A Critical Role of the Adenosine A_2AReceptor in Extrastriatal Neurons in Modulating Psychomotor Activity as Revealed by Opposite Phenotypes of Striatum and Forebrain A_2AReceptor Knock-Outs

Abstract

The function of striatal adenosine A2Areceptors (A2ARs) is well recognized because of their high expression levels and the documented antagonistic interaction between A2ARs and dopamine D2receptors in the striatum. However, the role of extrastriatal A2ARs in modulating psychomotor activity is largely unexplored because of the low level of expression and lack of tools to distinguish A2ARs in intrinsic striatal versus nonstriatal neurons. Here, we provided direct evidence for the critical role of A2ARs in extrastriatal neurons in modulating psychomotor behavior using newly developed striatum-specific A2AR knock-out (st-A2AR KO) mice in comparison with forebrain-specific A2AR KO (fb-A2AR KO) mice. In contrast to fb-A2AR KO (deleting A2ARs in the neurons of striatum as well as cerebral cortex and hippocampus), st-A2AR KO mice exhibited Cre-mediated selective deletion of the A2AR gene, mRNA, and proteins in the neurons (but not astrocytes and microglial cells) of the striatum only. Strikingly, cocaine- and phencyclidine-induced psychomotor activities were enhanced in st-A2AR KO but attenuated in fb-A2AR KO mice. Furthermore, selective inactivation of the A2ARs in extrastriatal cells by administering the A2AR antagonist KW6002 into st-A2AR KO mice attenuated cocaine effects, whereas KW6002 administration into wild-type mice enhanced cocaine effects. These results identify a critical role of A2ARs in extrastriatal neurons in providing a prominent excitatory effect on psychomotor activity. These results indicate that A2ARs in striatal and extrastriatal neurons exert an opposing modulation of psychostimulant effects and provide the first direct demonstration of a predominant facilitatory role of extrastriatal A2ARs.

Increased desensitization of dopamine D2 receptor-mediated response in the ventral tegmental area in the absence of adenosine A2A receptors

“…Consequently, dopamine release in other brain regions may be reduced, causing a hypodopaminergic state reported previously in A 2A receptor knockout mice (Chen et al, 2000;Fredholm et al, 2005;Soria et al, 2005;Castane et al, 2006;Soria et al, 2006;Shen et al, 2008). Table 1) by subtracting NSB from the total binding.…”

“…Although A 2A receptors are predominantly expressed in association with D 2 receptors in GABAergic enkephalinergic neurons, not the dynorphinergic neurons that form the GABAergic accumbens-mesencephic projections (Fenu et al, 1997;Lu et al, 1997;Svenningsson et al, 1999), deletion of A 2A receptors in the nucleus accumbens may still indirectly affect the activities of dopamine neurons in the VTA. On glutamatergic terminals, A 2A receptors were shown to modulate glutamate release in the striatum (Schiffmann et al, 2007) and mediate a prominent excitatory effect of psychostimulants (Shen et al, 2008). It is unknown whether A 2A receptors are expressed on glutamatergic terminals in the VTA, but a recent study indicated a role for forebrain A 2A receptors in the VTA, as deletion of forebrain A 2A receptors promoted survival of midbrain dopamine neurons in response to MPTP toxicity in mice (Carta et al, 2009).…”

“…Whatever the mechanism underlying interaction between D 2 and A 2A receptors in dopamine neurons, reduced D 2 receptor-mediated autoregulation of dopamine neuron activity in the VTA may contribute significantly to the dopaminergic state in A 2A receptor knockout mice (Chen et al, 2000;Fredholm et al, 2005;Soria et al, 2005;Castane et al, 2006;Soria et al, 2006;Shen et al, 2008). D 2 receptors are not activated during rhythmic single spike firing in vitro (Grace & Onn, 1989), but significantly contribute to burst firing of action potentials in vivo together with the intrinsic ion channel properties of dopamine neurons (Grace & Bunney, 1984) and excitatory inputs from other brain areas, with the activation of glutamatergic Nmethyl-D-aspartate receptors being most prominent (Overton & Clark, 1997).…”

“…However, extrastriatal A 2A receptors, for example those located on glutamatergic inputs to the striatum from the cerebral cortex (Schiffmann et al, 2007), albeit at low expression density, were found to mediate a prominent excitatory effects of psychostimulants, opposite to the effects of postsynaptic striatal A 2A receptors on striatopallidal neurons (Shen et al, 2008). The use of striatum and forebrain-specific A 2A receptor knockout mice has revealed that extrastriatal A 2A receptors in the forebrain predominently mediate the excitatory effects of psychostimulants, while striatal A 2A receptors mediate inhibitory effects of psychostimulants (Shen et al, 2008). These findings may suggest that A 2A receptors that are expressed outside the striatum, albeit at low densities, could play significant roles in neuronal functions.…”

“…In adenosine A 2A receptor knockout mice (Ledent et al, 1997), however, both the motor and reward effects of psychostimulants were reduced (Chen et al, 2000;Fredholm et al, 2005;Soria et al, 2005;Castane et al, 2006;Soria et al, 2006;Shen et al, 2008), contrary to the enhancing effects of A 2A receptor antagonists in wildtype mice. The discord between effects of A 2A receptor ligands and genetic silencing raises potential issues regarding the long-term use of A 2A receptor antagonists for the treatment of Parkinson's disease (Schwarzschild et al, 2006) and A 2A agonists for schizophrenia (Ferre, 1997).…”