Positive allosteric modulation of mGlu1 reverses cocaine-induced behavioral and synaptic plasticity through the integrated stress response and oligophrenin-1

ABSTRACT

Background

Cue-induced cocaine craving progressively intensifies (‘incubates') during abstinence from cocaine self-administration. Expression of ‘incubated' cocaine craving depends on elevated calcium-permeable AMPARs (CP-AMPARs) on medium spiny neurons in the nucleus accumbens (NAc) core. After incubation has occurred, stimulation of NAc mGlu1 receptors or systemic administration of mGlu1 positive allosteric modulators (PAM) removes CP-AMPARs from NAc synapses via dynamin-dependent internalization (mGlu1-LTD) and thereby reduces ‘incubated' cocaine craving. As mGlu1 PAMs 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 hours/day). Following >40 days of abstinence, we assessed the ability of an mGlu1 PAM 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 MSNs 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 the 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 males.