The two MSNs are differentially enriched in other G-protein-coupled receptors in addition to dopamine receptors. D1+ MSNs express higher levels of the acetylcholine muscarinic receptor 4 (M4; Bernard et al., 1992; Ince et al., 1997) and D2+ MSNs are enriched in both adenosine receptor 2A (A2A; Schiffmann et al., 1991; Schiffmann and Vanderhaeghen, 1993) and G-protein-coupled receptor 6 (Gpr6; Lobo et al., 2007; gensat.org). M4 is coupled to Gi/o, which would produce an opposite response, compared to D1 receptors, in D1+ MSNs by inhibiting cAMP/PKA activity. Indeed, a D1+ MSN selective M4 knockout displayed enhanced behavioral sensitization to cocaine and amphetamine (Jeon et al., 2010). Furthermore, recent studies using a designer receptor exclusively activated by a synthetic drug (DREADDs) showed that activation of the DREADD Gi/o-coupled human M4 receptor (hM4D) in D1+ MSNs diminished behavioral sensitization to amphetamine, with the opposite response seen in D2+ MSNs (Ferguson et al., 2011). Such data reveal the antagonizing role of M4 receptors in D1+ MSNs in drug abuse. As well, since the hM4D receptor potently inhibits these MSNs, the data provide insight into the effect of altered activity of these two MSNs in drug abuse, which will be discussed further below.
