Dopamine reduction of GABA currents in striatal medium-sized spiny neurons is mediated principally by the D1 receptor subtype

Dopamine modulates voltage- and ligand-gated currents in striatal medium-sized neurons (MSNs) through the activation of D1- and D2-like family receptors. GABA(A) receptor-mediated currents are reduced by D1 receptor agonists, but the relative contribution of D-1 or D-5 receptors in this attenuation has been elusive due to the lack of selective pharmacological agents. Here we examined GABA(A) receptor-mediated currents and the effects of D1 agonists on MSNs from wildtype and D-1 or D-5 receptor knockout (KO) mice. Immunohistochemical and single-cell RT-PCR studies demonstrated a lack of compensatory effects after genetic deletion of D-1 or D-5 receptors. However, the expression of GABA(A) receptor alpha 1 subunits was reduced in D-5 KO mice. At the functional level, whole-cell patch clamp recordings in dissociated MSNs showed that GABA peak current amplitudes were smaller in cells from D-5 KO mice indicating that lack of this receptor subtype directly affected GABA(A)-mediated currents. In striatal slices, addition of a D1 agonist reduced GABA currents significantly more in D-5 KO compared to D-1 KO mice. We conclude that D-1 receptors are the main D1-like receptor subtype involved in the modulation of GABA currents and that D-5 receptors contribute to the normal expression of these currents in the striatum.