Prefrontal cortex excitatory neurons show distinct response to heroin-associated cue and social stimulus after prolonged heroin abstinence in mice.

Substance use disorder (SUD) has been linked with social impairments. The social cognitive dysfunctions can further increase the risk of the development of SUD or relapse. Therefore, understanding the neural mechanism of substance exposure-associated social impairments is beneficial for the development of novel prevention or treatment strategies for SUD. The prefrontal cortex (PFC) is a key brain region involved in both social cognition and drug addiction. Specifically, the prelimbic part of PFC (PrL) regulates social interaction and heroin-seeking behavior. Therefore, in this study, we explored how PFC excitatory neurons respond to social stimuli after prolonged abstinence from heroin self-administration (SA). Using fiber photometry calcium imaging, we monitored calcium-dependent fluorescent signals in PrL CaMKII-expressing neurons during drug seeking and social interaction tests following 14 days of abstinence from heroin SA. We found that GCaMP6f signals in PrL CaMKII-expressing neurons were increased when heroin-associated cues were presented during drug-seeking tests in both male and female mice after prolonged heroin abstinence, although the baseline neuronal activity in home cage is lower in the heroin group. Conversely, the calcium signals in PrL CaMKII-expressing neurons during social investigation were decreased after heroin abstinence in both sexes, along with reduced total social interaction time. In addition, drug-seeking behavior is partially negatively correlated with social investigation time. These findings provide direct evidence showing that opioid exposure impairs the PFC functional response to social stimuli, which may potentially increase the risk for opioid relapse.