Cocaine use and abstinence induce long-term synaptic alterations in the excitatory input to nucleus accumbens (NAc) medium spiny neurons (MSNs). The NAc regulates reward-related behaviors through two parallel projections to the ventral pallidum (VP)-originating in D1 or D2-expressing MSNs (D1-MSNs; D2-MSNs). The activity of these projections depends on their excitatory synaptic inputs, but it is not known whether and how abstinence from cocaine affects the excitatory transmission to D1-MSNsand D2-MSNs. Here we examined different forms of cocaine-induced synaptic plasticity in the inputs from the basolateral amygdala (BLA) and medial prefrontal cortex (mPFC) to NAc D1-MSNsand putative D2-MSNs(pD2-MSNs) in the core and shell subcompartments of the NAc. We used the whole-cell patch-clamp technique to record excitatory postsynaptic currents from D1-tdTomato mice injected with ChR2 in either the BLA or the mPFC and retrograde tracer (RetroBeads) in the VP. We found that cocaine conditioned place preference (CPP) followed by abstinence potentiated the excitatory input from the BLA and mPFC to both D1-MSNsand pD2-MSNs. Interestingly, while the strengthening of the inputs to D1-MSNswas of postsynaptic origin and manifested as increased AMPA to NMDA ratio, in pD2-MSNsplasticity was predominantly presynaptic and was detected as changes in the paired-pulse ratio and coefficient of variation. Lastly, some of the changes were sex-specific. Overall our data show that abstinence from cocaine changes the excitatory inputs to both D1-MSNsand pD2-MSNsbut with different mechanisms. This may help understand how circuits converging into the VP change after cocaine exposure. →VP →VP →VP →VP →VP →VP →VP →VP →VP →VP →VP →VP →VP
