Adenosine A2A Receptors in Striatal Glutamatergic Terminals and GABAergic Neurons Oppositely Modulate Psychostimulant Action and DARPP-32 Phosphorylation

Abstract

Adenosine A2A receptors (A2AR) are located postsynaptically in striatopallidal GABAergic neurons, antagonizing dopamine D2 receptor functions, and are also located presynaptically at corticostriatal terminals, facilitating glutamate release. To address the hypothesis that these two A2AR populations differently control the action of psychostimulants, we characterized A2AR modulation of cocaine-induced effects at the level of DARPP-32 phosphorylation at Thr-34 and Thr-75, c-Fos expression, and psychomotor activity using two lines of cell-type selective A2AR knockout (KO) mice with selective A2AR deletion in GABAergic neurons (striatum-A2AR-KO mice), or with A2AR deletion in both striatal GABAergic neurons and projecting cortical glutamatergic neurons (forebrain-A2AR-KO mice). We demonstrated that striatum-A2AR KO mice lacked A2ARs exclusively in striatal GABAergic terminals whereas forebrain-A2AR KO mice lacked A2ARs in both striatal GABAergic and glutamatergic terminals leading to a blunted A2AR-mediated facilitation of synaptosomal glutamate release. The inactivation of A2ARs in GABAergic neurons reduced striatal DARPP-32 phosphorylation at Thr-34 and increased its phosphorylation at Thr-75. Conversely, the additional deletion of corticostriatal glutamatergic A2ARs produced opposite effects on DARPP-32 phosphorylation at Thr-34 and Thr-75. This distinct modulation of DARPP-32 phosphorylation was associated with opposite responses to cocaine-induced striatal c-Fos expression and psychomotor activity in striatum-A2AR KO (enhanced) and forebrain-A2AR KO mice (reduced). Thus, A2ARs in glutamatergic corticostriatal terminals and in GABAergic striatal neurons modulate the action of psychostimulants and DARPP-32 phosphorylation in opposite ways. We conclude that A2ARs in glutamatergic terminals prominently control the action of psychostimulants and define a novel mechanism by which A2ARs fine-tune striatal activity by integrating GABAergic, dopaminergic and glutamatergic signaling.

On the role of adenosine (A)2A receptors in cocaine-induced reward: a pharmacological and neurochemical analysis in rats

“…Striatal A 2A receptor populations inhibit the psychomotor activity of cocaine, while extrastriatal A 2A receptors appear to enhance it (Shen et al 2008(Shen et al , 2013. The present pharmacological and neurochemical analyses support the A 2A -induced antagonistic modulation of striatal DA-ergic neurotransmission via the antagonistic A 2A -D 2 receptor-receptor interactions at the plasma membrane level and their indirect interactions at the level of the intra-cellular signaling cascades Trifilieff et al 2011;Borroto-Escuela et al 2013).…”

Adenosine A2A Receptors in the Amygdala Control Synaptic Plasticity and Contextual Fear Memory

“…In fact, the acquisition and recall of conditioned fear also involves other limbic and neocortical areas in partially redundant circuits (Orsini and Maren, 2012). Similarly, it is possible that the selective deletion of A 2A Rs in the amygdala might bolster the impact of otherwise less relevant A 2A Rs in other brain regions, as we have previously observed to occur for the recruitment of striatal DARPP-32 (Shen et al, 2013), behavioral sensitization , or emotional responses (Wei et al, 2014) using cell-type-selective genetic eliminations of A 2A Rs. In fact, several studies have dissected the involvement of different brain regions in the processing of contextual and cued fear memory (Orsini and Maren, 2012), albeit the expression of both forms of contextual fear mostly depend on amygdala circuits (Goosens and Maren, 2001).…”

Optogenetic Activation of Adenosine A2A Receptor Signaling in the Dorsomedial Striatopallidal Neurons Suppresses Goal-Directed Behavior

“…Immunofluorescence was performed on free-floating sections (30 μm) using the procedure as we described recently (Augusto et al, 2013;Shen et al, 2013).…”