Activation of Astrocytic μ-Opioid Receptor Causes Conditioned Place Preference

Cell Rep. 2019 Jul 30;28(5):1154-1166.e5. doi: 10.1016/j.celrep.2019.06.071.


The underlying mechanisms of how positive emotional valence (e.g., pleasure) causes preference of an associated context is poorly understood. Here, we show that activation of astrocytic μ-opioid receptor (MOR) drives conditioned place preference (CPP) by means of specific modulation of astrocytic MOR, an exemplar endogenous Gi protein-coupled receptor (Gi-GPCR), in the CA1 hippocampus. Long-term potentiation (LTP) induced by a subthreshold stimulation with the activation of astrocytic MOR at the Schaffer collateral pathway accounts for the memory acquisition to induce CPP. This astrocytic MOR-mediated LTP induction is dependent on astrocytic glutamate released upon activation of the astrocytic MOR and the consequent activation of the presynaptic mGluR1. The astrocytic MOR-dependent LTP and CPP were recapitulated by a chemogenetic activation of astrocyte-specifically expressed Gi-DREADD hM4Di. Our study reveals that the transduction of inhibitory Gi-signaling into augmented excitatory synaptic transmission through astrocytic glutamate is critical for the acquisition of contextual memory for CPP.

Keywords: astrocyte; conditioned place preference; hippocampus; long-term potentiation opioid; μ-opioid receptor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Astrocytes / metabolism*
  • CA1 Region, Hippocampal / metabolism*
  • GTP-Binding Protein alpha Subunits, Gi-Go / genetics
  • GTP-Binding Protein alpha Subunits, Gi-Go / metabolism
  • Memory*
  • Mice
  • Mice, Knockout
  • Receptors, Metabotropic Glutamate / genetics
  • Receptors, Metabotropic Glutamate / metabolism
  • Receptors, Opioid, mu / genetics
  • Receptors, Opioid, mu / metabolism*


  • Receptors, Metabotropic Glutamate
  • Receptors, Opioid, mu
  • metabotropic glutamate receptor type 1
  • GTP-Binding Protein alpha Subunits, Gi-Go