Background: 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 Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD). We established a THC+CBD model of self-administration and reinstated drug seeking to determine if, similar to other addictive drugs, cannabis produces enduring synaptic changes in nucleus accumbens core (NAcore) thought to contribute vulnerability to drug reinstatement. Methods: Sprague Dawley rats were trained to self-administer THC+CBD (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 THC+CBD self-administration were assayed using four measures: dendritic spine morphology, long-term depression, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid/N-methyl-D-aspartate ratios, and behavioral pharmacology. Results: We described a novel rodent model of cannabis relapse involving intravenous THC+CBD self-administration and drug seeking induced by conditioned context, cues, and stress. Cued reinstatement of THC+CBD 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 acid/N-methyl-D-aspartate ratio was unaltered in THC+CBD-trained animals, akin to opioids, but not to psychostimulants. Conclusions: We report enduring consequences of THC+CBD 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.
Bibliographical noteFunding Information:
This work was supported by U.S. Public Health Service (Grant Nos. DA003906 , DA012513 , and DA015369 to PWK and Grant Nos. DA037722 and DA041462 to SS), U.S. Department of Defense (Grant No. W81XWH-13-2-0075 to PWK), Burroughs Wellcome Fund ( Grant No. 1012607 to SS), and National Institutes of Health (Grant No. GM072643 to VCC).
This work was supported by U.S. Public Health Service (Grant Nos. DA003906, DA012513, and DA015369 to PWK and Grant Nos. DA037722 and DA041462 to SS), U.S. Department of Defense (Grant No. W81XWH-13-2-0075 to PWK), Burroughs Wellcome Fund (Grant No. 1012607 to SS), and National Institutes of Health (Grant No. GM072643 to VCC).
© 2018 Society of Biological Psychiatry
- Drug abuse
- Nucleus accumbens
- Synaptic plasticity