Opioid Withdrawal Abruptly Disrupts Amygdala Circuit Function by Reducing Peptide Actions

While the physical signs of opioid withdrawal are most readily observable, withdrawal insidiously drives relapse and contrib-utes to compulsive drug use, by disrupting emotional learning circuits. How these circuits become disrupted during with-drawal is poorly understood. Because amygdala neurons mediate relapse, and are highly opioid sensitive, we hypothesized that opioid withdrawal would induce adaptations in these neurons, opening a window of disrupted emotional learning circuit function. Under normal physiological conditions, synaptic transmission between the basolateral amygdala (BLA) and the neigh-boring main island (Im) of GABAergic intercalated cells (ITCs) is strongly inhibited by endogenous opioids. Using patch-clamp electrophysiology in brain slices prepared from male rats, we reveal that opioid withdrawal abruptly reduces the ability of these peptides to inhibit neurotransmission, a direct consequence of a protein kinase A (PKA)-driven increase in the synaptic activity of peptidases. Reduced peptide control of neurotransmission in the amygdala shifts the excitatory/inhibitory balance of inputs onto accumbens-projecting amygdala cells involved in relapse. These findings provide novel insights into how peptidases control synaptic activity within the amygdala and presents restoration of endogenous peptide activity during withdrawal as a viable option to mitigate withdrawal-induced disruptions in emotional learning circuits and rescue the relapse behaviors exhibited during opioid withdrawal and beyond into abstinence.

Automated summary

Opioid withdrawal disrupts emotional learning circuits, leading to relapse and compulsive drug use. This study reveals that during withdrawal, protein kinase A (PKA) activation reduces the inhibitory effect of endogenous opioids on synaptic transmission in the amygdala, shifting the excitatory/inhibitory balance and contributing to relapse. Restoring endogenous peptide activity during withdrawal may mitigate these disruptions and prevent relapse behaviors.