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Research Articles, Behavioral/Cognitive

Cannabidiol Counteracts the Psychotropic Side-Effects of Δ-9-Tetrahydrocannabinol in the Ventral Hippocampus through Bidirectional Control of ERK1–2 Phosphorylation

Roger Hudson, Justine Renard, Christopher Norris, Walter J. Rushlow and Steven R. Laviolette
Journal of Neuroscience 30 October 2019, 39 (44) 8762-8777; https://doi.org/10.1523/JNEUROSCI.0708-19.2019
Roger Hudson
1Addiction Research Group,
2Department of Anatomy and Cell Biology, and
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Justine Renard
1Addiction Research Group,
2Department of Anatomy and Cell Biology, and
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Christopher Norris
1Addiction Research Group,
2Department of Anatomy and Cell Biology, and
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Walter J. Rushlow
1Addiction Research Group,
2Department of Anatomy and Cell Biology, and
3Department of Psychiatry, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada N6A 3K7
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Steven R. Laviolette
1Addiction Research Group,
2Department of Anatomy and Cell Biology, and
3Department of Psychiatry, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada N6A 3K7
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Abstract

Evidence suggests that the phytocannabinoids Δ-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) differentially regulate salience attribution and psychiatric risk. The ventral hippocampus (vHipp) relays emotional salience via control of dopamine (DA) neuronal activity states, which are dysregulated in psychosis and schizophrenia. Using in vivo electrophysiology in male Sprague Dawley rats, we demonstrate that intra-vHipp THC strongly increases ventral tegmental area (VTA) DA neuronal frequency and bursting rates, decreases GABA frequency, and amplifies VTA beta, gamma and ε oscillatory magnitudes via modulation of local extracellular signal-regulated kinase phosphorylation (pERK1–2). Remarkably, whereas intra-vHipp THC also potentiates salience attribution in morphine place-preference and fear conditioning assays, CBD coadministration reverses these changes by downregulating pERK1–2 signaling, as pharmacological reactivation of pERK1–2 blocked the inhibitory properties of CBD. These results identify vHipp pERK1–2 signaling as a critical neural nexus point mediating THC-induced affective disturbances and suggest a potential mechanism by which CBD may counteract the psychotomimetic and psychotropic side effects of THC.

SIGNIFICANCE STATEMENT Strains of marijuana with high levels of delta-9-tetrahydrocannabinol (THC) and low levels of cannabidiol (CBD) have been shown to underlie neuropsychiatric risks associated with high-potency cannabis use. However, the mechanisms by which CBD mitigates the side effects of THC have not been identified. We demonstrate that THC induces cognitive and affective abnormalities resembling neuropsychiatric symptoms directly in the hippocampus, while dysregulating dopamine activity states and amplifying oscillatory frequencies in the ventral tegmental area via modulation of the extracellular signal-regulated kinase (ERK) signaling pathway. In contrast, CBD coadministration blocked THC-induced ERK phosphorylation, and prevented THC-induced behavioral and neural abnormalities. These findings identify a novel molecular mechanism that may account for how CBD functionally mitigates the neuropsychiatric side effects of THC.

  • cannabidiol
  • delta-9-tetrahydrocannabinol
  • dopamine
  • extracellular signal-regulated kinase
  • ventral hippocampus
  • ventral tegmental area
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The Journal of Neuroscience: 39 (44)
Journal of Neuroscience
Vol. 39, Issue 44
30 Oct 2019
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Cannabidiol Counteracts the Psychotropic Side-Effects of Δ-9-Tetrahydrocannabinol in the Ventral Hippocampus through Bidirectional Control of ERK1–2 Phosphorylation
Roger Hudson, Justine Renard, Christopher Norris, Walter J. Rushlow, Steven R. Laviolette
Journal of Neuroscience 30 October 2019, 39 (44) 8762-8777; DOI: 10.1523/JNEUROSCI.0708-19.2019

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Cannabidiol Counteracts the Psychotropic Side-Effects of Δ-9-Tetrahydrocannabinol in the Ventral Hippocampus through Bidirectional Control of ERK1–2 Phosphorylation
Roger Hudson, Justine Renard, Christopher Norris, Walter J. Rushlow, Steven R. Laviolette
Journal of Neuroscience 30 October 2019, 39 (44) 8762-8777; DOI: 10.1523/JNEUROSCI.0708-19.2019
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Keywords

  • cannabidiol
  • delta-9-tetrahydrocannabinol
  • dopamine
  • extracellular signal-regulated kinase
  • ventral hippocampus
  • ventral tegmental area

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