A Model of Δ
Cannabis is the most widely used illicit drug, but knowledge of the neurological consequences of cannabis use is deficient. Two primary components of cannabis are Δ Sprague Dawley rats were trained to self-administer THCCBD (n 165) or were used as vehicle self-administering control animals (n 24). Reinstatement was initiated by context, cues, drug priming, and stress (yohimbine injection). Enduring neuroadaptations produced by THCCBD self-administration were assayed using four measures dendritic spine morphology, long-term depression, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acidN-methyl-D-aspartate ratios, and behavioral pharmacology. We described a novel rodent model of cannabis relapse involving intravenous THCCBD self-administration and drug seeking induced by conditioned context, cues, and stress. Cued reinstatement of THCCBD seeking depended on a sequence of events implicated in relapse to other addictive drugs, as reinstatement was prevented by daily treatment with N-acetylcysteine or acute intra-NAcore pretreatment with a neuronal nitric oxide synthase or matrix metalloprotease-9 inhibitor, all of which normalize impaired glutamate homeostasis. The capacity to induce N-methyl-D-aspartate long-term depression in NAcore medium spiny neurons was abolished and dendritic spine density was reduced, but alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acidN-methyl-D-aspartate ratio was unaltered in THCCBD-trained animals, akin to opioids, but not to psychostimulants. We report enduring consequences of THCCBD use on critical relapse circuitry and synaptic physiology in NAcore following rat self-administration and provide the first report of cue- and stress-induced reinstatement with this model.