Abstract
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.
Keywords
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Article info
Publication history
Published online: May 03, 2018
Accepted:
April 26,
2018
Received in revised form:
April 17,
2018
Received:
August 7,
2017
Identification
Copyright
© 2018 Society of Biological Psychiatry.
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Access this article on ScienceDirectLinked Article
- ErratumBiological PsychiatryVol. 85Issue 10
- N-Acetylcysteine in Treatment of Substance Use DisordersBiological PsychiatryVol. 85Issue 11
- PreviewSpencer et al. (1) present an innovative and comprehensive rodent model of cannabinoid self-administration that increases our understanding of the neurobiology of cannabis use disorder and promises new leads for its treatment. One major finding was the prevention of cue-induced reinstatement of self-administration by pretreatment with N-acetylcysteine (NAC). The authors relate this finding to a similar effect of NAC in inhibiting “cue-induced reinstatement to many addictive drugs.” They then imply a clinical extrapolation by mentioning “a clinical trial found that NAC reduced adolescent cannabis use” (2).
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