Angiotensin-converting enzyme gates brain circuit–specific plasticity via an endogenous opioid

Author:

Trieu Brian H.12ORCID,Remmers Bailey C.3ORCID,Toddes Carlee1ORCID,Brandner Dieter D.12ORCID,Lefevre Emilia M.3ORCID,Kocharian Adrina12ORCID,Retzlaff Cassandra L.3ORCID,Dick Rachel M.1ORCID,Mashal Mohammed A.3,Gauthier Elysia A.3,Xie Wei4ORCID,Zhang Ying5ORCID,More Swati S.4ORCID,Rothwell Patrick E.3ORCID

Affiliation:

1. Graduate Program in Neuroscience, University of Minnesota Medical School, Minneapolis, MN, USA.

2. Medical Scientist Training Program, University of Minnesota Medical School, Minneapolis, MN, USA.

3. Department of Neuroscience, University of Minnesota Medical School, Minneapolis, MN, USA.

4. Center for Drug Design, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA.

5. Minnesota Supercomputing Institute, University of Minnesota, Minneapolis, MN, USA.

Abstract

Angiotensin-converting enzyme (ACE) regulates blood pressure by cleaving angiotensin I to produce angiotensin II. In the brain, ACE is especially abundant in striatal tissue, but the function of ACE in striatal circuits remains poorly understood. We found that ACE degrades an unconventional enkephalin heptapeptide, Met-enkephalin-Arg-Phe, in the nucleus accumbens of mice. ACE inhibition enhanced µ-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 it led to a decrease in conditioned place preference caused by fentanyl administration and an enhancement of reciprocal social interaction. Our results raise the enticing prospect that central ACE inhibition can boost endogenous opioid signaling for clinical benefit while mitigating the risk of addiction.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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