Amphetamine-induced Fos is reduced in limbic cortical regions but not in the caudate or accumbens in a genetic model of NMDA receptor hypofunction.
A mouse strain has been developed that expresses low levels of the NR1 subunit of the NMDA receptor. These mice are a model of chronic developmental NMDA receptor hypofunction and may therefore have relevance to the hypothesized NMDA receptor hypofunction in schizophrenia. Many schizophrenia patients show exaggerated behavioral and neuronal responses to amphetamine compared to healthy subjects. Studies were designed to determine if the NR1-deficient mice would exhibit enhanced sensitivity to amphetamine. Effects of amphetamine on behavioral activation and Fos induction were compared between the NR1-deficient mice and wild-type controls. The NR1 hypomorphic mice and controls exhibited similar locomotor activation after administration of amphetamine at 2 mg/kg. The mutant mice showed slightly reduced peak locomotor activity and slightly increased stereotypy after 4 mg/kg amphetamine. There were no differences in Fos induction in response to amphetamine in the caudate putamen, nucleus accumbens, medial or central amygdala nuclei, or bed nucleus of the stria terminalis. However, amphetamine-induced Fos was substantially attenuated in the medial frontal (infralimbic) and cingulate cortices, basolateral amygdala, and in the lateral septum of the mutant mice. The results suggest a neuroanatomically selective activation deficit to amphetamine challenge in the NR1-deficient mice.
Miyamoto
Seiya
S
Department of Psychiatry, the Mental Health and Neuroscience Clinical Research Center, USA. s2miya@marianna-u.ac.jp
Snouwaert
John N
JN
Koller
Beverly H
BH
Moy
Sheryl S
SS
Lieberman
Jeffrey A
JA
Duncan
Gary E
GE
D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002421:Caudate Nucleus / Q000187:drug effects / Q000378:metabolism*; D002452:Cell Count / Q000379:methods; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D007150:Immunohistochemistry / Q000379:methods; D008032:Limbic System / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008957:Models, Genetic; D009043:Motor Activity / Q000187:drug effects; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism*; D016761:Oncogene Proteins v-fos / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D018765:Dopamine Uptake Inhibitors; C409466:NR1 NMDA receptor; D016761:Oncogene Proteins v-fos; D016194:Receptors, N-Methyl-D-Aspartate; D000661:Amphetamine