Antipsychotic-like Effects of M4 Positive Allosteric Modulators Are Mediated by CB2 Receptor-Dependent Inhibition of Dopamine Release

Daniel J. Foster, Jermaine M. Wilson, Daniel H. Remke, M. Suhaib Mahmood, M. Jashim Uddin, Jürgen Wess, Sachin Patel, Lawrence J. Marnett, Colleen M. Niswender, Carrie K. Jones, Zixiu Xiang, Craig W. Lindsley, Jerri M. Rook, P. Jeffrey Conn*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

76 Scopus citations

Abstract

Muscarinic receptors represent a promising therapeutic target for schizophrenia, but the mechanisms underlying the antipsychotic efficacy of muscarinic modulators are not well understood. Here, we report that activation of M4 receptors on striatal spiny projection neurons results in a novel form of dopaminergic regulation resulting in a sustained depression of striatal dopamine release that is observed more than 30 min after removal of the muscarinic receptor agonist. Furthermore, both the M4-mediated sustained inhibition of dopamine release and the antipsychotic-like efficacy of M4 activators were found to require intact signaling through CB2 cannabinoid receptors. These findings highlight a novel mechanism by which striatal cholinergic and cannabinoid signaling leads to sustained reductions in dopaminergic transmission and concurrent behavioral effects predictive of antipsychotic efficacy.

Original languageEnglish (US)
Pages (from-to)1244-1252
Number of pages9
JournalNeuron
Volume91
Issue number6
DOIs
StatePublished - Sep 21 2016
Externally publishedYes

ASJC Scopus subject areas

  • Neuroscience(all)

Fingerprint

Dive into the research topics of 'Antipsychotic-like Effects of M4 Positive Allosteric Modulators Are Mediated by CB2 Receptor-Dependent Inhibition of Dopamine Release'. Together they form a unique fingerprint.

Cite this