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The loss of NMDAR‐dependent LTD following cannabinoid self‐administration is restored by positive allosteric modulation of CB1 receptors

Glutamatergic plasticity in the nucleus accumbens core (NAcore) is a key neuronal process in appetitive learning and contributes to pathologies such as drug addiction. Understanding how this plasticity factors into cannabis addiction and relapse has been hampered by the lack of a rodent model of cannabis self‐administration. We used intravenous self‐administration of two constituents of cannabis, Δ9‐tetrahydrocannabinol (THC) and cannabidiol (CBD) to examine how contingent cannabis use and cue‐induced cannabinoid‐seeking alters glutamatergic neurotransmission and synaptic plasticity in NAcore. NMDA receptor (NMDAR)–dependent long‐term depression (LTD) in the NAcore was lost after cannabinoid, but not sucrose self‐administration. Surprisingly, when rats underwent cue‐induced cannabinoid seeking, LTD was restored. Loss of LTD was accompanied by desensitization of cannabinoid receptor 1 (CB1R). CB1R are positioned to regulate synaptic plasticity by being expressed on glutamatergic terminals and negatively regulating presynaptic excitability and glutamate release. Supporting this possibility, LTD was restored by promoting CB1R signaling with the CB1 positive allosteric modulator GAT211. These data implicate NAcore CB1R as critical regulators of metaplasticity induced by cannabis self‐administration and the cues predicting cannabis availability.