To determine if miRNAs may play a role in regulating the motivational effects of addictive drugs, we recently examined the effects of conditionally deleting Argonaut 2 (Ago2) in D2 receptor-expressing medium spiny neurons (MSNs) in striatum. These neurons, also known as striatopallidal or “indirect” neurons, are thought to play a key role in response inhibition, with deficits in their function perhaps contributing to the development of compulsive drug use.104 Ago2 is a core component of the RNA-induced silencing complex (RISC), which regulates the maturation and function of miRNAs. Deletion of Ago2 broadly in striatopallidal neurons was achieved by breeding Ago.fl/fl mice with mice expressing Cre recombinase under the control of the D2 receptor promoter. It was found that brain anatomy and striatal integrity were not impacted but, as expected, miRNA expression and function was disrupted by deletion of Ago2 in these neurons.105 Importantly, this genetic manipulation abolished the rewarding effects of cocaine, measured using a conditioned place preference (CPP) procedure.105 Processes independent of drug reinforcement, such as spatial learning deficits, can confound CPP. Therefore, to more rigorously investigate the involvement
