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The schizophrenia susceptibility gene neuregulin 1 modulates tolerance to the effects of cannabinoids.

Abstract

Cannabis increases the risk of schizophrenia in genetically vulnerable individuals. In this study we aim to show that the schizophrenia susceptibility gene neuregulin 1 (Nrg1) modulates the development of tolerance to cannabinoids in mice. Nrg1 heterozygous (HET) and wild-type (WT) mice were treated daily for 15 d with the synthetic analogue of Δ9-tetrahydrocannabinol, CP55,940 (0.4 mg/kg). We measured the impact of this exposure on locomotor activity, anxiety, prepulse inhibition (PPI), body temperature and FosB/ΔFosB immunohistochemistry. Tolerance to CP55,940-induced hypothermia and locomotor suppression developed more rapidly in Nrg1 HET mice than WT mice. Conversely in the light-dark test, while tolerance to the anxiogenic effect of CP55,940 developed in WT mice over days of testing, Nrg1 hypomorphs maintained marked anxiety even after 15 d of treatment. Repeated cannabinoid exposure selectively increased FosB/ΔFosB expression in the lateral septum, ventral part (LSV) of Nrg1 HET but not WT mice. On day 1 of exposure opposite effects of CP55,940 treatment were observed on PPI, i.e. it was facilitated in Nrg1 hypomorphs and impaired in WT mice, despite the drug significantly impairing the acoustic startle reflex equally in both genotypes. These effects of CP55,940 on PPI were not maintained as both genotypes became tolerant to cannabinoid action with repeated exposure. Our results highlight that Nrg1 modulates the development of cannabinoid tolerance dependent on the parameter being measured. Furthermore, these data reinforce the notion that the VLS is an important brain region involved in Nrg1-cannabinoid interactions.

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  • Authors+Show Affiliations

    ,

    Department of Pharmacology, Bosch Institute, University of Sydney, Australia.

    , , , , ,

    Source

    MeSH

    Animals
    Anxiety
    Behavior, Animal
    Brain
    Cannabinoids
    Cyclohexanols
    Disease Models, Animal
    Dronabinol
    Drug Tolerance
    Exploratory Behavior
    Genotype
    Heterozygote
    Male
    Mice
    Mice, Mutant Strains
    Motor Activity
    Neuregulin-1
    Proto-Oncogene Proteins c-fos
    Psychotropic Drugs
    Reflex, Startle
    Schizophrenia

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    20701826

    Citation

    * When formatting your citation, note that all book, journal, and database titles should be italicized* Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - The schizophrenia susceptibility gene neuregulin 1 modulates tolerance to the effects of cannabinoids. AU - Boucher,Aurélie A, AU - Hunt,Glenn E, AU - Micheau,Jacques, AU - Huang,Xufeng, AU - McGregor,Iain S, AU - Karl,Tim, AU - Arnold,Jonathon C, Y1 - 2010/08/12/ PY - 2010/8/13/entrez PY - 2010/8/13/pubmed PY - 2012/1/10/medline SP - 631 EP - 43 JF - The international journal of neuropsychopharmacology JO - Int. J. Neuropsychopharmacol. VL - 14 IS - 5 N2 - Cannabis increases the risk of schizophrenia in genetically vulnerable individuals. In this study we aim to show that the schizophrenia susceptibility gene neuregulin 1 (Nrg1) modulates the development of tolerance to cannabinoids in mice. Nrg1 heterozygous (HET) and wild-type (WT) mice were treated daily for 15 d with the synthetic analogue of Δ9-tetrahydrocannabinol, CP55,940 (0.4 mg/kg). We measured the impact of this exposure on locomotor activity, anxiety, prepulse inhibition (PPI), body temperature and FosB/ΔFosB immunohistochemistry. Tolerance to CP55,940-induced hypothermia and locomotor suppression developed more rapidly in Nrg1 HET mice than WT mice. Conversely in the light-dark test, while tolerance to the anxiogenic effect of CP55,940 developed in WT mice over days of testing, Nrg1 hypomorphs maintained marked anxiety even after 15 d of treatment. Repeated cannabinoid exposure selectively increased FosB/ΔFosB expression in the lateral septum, ventral part (LSV) of Nrg1 HET but not WT mice. On day 1 of exposure opposite effects of CP55,940 treatment were observed on PPI, i.e. it was facilitated in Nrg1 hypomorphs and impaired in WT mice, despite the drug significantly impairing the acoustic startle reflex equally in both genotypes. These effects of CP55,940 on PPI were not maintained as both genotypes became tolerant to cannabinoid action with repeated exposure. Our results highlight that Nrg1 modulates the development of cannabinoid tolerance dependent on the parameter being measured. Furthermore, these data reinforce the notion that the VLS is an important brain region involved in Nrg1-cannabinoid interactions. SN - 1469-5111 UR - https://www.unboundmedicine.com/medline/citation/20701826/abstract/The_schizophrenia_susceptibility_gene_neuregulin_1_modulates_tolerance_to_the_effects_of_cannabinoids_ L2 - https://academic.oup.com/ijnp/article-lookup/doi/10.1017/S146114571000091X DB - PRIME DP - Unbound Medicine ER -