Antipsychotic-like Effects of M-4 Positive Allosteric Modulators Are Mediated by CB2 Receptor-Dependent Inhibition of Dopamine Release

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

来源：Neuron, 2016, 91(6): 1244-1252.

DOI：10.1016/j.neuron.2016.08.017

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 M-4 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 M-4-mediated sustained inhibition of dopamine release and the antipsychotic- like efficacy of M-4 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.

• 出版日期2016-9-21