Synaptic depression via mGluR1 positive allosteric modulation suppresses cue-induced cocaine craving

Cue-induced cocaine craving is a major cause of relapse in abstinent addicts. In rats, cue-induced craving progressively intensifies (incubates) during withdrawal from extended-access cocaine self-administration. After ~1 month of withdrawal, incubated craving is mediated by Ca 2+-permeable AMPARs (CP-AMPARs) that accumulate in the nucleus accumbens (NAc). We found that decreased mGluR1 surface expression in the NAc precedes and enables CP-AMPAR accumulation. Thus, restoring mGluR1 tone by administering repeated injections of an mGluR1 positive allosteric modulator (PAM) prevented CP-AMPAR accumulation and incubation, whereas blocking mGluR1 transmission at even earlier withdrawal times accelerated CP-AMPAR accumulation. In studies conducted after prolonged withdrawal, when CP-AMPAR levels and cue-induced craving are high, we found that systemic administration of an mGluR1 PAM attenuated the expression of incubated craving by reducing CP-AMPAR transmission in the NAc to control levels. These results demonstrate a strategy whereby recovering addicts could use a systemically active compound to protect against cue-induced relapse. Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: Relapse, often triggered by environmental cues previously associated with cocaine use, is a major problem in treating cocaine addiction. Addicts remain vulnerable to relapse long after the acute withdrawal phase. In a rat model of this phenomenon, cue-induced cocaine craving progressively intensifies (" incubates ") during the first months of withdrawal from extended-access cocaine self-administration 1. Incubation models a human scenario in which heavy drug use is interrupted by hospitalization or incarceration 2 , and involves neuroadaptations in the circuitry underlying motivation and addiction 1. The nucleus accumbens (NAc) is a brain region that plays a central role in this circuitry, and is comprised mainly of medium spiny neurons (MSN). These MSN mediate motivated behaviors by serving as an interface between cortical and limbic regions and the motor circuitry 3. AMPA receptor (AMPAR) transmission onto NAc MSN is critical for drug-seeking in animal models of cocaine addiction 4. In drug-naïve rats and rats with limited cocaine exposure, AMPAR transmission in the NAc is mediated by GluA2-containing Ca 2+-impermeable AMPARs (CI-AMPARs) 5. However, high conductance Ca 2+-permeable AMPARs (CP-AMPARs) accumulate in NAc synapses during withdrawal from extended-access cocaine self-administration 6,7. After elevation of CP-AMPAR transmission has occurred, intra-NAc core injection of the selective CP-AMPAR antagonist naspm markedly reduces cue-induced cocaine-seeking 6. These results establish that CP-AMPAR transmission in the NAc mediates …

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