb-A 2A R KO mice: consistent with our previous findings with fb-A 2A R KO (Bastia et al, 2005;Xiao et al, 2006) and gb-A 2A R KO mice (Chen et al, 2000(Chen et al, , 2003, cocaine-induced psychomotor activity is attenuated in fb-A 2A R KO mice. Importantly, selective inactivation of intrinsic striatal A 2A Rs (st-A 2A R KO mice) enhanced cocaineinduced psychomotor activity.…”

“…Thus, consistent with the previously reported effect of the combined treatment of cocaine and A 2A R antagonists (Filip et al, 2006) These results identify a critical role of extrastriatal A 2A Rs to provide a prominent excitatory effect to counter the documented inhibitory effect of striatal A 2A Rs on cocaine-induced psychomotor activity. The high level of A 2A Rs in the striatum (Svenningsson et al, 1999) (Chen et al, 2000(Chen et al, , 2003Bastia et al, 2005), increased anxiety (Ledent et al, 1997), attenuated depressive behaviors (El Yacoubi et al, 2001), attenuated prepulse inhibition (Wang et al, 2003), and increased aggressive behavior (Ledent et al, 1997) in global A 2A R KO mice or WT mice treated with A 2A R antagonists. These cognitive behavioral changes in global A 2A R KO mice cannot be fully accounted for by the antagonistic A 2A R-D 2 R interaction in striatal neurons.…”

“…This functional antagonism is the basis for the development of A 2A R antagonists as a promising nondopaminergic pharmacological therapy for Parkinson's disease , whereas A 2A R agonists have been proposed as potential therapeutic agents for schizophrenia (Ferre, 1997) and other psychotic disorders (Fredholm et al, 2005). However, contrary to the antagonistic A 2A R-D 2 R interaction model in the striatum and certain pharmacological data (Filip et al, 2006), genetic inactivation of A 2A Rs either globally or specifically in forebrain region attenuates, rather than enhances, the psychostimulant effects of cocaine (Chen et al, 2000), amphetamine (Chen et al, 2003;Bastia et al, 2005), or L-dopa (Fredduzzi et al, 2002;Xiao et al, 2006). These observations suggest that the activation of A 2A Rs in extrastriatal cells may oppose postsynaptic A 2A R function in striatopallidal neurons on the modulation of psychomotor activity.…”

“…In the combined treatment, KW6002 was injected 10 min before cocaine treatment. Horizontal locomotor activity (ambulation, horizontal consecutive adjacent beam breaks), fine movement (horizontal single beam break), and rearing (vertical beam break) were monitored for 120 -180 min after drug administration and analyzed as described previously (Chen et al, 2000(Chen et al, , 2003.…”

Stimulation of Adenosine Receptors Selectively Activates Gene Expression in Striatal Enkephalinergic Neurons

“…For instance, there is experimental evidence for the existence of selective gene expression in GABAergic enkephalinergic neurons during sensitization to the behavioral effects of psychostimulants (Uslaner et al, 2001). In fact, genetic inactivation of A 2A receptors has been reported to attenuate amphetamineinduced behavioral sensitization (Chen et al, 2003).…”