Dopamine modulation of membrane excitability in striatal spiny neurons is altered in DARPP-32 knockout mice.

The phosphoprotein DARPP-32 (dopamine and cAMP-regulated phosphoprotein 32 kDa) plays a central role in mediating the actions of a variety of neurotransmitters in medium spiny neurons of the striatum (Greengard, 1990; Fienberg et al., 1998). This study examines D1 and D2 dopamine (DA) agonist effects on the membrane properties of identified striatal neurons recorded in slices obtained from wild-type and DARPP-32-knockout mice. In wild-type spiny cells, DA D1 receptor activation decreased cell excitability, causing a 58.8 +/- 13.5% increase in rheobase current required to evoke spike discharge. In contrast, D1 agonist administration did not alter cell excitability when applied to spiny cells in slices prepared from the DARPP-32 knockout mice. D2 agonist administration decreased cell excitability in both wild-type and knockout mice. The response produced by combined D1 and D2 agonist stimulation was dependent on the sequence of agonist administration. Thus, the D1 agonist-induced decrease in excitability was reversed to a facilitation of spiking upon subsequent D2 agonist administration. In contrast, D2 agonist applied simultaneously with the D1 agonist only produced a reduction in excitability. This type of D1-dependent modulation was not present in slices from the DARPP-32 knockout mice.