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

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.