Neuronal cell adhesion molecule regulating neural systems underlying addiction

  • Hiroki Ishiguro
    Department of Neuropsychiatry and Clinical Ethics University of Yamanashi Chuo Japan
  • Kunio Miyake
    Department of Health Sciences University of Yamanashi Chuo Japan
  • Koichi Tabata
    Department of Neuropsychiatry and Clinical Ethics University of Yamanashi Chuo Japan
  • Chiaki Mochizuki
    Department of Neuropsychiatry and Clinical Ethics University of Yamanashi Chuo Japan
  • Takeshi Sakurai
    Medical Innovation Center Kyoto University Kyoto Japan
  • Emmanuel S. Onaivi
    Department of Biology William Paterson University Wayne New Jersey

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<jats:title>Abstract</jats:title><jats:sec><jats:title>Aims</jats:title><jats:p>The human <jats:italic><jats:styled-content style="fixed-case">NRCAM</jats:styled-content></jats:italic> gene is associated with polysubstance use. <jats:italic>Nrcam</jats:italic> knockout mice do not acquire a preference for addictive substances. We aimed to elucidate the role of <jats:italic>Nrcam</jats:italic> in specific neural circuits underlying congenital preference for substances and the acquisition of addiction.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>We analyzed gene expression patterns of neural molecules to find a common addiction pathway dependent on <jats:italic>Nrcam</jats:italic> function. We examined monoaminergic, glutamatergic, and <jats:styled-content style="fixed-case">GABA</jats:styled-content>ergic systems in the brains of <jats:italic>Nrcam</jats:italic> knockout mice following treatment with methamphetamine (<jats:styled-content style="fixed-case">METH</jats:styled-content>) or saline (<jats:styled-content style="fixed-case">SAL</jats:styled-content>) using micro‐array gene expression analysis, which was replicated using TaqMan gene expression analysis. To find a common addiction pathway, we examined similarities and differences between the expression patterns of molecules in <jats:styled-content style="fixed-case">METH</jats:styled-content>‐treated mice and in <jats:italic>Nrcam</jats:italic> knockout mice treated with cocaine (<jats:styled-content style="fixed-case">COC</jats:styled-content>).</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Glutaminase expression in brain was reduced in <jats:italic>Nrcam</jats:italic> heterozygous mice after <jats:styled-content style="fixed-case">METH</jats:styled-content> and <jats:styled-content style="fixed-case">COC</jats:styled-content> treatment, consistent with our previous study. Metabotropic glutamate receptor 2 expression was reduced in <jats:italic>Nrcam</jats:italic> heterozygous mice that received either <jats:styled-content style="fixed-case">METH</jats:styled-content> or <jats:styled-content style="fixed-case">COC</jats:styled-content> treatment. Several other molecules could act in independent addiction pathways involving <jats:styled-content style="fixed-case">METH</jats:styled-content> or <jats:styled-content style="fixed-case">COC</jats:styled-content>. We also found that <jats:styled-content style="fixed-case">GABA</jats:styled-content> receptor subunit g2 expression was reduced in <jats:italic>Nrcam</jats:italic> heterozygous mice that underwent <jats:styled-content style="fixed-case">SAL</jats:styled-content> treatment, and that <jats:styled-content style="fixed-case">METH</jats:styled-content> treatment attenuated this reduction.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>Nrcam differentially regulates glutamatergic and <jats:styled-content style="fixed-case">GABA</jats:styled-content>ergic molecules in naive brains and in brains of animals with acquired addiction. Elucidating the complex neural mechanisms underlying polysubstance use will uncover biological features of addiction and may contribute to the development of effective pharmaceutical treatments.</jats:p></jats:sec>

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