A Model of Δ9-Tetrahydrocannabinol Self-administration and Reinstatement That Alters Synaptic Plasticity in Nucleus Accumbens.
Sade M Spencer, Daniela Neuhofer, Vivian C Chioma, Constanza Garcia-Keller, Danielle J Schwartz, Nicholas B Allen, Michael D Scofield, Tara Ortiz-Ithier, Peter W Kalivas
Biological Psychiatry October 15, 2018 DOI: 10.1016/j.biopsych.2018.04.016 (opens in new tab)
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Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical rodent self-administration and reinstatement study Peer reviewed |
|---|---|
| Sample size | 189 |
| Population | Sprague Dawley rats |
| Interventions | Δ9-tetrahydrocannabinol (THC) cannabidiol (CBD) N-acetylcysteine matrix metalloprotease-9 inhibitor yohimbine |
| Topics | CBD Neuroplasticity Cannabis |
| Keywords | Drug abuse Nucleus accumbens Reinstatement Δ9-tetrahydrocannabinol |
| Key points | THC+CBD self-administration produced enduring changes in nucleus accumbens core: NMDA long-term depression was abolished and dendritic spine density reduced, with AMPA/NMDA ratios unchanged, resembling opioid rather than psychostimulant effects. Cue- and stress-induced reinstatement occurred and was prevented by N-acetylcysteine or intra-NAcore inhibition of neuronal nitric oxide synthase or matrix metalloprotease-9. |
Abstract
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. 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. 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. 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.
Comparable studies
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| The alkaloids of Banisteriopsis caapi, the plant source of the Amazonian hallucinogen Ayahuasca, stimulate adult neurogenesis in vitro Progenitor cells from subventricular and subgranular zones of adult mice brains | 2017 | In vitro experimental study | |
| N,N-dimethyltryptamine compound found in the hallucinogenic tea ayahuasca, regulates adult neurogenesis in vitro and in vivo Mice | 2020 | In vitro and in vivo experimental study |
Citations in the library
Cited by 14
- Which Came First? Utility of Preclinical Models in Cracking the Chicken-or-Egg Relationship between Cannabis Use and Schizophrenia Current Addiction Reports February 27, 2026
- Cannabinoid use generalizes stress responses: involvement of astrocyte plasticity and activation of matrix metalloproteinases in the nucleus accumbens core. Molecular Psychiatry June 11, 2026
- Prior cannabis vapor exposure impairs pattern separation in rodents of multiple ages but is rescued by citicoline administration. Neuroscience May 25, 2026
- Cannabinoid use generalizes stress responses by altering the astrocyte plasticity through extracellular matrix signaling in the nucleus accumbens core. Research Square August 21, 2025
- Investigation of Cannabidiol in the Mouse Drug Discrimination Paradigm. Cannabis and Cannabinoid Research April 2024
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Cites 7
- Disruption of hippocampal synaptic transmission and long‐term potentiation by psychoactive synthetic cannabinoid ‘Spice’ compounds: comparison with Δ9‐tetrahydrocannabinol Addiction Biology January 5, 2016
- Delta-9-tetrahydrocannabinol (THC) history fails to affect THC's ability to induce place preferences in rats. Pharmacology, Biochemistry, and Behavior May 2016
- Cannabidiol potentiates Δ⁹-tetrahydrocannabinol (THC) behavioural effects and alters THC pharmacokinetics during acute and chronic treatment in adolescent rats. Psychopharmacology November 2011
- Neural basis of Delta-9-tetrahydrocannabinol and cannabidiol: effects during response inhibition. Biological Psychiatry December 1, 2008
- Divergent effects of cannabidiol on the discriminative stimulus and place conditioning effects of Delta(9)-tetrahydrocannabinol. Drug and Alcohol Dependence April 1, 2008
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