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

Journal Article


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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 D9-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/DFosB 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/DFosB 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.

Authors


  •   Boucher, Aurelie (external author)
  •   Hunt, Glenn E. (external author)
  •   Micheau, Jacques (external author)
  •   Huang, Xu-Feng
  •   Prof Iain McGregor, Iain S. (external author)
  •   Karl, Tim (external author)
  •   Dr Jonathon Arnold, Jonathon (external author)

Publication Date


  • 2011

Citation


  • Boucher, A., Hunt, G. E., Micheau, J., Huang, X., McGregor, I., Karl, T. & Arnold, J. (2011). The schizophrenia susceptibility gene neuregulin 1 modulates tolerance to the effects of canabinoids. International Journal of Neuropsychopharmacology, 14 (5), 631-643.

Scopus Eid


  • 2-s2.0-79956013167

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=1853&context=hbspapers

Ro Metadata Url


  • http://ro.uow.edu.au/hbspapers/805

Has Global Citation Frequency


Number Of Pages


  • 12

Start Page


  • 631

End Page


  • 643

Volume


  • 14

Issue


  • 5

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 D9-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/DFosB 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/DFosB 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.

Authors


  •   Boucher, Aurelie (external author)
  •   Hunt, Glenn E. (external author)
  •   Micheau, Jacques (external author)
  •   Huang, Xu-Feng
  •   Prof Iain McGregor, Iain S. (external author)
  •   Karl, Tim (external author)
  •   Dr Jonathon Arnold, Jonathon (external author)

Publication Date


  • 2011

Citation


  • Boucher, A., Hunt, G. E., Micheau, J., Huang, X., McGregor, I., Karl, T. & Arnold, J. (2011). The schizophrenia susceptibility gene neuregulin 1 modulates tolerance to the effects of canabinoids. International Journal of Neuropsychopharmacology, 14 (5), 631-643.

Scopus Eid


  • 2-s2.0-79956013167

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=1853&context=hbspapers

Ro Metadata Url


  • http://ro.uow.edu.au/hbspapers/805

Has Global Citation Frequency


Number Of Pages


  • 12

Start Page


  • 631

End Page


  • 643

Volume


  • 14

Issue


  • 5