Positive Allosteric Modulation of mGlu1 Reverses Cocaine-Induced Behavioral and Synaptic Plasticity Through the Integrated Stress Response and Oligophrenin-1

Alex B. Kawa, Eun Kyung Hwang, Jonathan R. Funke, Hongyi Zhou, Mauro Costa-Mattioli, Marina E. Wolf

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


Background: Cue-induced cocaine craving progressively intensifies (incubates) during abstinence from cocaine self-administration. Expression of incubated cocaine craving depends on elevated calcium-permeable AMPA receptors (CP-AMPARs) on medium spiny neurons in the nucleus accumbens (NAc) core. After incubation has occurred, stimulation of NAc metabotropic glutamate 1 (mGlu1) receptors or systemic administration of mGlu1 positive allosteric modulators removes CP-AMPARs from NAc synapses via dynamin-dependent internalization (mGlu1 long-term depression [LTD]) and thereby reduces incubated cocaine craving. Because mGlu1 positive allosteric modulators are potential therapeutics for cocaine craving, it is important to further define the mechanism triggering this mGlu1-LTD. Methods: Male and female rats self-administered saline or cocaine (10 days) using a long access regimen (6 h/day). Following ≥40 days of abstinence, we assessed the ability of an mGlu1 positive allosteric modulator to inhibit expression of incubated craving and remove CP-AMPARs from NAc synapses under control conditions, after blocking the integrated stress response (ISR), or after knocking down oligophrenin-1, a mediator of the ISR that can promote AMPAR endocytosis. AMPAR transmission in NAc medium spiny neurons was assessed with ex vivo slice recordings. Results: mGlu1 stimulation reduced cue-induced craving and removed synaptic CP-AMPARs. When the ISR was blocked prior to mGlu1 stimulation, there was no reduction in cue-induced craving, nor were CP-AMPARs removed from the synapse. Further, selective knockdown of oligophrenin-1 blocked mGlu1-LTD. Conclusions: Our results indicate that mGlu1-LTD in the NAc and consequently the reduction of cue-induced seeking occur through activation of the ISR, which induces translation of oligophrenin-1. We also demonstrate CP-AMPAR accumulation and mGlu1 reversal in female rats, as previously shown in male rats.

Original languageEnglish (US)
Pages (from-to)871-879
Number of pages9
JournalBiological Psychiatry
Issue number11
StatePublished - Dec 1 2022


  • AMPA receptor
  • Incubation of cocaine craving
  • Integrated stress response
  • Nucleus accumbens
  • OPHN1
  • mGluR-LTD

ASJC Scopus subject areas

  • Biological Psychiatry


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