NrCAM-regulating neural systems and addiction-related behaviors.
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.
Department of Neuropsychiatry and Clinical Ethics, Graduate School of Medical Science, University of Yamanashi, Chuo, Yamanashi, Japan; Department of Medical Genetics, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan.
Hiroki
H
Ishiguro
Frank S
FS
Hall
Yasue
Y
Horiuchi
Takeshi
T
Sakurai
Akitoyo
A
Hishimoto
Martin
M
Grumet
George R
GR
Uhl
Emmanuel S
ES
Onaivi
Tadao
T
Arinami
D000223:Adaptation, Psychological / Q000187:drug effects; D000428:Alcohol Drinking / Q000503:physiopathology; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D001007:Anxiety / Q000503:physiopathology; D016739:Behavior, Addictive / Q000503:physiopathology*; D015815:Cell Adhesion Molecules / Q000502:physiology*; D002492:Central Nervous System Depressants / Q000494:pharmacology; D003213:Conditioning, Psychological / Q000187:drug effects; D000431:Ethanol / Q000494:pharmacology; D005106:Exploratory Behavior / Q000187:drug effects; D009075:MSH Release-Inhibiting Hormone / Q000494:pharmacology; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009020:Morphine / Q000494:pharmacology; D011930:Reaction Time / Q000187:drug effects; D012919:Social Behavior
D000701:Analgesics, Opioid; D015815:Cell Adhesion Molecules; D002492:Central Nervous System Depressants; C491151:Nrcam protein, mouse; D000431:Ethanol; D009020:Morphine; D009075:MSH Release-Inhibiting Hormone