DARPP-32 is another signaling molecule that has been extensively studied in response to drugs of abuse. It is well known that acute psychostimulants lead to PKA phosphorylation of DARPP-32 at threonine 34 (T34), causing it to become a potent inhibitor of protein phosphatase 1 (PP-1), which regulates the phosphorylation state of many effector proteins, including transcription factors, ionotropic receptors, and ion channels (Greengard et al., 1999). However, until recently, it was unclear which MSN subtype mediates this biochemical change. Greengard et al. (1999) generated BAC transgenic mouse models that enable the evaluation of DARPP-32 phosphorylation in D1+ or D2+ MSNs by expressing tagged versions of DARPP-32 using D1 or D2 BACs allowing for immunoprecipitation of DARPP-32 from each MSN subtype. These studies demonstrated that acute cocaine treatment increases T34 phosphorylation in D1+ MSNs and induces phosphorylation of threonine 75 (T75) by Cdk5, which inhibits PKA signaling, selectively in D2+ MSNs (Bateup et al., 2008). Finally this group showed that deletion of DARPP-32 from each MSN subtype using D1-Cre and D2-Cre BAC transgenic mice results in opposite regulation of cocaine-induced locomotor
