RT Journal Article SR Electronic T1 Angiotensin-converting enzyme governs endogenous opioid signaling and synaptic plasticity in nucleus accumbens JF bioRxiv FD Cold Spring Harbor Laboratory SP 2021.09.08.459469 DO 10.1101/2021.09.08.459469 A1 Brian H. Trieu A1 Bailey C. Remmers A1 Carlee Toddes A1 Dieter D. Brandner A1 Wei Xie A1 Swati S. More A1 Patrick E. Rothwell YR 2021 UL http://biorxiv.org/content/early/2021/09/09/2021.09.08.459469.abstract AB Angiotensin-converting enzyme (ACE) regulates blood pressure by cleaving angiotensin I to produce angiotensin II. In the brain, ACE is expressed at uniquely high levels in the striatonigral pathway, but its central function remains poorly understood. We find that ACE degrades an unconventional enkephalin heptapeptide, Met-enkephalin-Arg-Phe, in the nucleus accumbens of mice. ACE inhibition enhanced mu opioid receptor activation by Met-enkephalin-Arg-Phe, causing a cell type-specific long-term depression of glutamate release onto medium spiny projection neurons expressing the Drd1 dopamine receptor. Systemic ACE inhibition was not intrinsically rewarding, but decreased the conditioned place preference caused by fentanyl administration, and enhanced reciprocal social interaction. Our results raise the enticing prospect that central ACE inhibition can boost endogenous opioid signaling for clinical benefit, while mitigating risk of addiction.Competing Interest StatementThe authors have declared no competing interest.