Sex-specific prefrontal cortex dysfunction underlying opioid-induced cognitive impairment

Women transition to addiction faster and experience greater difficulties remaining abstinent; however, what drives this is unknown. Although poorly understood, loss of cognitive control following chronic drug use has been linked to decreased activation of frontal cortical regions. We show that self-administration of the opioid, remifentanil, causes a long-lasting decrease in ex vivo excitability but augments firing capacity of pyramidal neurons in the prelimbic cortex. This phenomenon occurs faster in females, manifests from sex-specific changes in excitatory and inhibitory synaptic regulation and aligns with impairments in cognitive flexibility. Further, chemogenetic induction of a hypoactive pyramidal neuron state in drug-naive mice produces deficits, while compensating for this hypoactive state protects against cognitive inflexibility resulting from opioid self-administration. These data define cellular and synaptic mechanisms by which opioids impair prefrontal function and cognitive control and indicate that interventions aimed at treating opioid addiction must be tailored based on biological sex.