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CELLULAR AND MOLECULAR

Dopamine Modulation of Membrane Excitability in Striatal Spiny Neurons is Altered in DARPP-32 Knockout Mice

Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, Pennsylvania (S.-P.O.); Laboratory of Molecular and Cellular Neuroscience, the Rockefeller University, New York, New York (A.A.F.); Departments of Neuroscience and Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania (A.A.G.)

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.

Address correspondence to: Dr. Shao-Pii Onn, 288 Queen Lane, Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA 19129. E-mail: shao-pii.onn{at}drexel.edu

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