Pharmacological modulation of AMPA receptor phosphorylation by dopamine and muscarinic receptor agents in the rat medial prefrontal cortex

Two key transmitters in the medial prefrontal cortex (mPFC), dopamine and acetylcholine, are believed to interact with each other to modulate local glutamatergic transmission, although molecular mechanisms underlying their crosstalk are poorly understood. Here we investigated effects of pharmacological manipulations of dopamine and muscarinic receptors on phosphorylation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in the adult rat mPFC in vivo. We found that an agonist selective for G_αs-coupled dopamine D₁ receptors, SKF81297, increased AMPA receptor GluA1 subunit phosphorylation at a protein kinase A-sensitive site (S845), while SKF81297 had no effect on GluA1 phosphorylation at S831. An agonist for G_αi/o-coupled dopamine D₂ receptors, quinpirole, also increased S845 but not S831 phosphorylation. When coinjected, the two agonists induced an additive increase in S845 phosphorylation. The D₁ receptor antagonist SCH23390 blocked the SKF81297/quinpirole-stimulated S845 phosphorylation. The D₂ antagonist eticlopride also partially blocked S845 responses to SKF81297/quinpirole. VU0152100, a positive allosteric modulator selective for G_αi/o-coupled muscarinic M₄ receptors, reduced the S845 phosphorylation induced by SKF81297 and quinpirole injected alone or together. In contrast, coinjection of subthreshold doses of tropicamide, an M₄ antagonist, and SKF81297 facilitated S845 phosphorylation. Additionally, coadministered SFK81297 and quinpirole increased the abundance of mPFC GluA1 at extrasynaptic sites. These data reveal that both D₁ and D₂ receptors upregulate GluA1 phosphorylation in mPFC neurons probably via a direct and indirect mechanism, respectively. The indirect mechanism involves M₄ receptors which generally counteract the effect of dopamine on GluA1 phosphorylation.