Abstract
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.
Footnotes
-
This work was supported by USPHS MH 01055, MH 292670, MH 57440, MH 45156, DA10044 (to A.A.G.), MH 63498 (to S.-P.O.), and MH 40899 (to P.G. and A.A.F.).
-
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
-
DOI: 10.1124/jpet.103.050062.
-
ABBREVIATIONS: DA, dopamine; DARPP-32, dopamine and cAMP-regulated phosphoprotein 32 KDa; (±)-SKF 38393, 2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; DMSO, dimethyl sulfoxide; SCH23390, R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine.
- Received February 5, 2003.
- Accepted May 29, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|