Adenosine A2A receptors inhibit the conductance of NMDA receptor channels in rat neostriatal neurons

Abstract

Whole-cell patch clamp experiments were carried out in rat striatal brain slices. In a subset of striatal neurons (70-80%), NMDA-induced inward currents were inhibited by the adenosine A2A receptor selective agonist CGS 21680. The non-selective adenosine receptor antagonist 8-(p-sulphophenyl)-theophylline and the A2A receptor selective antagonist 8-(3-chlorostyryl)caffeine abolished the inhibitory action of CGS 21680. Intracellular GDP-beta-S, which is known to prevent G protein-mediated reactions, also eliminated the effect of CGS 21680. Extracellular dibutyryl cAMP, a membrane permeable analogue of cAMP, and intracellular Sp-cAMPS, an activator of cAMP-dependent protein kinases (PKA), both abolished the CGS 21680-induced inhibition. By contrast, Rp-cAMPS and PKI 14-24 amide, two inhibitors of PKA had no effect. Intracellular U-73122 (a phospholipase C inhibitor) and heparin (an inositoltriphosphate antagonist) prevented the effect of CGS 21680. Finally, a more efficient buffering of intracellular Ca2+ by a substitution of EGTA (11 mM) by BAPTA (5.5 mM) acted like U-73122 or heparin. Hence, A2A receptors appear to negatively modulate NMDA receptor channel conductance via the phospholipase C/inositoltriphosphate/Ca2+ pathway rather than the adenylate cyclase/PKA pathway.

Selective inactivation of adenosine A2A receptors in striatal neurons enhances working memory and reversal learning

“…A 2A R modulation of NMDAR current at post-synaptic striatal neurons (Norenberg et al 1998), as well as A 2A R heterodimerization and functional interaction with mGlu 5 Rs (Ferre et al 2002), further suggest that striatal A 2A R activity may also modify working memory by modulating striatal glutamatergic signaling. The modification of the striatal function potentially through dopaminergic and/or glutamatergic mechanisms by striatal A 2A Rs might be expected to alter the processing of cortical information entering the striatum, as well as striatal projections to efferent targets such as the prefrontal cortex (Simpson et al 2010).…”

“…They are abundantly expressed in the striatum and are largely found on post-synaptic striatopallidal medium spiny neurons (MSNs) of the "indirect" pathway (e.g., Schiffmann et al 1991a,b;Rosin et al 1998;Rebola et al 2005) where they colocalize and interact with receptors of other neurotransmitter and neuromodulatory systems to influence synaptic plasticity and behavior Wei et al 2011). Specifically, striatal A 2A Rs interact antagonistically with dopamine D 2 receptors (D 2 Rs) (Hillion et al 2002;Canals et al 2003) and oppose N-methyl-D-aspartate receptor (NMDAR) function (Norenberg et al 1998;Wirkner et al 2000;Gerevich et al 2002). In contrast, striatal A 2A Rs may also interact synergistically with metabotropic glutamate 5 receptors (mGlu 5 Rs) (Ferre et al 2002;Kachroo et al 2005) and cannabinoid CB1 receptors (CB 1 Rs) (Tebano et al 2009;Lerner et al 2010).…”

Modulation of Ca2+-currents by sequential and simultaneous activation of adenosine A1 and A2A receptors in striatal projection neurons

“…In many cells, the signaling cascades ignited by these two classes of G proteins have opposed actions [30][31][32][33][34]. Therefore, an implicit hypothesis predicts that the signaling cascades that control Ca 2+ -currents and excitability via A 1 -and A 2A -receptors would have a push-pull kind of effects: One would decrease and the other would increase the activity of many final effectors in cells expressing both receptors [12,32,33,[35][36][37]. However, to our knowledge, the modulatory actions of both adenosine receptors on Ca 2+ -currents, expressed by the same SPNs, have not been described.…”

Expression of Adenosine A2A Receptors in the Rat Lumbar Spinal Cord and Implications in the Modulation of N-Methyl-d-Aspartate Receptor Currents

“…20 -22 Finally, it is noteworthy that in rat neostriatal neurons, activation of A 2A receptors has been shown to inhibit the conductance of N-methyl-daspartate (NMDA) receptors through an intracellular pathway. 23,24 Therefore, a similar mechanism in the spinal cord could be relevant in regard to the involvement of the NMDA receptors in pain pathways. Indeed, the plastic phenomenon called wind-up is related to the activation of NMDA receptors and is responsible for the development of hyperalgesia.…”