Upregulation of AMPA receptor GluA1 phosphorylation by blocking adenosine A₁ receptors in the male rat forebrain

The adenosine A₁ receptor is a G_αi/o protein-coupled receptor and inhibits upon activation cAMP formation and protein kinase A (PKA) activity. As a widely expressed receptor in the mammalian brain, A₁ receptors are implicated in the modulation of a variety of neuronal and synaptic activities. In this study, we investigated the role of A₁ receptors in the regulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in the adult rat brain in vivo.

Adult male Wistar rats were used in this study. After a systemic injection of the A₁ antagonist DPCPX, rats were sacrificed and several forebrain regions were collected for assessing changes in phosphorylation of AMPA receptors using Western blots.

A systemic injection of the A₁ antagonist DPCPX induced an increase in phosphorylation of AMPA receptor GluA1 subunits at a PKA-dependent site, serine 845 (S845), in the two subdivisions of the striatum, the caudate putamen, and nucleus accumbens. DPCPX also increased S845 phosphorylation in the medial prefrontal cortex (mPFC) and hippocampus. The DPCPX-stimulated S845 phosphorylation was a transient and reversible event. Blockade of G_αs/olf -coupled dopamine D₁ receptors with a D₁ antagonist SCH23390 abolished the responses of S845 phosphorylation to DPCPX in the striatum, mPFC, and hippocampus. DPCPX had no significant impact on phosphorylation of GluA1 at serine 831 and on expression of total GluA1 proteins in all forebrain regions surveyed.

These data demonstrate that adenosine A₁ receptors maintain an inhibitory tone on GluA1 S845 phosphorylation under normal conditions. Blocking this inhibitory tone leads to the upregulation of GluA1 S845 phosphorylation in the striatum, mPFC, and hippocampus via a D₁ -dependent manner.