NrCAM-regulating neural systems and addiction-related behaviors

Hiroki Ishiguro, Frank S. Hall, Yasue Horiuchi, Takeshi Sakurai, Akitoyo Hishimoto, Martin Grumet, George R. Uhl, Emmanuel S. Onaivi, Tadao Arinami

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

We have previously shown that a haplotype associated with decreased NrCAM expression in brain is protective against addiction vulnerability for polysubstance abuse in humans and that Nrcam knockout mice do not develop conditioned place preferences for morphine, cocaine or amphetamine. In order to gain insight into NrCAM involvement in addiction vulnerability, which may involve specific neural circuits underlying behavioral characteristics relevant to addiction, we evaluated several behavioral phenotypes in Nrcam knockout mice. Consistent with a potential general reduction in motivational function, Nrcam knockout mice demonstrated less curiosity for novel objects and for an unfamiliar conspecific, showed also less anxiety in the zero maze. Nrcam heterozygote knockout mice reduced alcohol preference and buried fewer marbles in home cage. These observations provide further support for a role of NrCAM in substance abuse including alcoholism vulnerability, possibly through its effects on behavioral traits that may affect addiction vulnerability, including novelty seeking, obsessive compulsion and responses to aversive or anxiety-provoking stimuli. Additionally, in order to prove glutamate homeostasis hypothesis of addiction, we analyzed glutamatergic molecules regulated by NRCAM expression. Glutaminase appears to be involved in NrCAM-related molecular pathway in two different tissues from human and mouse. An inhibitor of the enzyme, prolyl-leucyl-glycinamide, treatment produced, at least, some of the phenotypes of mice shown in alcohol preference and in anxiety-like behavior. Thus, NrCAM could affect addiction-related behaviors via at least partially modulation of some glutamatergic pathways and neural function in brain.

Original languageEnglish (US)
Pages (from-to)343-353
Number of pages11
JournalAddiction Biology
Volume19
Issue number3
DOIs
StatePublished - May 2014

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All Science Journal Classification (ASJC) codes

  • Medicine (miscellaneous)
  • Pharmacology
  • Psychiatry and Mental health

Keywords

  • Behavior
  • cell adhesion molecule
  • glutamate

Cite this

Ishiguro, H., Hall, F. S., Horiuchi, Y., Sakurai, T., Hishimoto, A., Grumet, M., Uhl, G. R., Onaivi, E. S., & Arinami, T. (2014). NrCAM-regulating neural systems and addiction-related behaviors. Addiction Biology, 19(3), 343-353. https://doi.org/10.1111/j.1369-1600.2012.00469.x