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Dose mediates the protracted effects of adolescent THC exposure on reward and stress reactivity in males relevant to perturbation of the basolateral amygdala transcriptome

Molecular Psychiatry volume 28, pages 2583–2593 (2023)Cite this article

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Abstract

Despite the belief that cannabis is relatively harmless, exposure during adolescence is associated with increased risk of developing several psychopathologies in adulthood. In addition to the high levels of use amongst teenagers, the potency of ∆-9-tetrahydrocannabinol (THC) has increased more than fourfold compared to even twenty years ago, and it is unclear whether potency influences the presentation of THC-induced behaviors. Expanded knowledge about the impact of adolescent THC exposure, especially high dose, is important to delineating neural networks and molecular mechanisms underlying psychiatric risk. Here, we observed that repeated exposure to low (1.5 mg/kg) and high (5 mg/kg) doses of THC during adolescence in male rats produced divergent effects on behavior in adulthood. Whereas low dose rats showed greater sensitivity to reward devaluation and also self-administered more heroin, high dose animals were significantly more reactive to social isolation stress. RNA sequencing of the basolateral amygdala, a region linked to reward processing and stress, revealed significant perturbations in transcripts and gene networks related to synaptic plasticity and HPA axis that were distinct to THC dose as well as stress. In silico single-cell deconvolution of the RNAseq data revealed a significant reduction of astrocyte-specific genes related to glutamate regulation in stressed high dose animals, a result paired anatomically with greater astrocyte-to-neuron ratios and hypotrophic astrocytes. These findings emphasize the importance of dose and behavioral state on the presentation of THC-related behavioral phenotypes in adulthood and dysregulation of astrocytes as an interface for the protracted effects of high dose THC and subsequent stress sensitivity.

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Fig. 1: Overview of the behavioral experiments conducted in the study.
Fig. 2: Effects of adolescent THC on sucrose self-administration, reward devaluation, and heroin self-administration.
Fig. 3: Stress effects in rats with adolescent THC experience.
Fig. 4: Overview of the DESeq analysis from the BLA.
Fig. 5: DEG-enriched Gene Networks from the BLA transcriptome.
Fig. 6: Results from CIBERSORTx in silico cytometry and immunohistochemistry.

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Acknowledgements

We thank Drs. Qian Wang and Bin Zhang for their intellectual input on the MEGENA gene network analysis and Nayana Patel for assistance with the plasma corticosterone analysis.

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  1. Icahn School of Medicine at Mount Sinai, Departments of Neuroscience and Psychiatry, Addiction Institute of Mount Sinai, New York, NY, USA

    Jacqueline-Marie N. Ferland, Randall J. Ellis, Gregory Rompala, Joseph A. Landry, James E. Callens, Annie Ly, Micah D. Frier, Teddy O. Uzamere & Yasmin L. Hurd

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  1. Jacqueline-Marie N. Ferland
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JMF and YLH designed the experiments. JMF, JAL, JEC, AL, MDF, and TOU conducted the experiments. RJE and GR provided computational genomics analyses for RNAseq data. JMF completed all behavioral and molecular analyses. JMF and YLH wrote the manuscript and all authors reviewed the manuscript and provided comments.

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Correspondence to Yasmin L. Hurd.

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Ferland, JM.N., Ellis, R.J., Rompala, G. et al. Dose mediates the protracted effects of adolescent THC exposure on reward and stress reactivity in males relevant to perturbation of the basolateral amygdala transcriptome. Mol Psychiatry 28, 2583–2593 (2023). https://doi.org/10.1038/s41380-022-01467-0

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