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Remifentanil self-administration in mice promotes sex-specific prefrontal cortex dysfunction underlying deficits in
Eden M Anderson1, Annabel Engelhardt1, Skyler Demis1
1Department of Biomedical Sciences, Marquette University, Milwaukee, WI, 53233, USA.
Summary
Chronic opioid use impairs cognitive control. This study reveals sex-specific changes in prefrontal cortex neuronal activity and synaptic function, impacting cognitive flexibility. Interventions should consider biological sex.
Area of Science:
- Neuroscience
- Neuropharmacology
- Cognitive Science
Background:
- Opioid analgesics are widely used for pain but can cause cognitive impairments.
- The underlying neural mechanisms of opioid-induced cognitive dysfunction, particularly sex differences, remain poorly understood.
- Chronic opioid use is linked to altered prefrontal cortex (PFC) activity and reduced cognitive control.
Purpose of the Study:
- To investigate the long-lasting effects of remifentanil self-administration on PFC neuronal excitability and cognitive flexibility.
- To determine sex-specific differences in opioid-induced neuroplasticity within the medial PFC.
- To elucidate the synaptic mechanisms underlying impaired cognitive flexibility.
Main Methods:
- Self-administration of remifentanil in male and female rodents.
- Ex vivo electrophysiological recordings of layer 5/6 pyramidal neurons in the prelimbic and infralimbic PFC.
- Assessment of cognitive flexibility using an operant-based attentional set-shifting task.
- Chemogenetic manipulation to assess causal relationships.
Main Results:
- Remifentanil self-administration induced a long-lasting hypoactive state in female PFC neurons after 5 days, associated with cognitive flexibility deficits.
- Male PFC neurons initially showed hyperactivity (10-16 days) before developing hypoactivity (25-30 days), with distinct synaptic alterations.
- In females, hypoactivity was linked to reduced AMPA receptor-mediated transmission; in males, it involved GABAB signaling.
- Chemogenetic reversal of the hypoactive state restored cognitive flexibility and normalized neural plasticity.
Conclusions:
- Opioid-induced hypoactivity in the medial PFC underlies deficits in cognitive flexibility.
- Sex-specific alterations in neuronal excitability and synaptic transmission mediate these cognitive impairments.
- Targeting opioid-induced adaptations requires sex-tailored therapeutic strategies.
