Dopamine Reduction of GABA Currents in Striatal Medium-sized Spiny Neurons is Mediated Principally by the D 1 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. GABAA receptor-mediated currents are reduced by D1 receptor agonists, but the relative contribution of D1 or D5 receptors in this attenuation has been elusive due to the lack of selective pharmacological agents. Here we examined GABAA receptor-mediated currents and the effects of D1 agonists on MSNs from wildtype and D1 or D5 receptor knockout (KO) mice. Immunohistochemical and single-cell RT-PCR studies demonstrated a lack of compensatory effects after genetic deletion of D1 or D5 receptors. However, the expression of GABAA receptor α1 subunits was reduced in D5 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 D5 KO mice indicating that lack of this receptor subtype directly affected GABAA-mediated currents. In striatal slices, addition of a D1 agonist reduced GABA currents significantly more in D5 KO compared to D1 KO mice. We conclude that D1 receptors are the main D1-like receptor subtype involved in the modulation of GABA currents and that D5 receptors contribute to the normal expression of these currents in the striatum.