As stated earlier, Ferguson et al. (2011) used herpes simplex virus (HSV) vectors to express an engineered GPCR (a Gi/o-coupled human muscarinic M4 designer receptor exclusively activated by a designer drug, hM4D) that is activated by an otherwise pharmacologically inert ligand using enkephalin and dynorphin promoters to selectively silence D1+ or D2+ MSNs in the dStr. The authors showed that transiently disrupting D2+ MSN activity in dStr facilitated amphetamine sensitization, whereas decreasing excitability of D1+ MSNs impaired the persistence of amphetamine-induced sensitization. Finally, abolishing D2+ MSNs in the NAc at adult ages using diptheria toxin receptor enhances the rewarding effect of amphetamine (Durieux et al., 2009). Such data are in accordance with our optogenetic findings, and together implicate opposite roles of D1+ vs. D2+ MSNs in drug addiction, with D1+ MSNs promoting both reward and sensitizing responses to psychostimulants and D2+ MSNs dampening these behaviors.
