Long-lasting, drug-induced adaptations within the nucleus accumbens (NAc) have been proposed to contribute to drug-mediated addictive behaviors. Here we have used an optogenetic approach to examine the role of NAc medium spiny neurons (MSNs) expressing dopamine D2 receptors (D2Rs) in cocaine-induced behavioral sensitization. Adeno-associated viral vectors encoding channelrhodopsin-2 (ChR2) were delivered into the NAc of D2R-Cre transgenic mice. This allowed us to selectively photostimulate D2R-MSNs in NAc. D2R-MSNs form local inhibitory circuits, because photostimulation of D2R-MSN evoked inhibitory postsynaptic currents (IPSCs) in neighboring MSNs. Photostimulation of NAc D2R-MSN in vivo affected neither the initiation nor the expression of cocaine-induced behavioral sensitization. However, photostimulation during the drug withdrawal period attenuated expression of cocaine-induced behavioral sensitization. These results show that D2R-MSNs of NAc play a key role in withdrawal-induced plasticity and may contribute to relapse after cessation of drug abuse.

Repetitive exposure to addictive drugs causes synaptic modification in the mesocorticolimbic dopamine (DA) system. Dopamine D1 receptors (D1R) or D2 receptors (D2R) expressed in the medium spiny neurons (MSNs) of the nucleus accumbens (NAc) play critical roles in the control of addictive behaviors. Optogenetic activation of D2R-expressing MSNs (D2R-MSNs) in the NAc previously demonstrated that these neurons play a key role in withdrawal-induced plasticity. Here, we examined the effect of optogenetic inhibition of D2R-MSNs in the NAc on cocaine-induced behavioral sensitization. Adeno-associated viral vectors encoding archaerhodopsin (ArchT) were delivered into the NAc of D2-Cre transgenic mice. Activation of ArchT produced photoinhibition of D2R-MSNs and caused disinhibition of neighboring MSNs in the NAc. However, such optogenetic silencing of D2R-MSNs in the NAc in vivo affected neither the initiation nor the expression of cocaine-induced behavioral sensitization. Similarly, photoinhibition of NAc D2R-MSNs in the NAc during the drug withdrawal period did not affect the expression of cocaine-induced behavioral sensitization. More detailed analysis of the effects of optogenetic activation of D2R-MSNs suggests that D2R-MSNs in the NAc exert important modulatory effects on neighboring MSN neurons, which may control the balanced output of NAc MSNs to control addictive behaviors.