Increased Excitability and Synaptic Plasticity of Drd1-and Drd2-Expressing Prelimbic Neurons Projecting to Nucleus Accumbens after Heroin Abstinence Are Reversed by Cue-Induced Relapse and Protein Kinase A Inhibition

Dysregulation of the input from the prefrontal cortex (PFC) to the nucleus accumbens (NAc) contributes to cue-induced opioid seek-ing but the heterogeneity in, and regulation of, prelimbic (PL)-PFC to NAc (PL->NAc) neurons that are altered has not been compre-hensively explored. Recently, baseline and opiate withdrawal-induced differences in intrinsic excitability of Drd1+ (D1+) versus Drd2+ (D2+) PFC neurons have been demonstrated. Thus, here we investigated physiological adaptations of PL->NAc D1+ versus D2+ neurons after heroin abstinence and cue-induced relapse. Drd1-Cre+ and Drd2-Cre+ transgenic male Long-Evans rats with vir-ally labeled PL->NAc neurons were trained to self-administer heroin followed by 1 week of forced abstinence. Heroin abstinence sig-nificantly increased intrinsic excitability in D1+ and D2+ PL->NAc neurons and increased postsynaptic strength selectively in D1+ neurons. These changes were normalized by cue-induced relapse to heroin seeking. Based on protein kinase A (PKA)-dependent changes in the phosphorylation of plasticity-related proteins in the PL cortex during abstinence and cue-induced relapse to cocaine seeking, we assessed whether the electrophysiological changes in D1+ and D2+ PL->NAc neurons during heroin abstinence were regulated by PKA. In heroin-abstinent PL slices, application of the PKA antagonist (R)-adenosine, cyclic 3',5'-(hydrogenphosphoro-thioate) triethylammonium (RP-cAMPs) reversed intrinsic excitability in both D1+ and D2+ neurons and postsynaptic strength in only D1+ neurons. Additionally, in vivo bilateral intra-PL infusion of RP-cAMPs after abstinence from heroin inhibited cue-induced relapse to heroin seeking. These data reveal that PKA activity in D1+ and D2+ PL->NAc neurons is not only required for absti-nence-induced physiological adaptations but is also required for cue-induced relapse to heroin seeking.

Automated summary

The dysregulation of prefrontal cortex (PFC) to nucleus accumbens (NAc) input is a significant factor in cue-induced opioid seeking. The physiological adaptations of different subtypes of PFC neurons after heroin abstinence and relapse were investigated. The activity of protein kinase A (PKA) in these neurons is crucial for both abstinence-induced physiological changes and cue-induced relapse to heroin seeking.