Figure 1. Time- and sex-dependent adaptations in PFC pyramidal neuron physiology and underlying mechanisms.

Data indicate that in males, short-term exposure to opiods increases the intrinsic excitability PrL pyramidal neurons, in part through a downregulation in metabotropic inhibitory signaling mediated by GABA_BR-Girk transmission (A-B). Following prolonged exposure, the activation threshold is increased (reduced excitability) in males – a phenomenon that occurs after only two weeks of self-administration in females (A-B). Hypoexcitable states appear to reflect reductions in synaptic AMPAR transmission as well as increased GABA_A transmission and coincides with an increase in action potential frequency at more depolarized potentials (B) indicating that while these neurons are more difficult to initiate firing, once activated, mechanisms normally in place to restore firing to basal levels is impaired. Although the function implications are unclear, hypoactivation states may contribute to an impaired ability of the mPFC to exert inhibitory control, that may be further exacerbated by increased (disorganized) firing that disrupts cortical information processing or may contribute to the pathological strengthening of drug-seeking/taking behavior in response to drug-associated cues.