Extended Amygdala CRF Projections to Striatal Striosomes Potentiate Dopamine Suppression During Fentanyl Withdrawal

Opioid withdrawal is a powerful negative affective state that promotes continued drug use and relapse, and is often associated with hypodopaminergic states. Although corticotropin-releasing factor (CRF) signaling in the extended amygdala has been strongly implicated in stress and negative affect, how withdrawal-recruited CRF systems suppress dopamine release remains poorly understood. Here, we identify an extended amygdala-striosome-dopamine pathway engaged during fentanyl withdrawal. Naloxone-precipitated fentanyl withdrawal selectively recruited CRF neurons in the central amygdala and bed nucleus of the stria terminalis. These CRF neurons provided monosynaptic input to dorsostriatal medium spiny neurons (MSNs). Because striosomal MSNs are positioned to regulate dopamine release, we next found that CRF enhanced glutamatergic synaptic transmission onto striosomal MSNs, with CRF receptor 1 (CRFR1) signaling required for the postsynaptic strengthening of excitatory transmission. In vivo dopamine photometry further revealed that naloxone-precipitated withdrawal amplified striosome-mediated suppression of dopamine release, and this amplification was prevented by CRFR1 antagonism. Together, these findings reveal a mechanism by which withdrawal-recruited CRF signaling potentiates striosomal control of dopamine release. This extended amygdala-striosome-dopamine pathway may contribute to the hypodopaminergic negative affective state that drives opioid withdrawal and relapse vulnerability. HighlightsO_LIFentanyl withdrawal selectively recruits CeA and BNST CRF neurons C_LIO_LICeA and BNST CRF neurons provide monosynaptic input to striatal MSNs C_LIO_LICRF potentiates glutamatergic transmission onto striosomal MSNs via CRFR1 C_LIO_LICRFR1 signaling amplifies striosome-mediated dopamine suppression during withdrawal C_LI