Drug refraining and seeking potentiate synapses on distinct populations of accumbens medium spiny neurons

Cocaine-associated cues and contexts can precipitate drug seeking in humans and experimental animals. Glutamatergic synapses in the core subcompartment of the nucleus accumbens (NAcore) undergo transient potentiation in response to presenting drug-associated cues. The NAcore contains two populations of medium spiny neurons (MSNs) that differentially express D1 or D2 dopamine receptors. By recording the ratio of AMPA and NMDA glutamate receptor currents (AMPA:NMDA) from MSNs in NAcore tissue slices, we endeavored to understand which subpopulation of MSN was undergoing transient potentiation. Transgenic female and male mice differentially expressing fluorescent reporters in D1- or D2-MSNs were withdrawn for 2-3 weeks after being trained to self-administer cocaine. In some mice, discrete cocaine-conditioned cues were isolated from the drug-associated context via extinction training, which causes rodents to refrain from drug seeking in the extinguished context. By measuring AMPA:NMDA in the drug context with our without contextual or discrete cues, and with or without extinction training, we made three discoveries. 1) Mice refraining from cocaine seeking in the extinguished context showed selective elevation in AMPA:NMDA in D2-MSNs. 2) Without extinction training, the drug-associated context selectively increased AMPA:NMDA in D1-MSNs. 3) Mice undergoing cue-induced cocaine seeking after extinction training in the drug-associated context showed AMPA:NMDA increases in both D1- and D2-MSNs. These findings reveal that the NAcore codes drug-seeking through transient potentiation of D1-MSNs, and that refraining from cocaine-seeking in an extinguished context is coded through transient potentiation of D2-MSNs. SIGNIFICANCE STATEMENT Relapse is a primary symptom of addiction that can involve competition between the motivation to use and to refrain from drug use. Drug-associated cues induce relapse, which is correlated with transiently potentiated glutamatergic synapses in the nucleus accumbens core. We determined which of two cell populations in the accumbens core, D1- or D2-expressing neurons, undergo transient synaptic potentiation. Mice were trained to self-administer cocaine, and withdrawn with or without extinguishing responding in the drug-associated context. Extinguished mice showed transient potentiation in D2-expressing neurons in the extinguished environment, and all mice engaged in context- or cue-induced drug seeking showed transient potentiation of D1-expressing neurons. A simple binary engram in accumbens for drug-seeking and refraining offers opportunities for cell-specific therapies.