Amphetamine-Induced Fos is Reduced in Limbic Cortical Regions but not in the Caudate or Accumbens in a Genetic Model of NMDA Receptor Hypofunction

Abstract

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.

Genetic NMDA Receptor Deficiency Disrupts Acute and Chronic Effects of Cocaine but not Amphetamine

“…They also suggest that the activation of the corticostriatal pathway is critical for the stimulatory effects of cocaine, as its ability to induce c-fos expression is diminished in mice with reduced NMDA receptor expression. Although dopamine-and amphetamine-stimulated c-fos expression in the striatum is also affected by NMDA receptor-mediated glutamatergic signaling from the frontal cortex (Konradi et al, 1996;Cenci and Björklund, 1993;Badiani et al, 1998), our results are in line with reports suggesting that amphetamine c-fos induction might be less sensitive to decreased NMDA receptor function (Dalia and Wallace, 1995;Morelli, 1997;Ganguly and Keefe, 2000;Miyamoto S et al, 2004).…”

Behavioral genetic contributions to the study of addiction-related amphetamine effects

“…Deletion of GluRε1 caused a reduction of locomotor stimulation in response to acute methamphetamine, as well as a lower magnitude of sensitization to repeated methamphetamine exposure (Miyamoto et al, 2004b). Mice carrying a hypomorphic allele of NR1 (the receptor subunit common to all NMDA-type heteromers) also exhibited decreased locomotion relative to WT mice in response to acute amphetamine, but interpretation of this result may be complicated by the increased stereotypy of this strain (Miyamoto et al, 2004a). Further, a mutant with an NR1 NMDA receptor subunit with reduced function that was expressed only in dopamine D1 receptor-containing cells, did not exhibit an alteration in amphetamine response (Heusner and Palmiter, 2005).…”

Case–control association study of 59 candidate genes reveals the DRD2 SNP rs6277 (C957T) as the only susceptibility factor for schizophrenia in the Bulgarian population

“…2 Furthermore, common antipsychotic medications are capable of affecting the positive symptoms of the disease 2 as a result of antagonistic or partially agonistic interactions with the dopamine D2 receptor, whereas dopamine agonists, such as amphetamines, provoke schizophrenia-like psychosis. 2,11,21 The dopamine receptor genes comprise a large superfamily that encodes G-protein-coupled receptors important for regulation of some higher functions, such as locomotion, cognition and emotions. [22][23][24] Five human dopamine receptors are described and classified into two major groups, dopamine 1-like (D1) and dopamine 2-like (D2), in accordance with their transcriptional and pharmacological properties.…”