Dopamine reduction of GABA currents in striatal medium-sized spiny neurons is mediated principally by the D(1)...

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 alpha1 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.