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Anxiety and cognitive-related effects of Δ 9-tetrahydrocannabinol (THC) are differentially mediated through distinct GSK-3 vs. Akt-mTOR pathways in the nucleus accumbens of male rats

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Abstract

Rationale

Δ9-tetrahydrocannabinol (THC) is the primary psychoactive compound in cannabis and is responsible for cannabis-related neuropsychiatric side effects, including abnormal affective processing, cognitive and sensory filtering deficits and memory impairments. A critical neural region linked to the psychotropic effects of THC is the nucleus accumbens shell (NASh), an integrative mesocorticolimbic structure that sends and receives inputs from multiple brain areas known to be dysregulated in various disorders, including schizophrenia and anxiety-related disorders. Considerable evidence demonstrates functional differences between posterior vs. anterior NASh sub-regions in the processing of affective and cognitive behaviours influenced by THC. Nevertheless, the neuroanatomical regions and local molecular pathways responsible for these psychotropic effects are not currently understood.

Objectives

The objectives of this study were to characterize the effects of intra-accumbens THC in the anterior vs. posterior regions of the NASh during emotional memory formation, sensorimotor gating and anxiety-related behaviours.

Methods

We performed an integrative series of translational behavioural pharmacological studies examining anxiety, sensorimotor gating and fear-related associative memory formation combined with regionally specific molecular signalling analyses in male Sprague Dawley rats.

Results

We report that THC in the posterior NASh causes distortions in emotional salience attribution, impaired sensory filtering and memory retention and heightened anxiety, through a glycogen-synthase-kinase-3 (GSK-3)-β-catenin dependent signalling pathway. In contrast, THC in the anterior NASh produces anxiolytic effects via modulation of protein kinase B (Akt) phosphorylation states.

Conclusions

These findings reveal critical new insights into the neuroanatomical and molecular mechanisms associated with the differential neuropsychiatric side effects of THC in dissociable nucleus accumbens sub-regions.

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Acknowledgements

This work was supported by the Canadian Institute of Health Research (PJT-159586), the Natural Science and Engineering Research Council of Canada (N.S.E.R.C.), CanaQuest Inc, MITACs and the J&J Memorial Tournament Fund.

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Authors and Affiliations

  1. Addiction Research Group, Schulich School of Medicine & Dentistry, University of Western Ontario, 468 Medical Science Building, Ontario, London, N6A5C1, Canada

    Roger Hudson, Christopher Norris, Hanna J. Szkudlarek, Dinat Khan, Susanne Schmid, Walter J. Rushlow & Steven R. Laviolette

  2. Department of Anatomy & Cell Biology, Schulich School of Medicine & Dentistry, University of Western Ontario London, Ontario, N6A5C1, Canada

    Roger Hudson, Christopher Norris, Hanna J. Szkudlarek, Dinat Khan, Susanne Schmid, Walter J. Rushlow & Steven R. Laviolette

  3. Department of Psychiatry, Schulich School of Medicine & Dentistry, University of Western Ontario London, Ontario, N6A5C1, Canada

    Walter J. Rushlow & Steven R. Laviolette

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  1. Roger Hudson
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Hudson, R., Norris, C., Szkudlarek, H.J. et al. Anxiety and cognitive-related effects of Δ 9-tetrahydrocannabinol (THC) are differentially mediated through distinct GSK-3 vs. Akt-mTOR pathways in the nucleus accumbens of male rats. Psychopharmacology 239, 509–524 (2022). https://doi.org/10.1007/s00213-021-06029-w

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