Effect of MK‐801 on gene expressions in the amygdala of rats

Abstract

Rodents treated with N-methyl-D-aspartate (NMDA) antagonists have been thought to be an animal model of schizophrenia. In this study, we examined gene expression in the amygdala of rats chronically treated with MK-801, as well as behavioral changes, such as social behavior, in these animals. The social interaction test, a measure of social behavior, and locomotor activity was performed in male Wistar rats injected with MK-801 (0.13 mg/kg i.p.) or saline for 14 days. Changes in mRNA levels were analyzed using a GeneChip microarray system. Real-time quantitative PCR (RT-qPCR) assay was subsequently conducted to confirm the results of the microarray analysis. MK-801 decreased social interaction and increased locomotor activity in rats, consistent with previous reports. We found 23 downregulated genes and 16 upregulated genes, with the gene encoding arginine-vasopressin (AVP) being most downregulated, and that for transthyretin (Ttr) most upregulated. mRNA levels, quantified by RT-qPCR assay, were altered for genes related to neuropeptides (AVP, Sstr2), the arachidonic cascade (Ptgds), myelination (Mobp, Enpp2), neurotrophic factors (Igfbp2), and hormonal milieu (Ttr). Downregulation of the AVP gene in the amygdala of MK-801-treated rats may provide a basis for the ability of AVP-analogues to ameliorate the behavioral disturbances caused by blockade of the NMDA receptor. The results of this study provide an insight into the neural substrates responsible for the generation of psychotic symptoms.

Current pharmacological models of social withdrawal in rats

“…Therefore it seems that in terms of the face validity of this model, the deficits in social behaviour induced by MK-801 are mainly acute. Interestingly, a study to investigate the changes in gene expression in the amygdala after subchronic treatment with MK-801 found reduced mRNA production of vasopressin and increased production of transthyretrin (Matsuoka et al, 2008). As for PCP, however, clinical observations have reported conflicting results with regard to vasopressin expression in schizophrenia, so it is difficult to confirm the construct validity of this model.…”

The discovery of potent agonists for GPR88, an orphan GPCR, for the potential treatment of CNS disorders

“…2 Additional studies with GPR88 knock-out mice showed increased glutamatergic excitation and reduced GABAergic inhibition in medium spiny neurons, thereby enhancing neuronal firing rates in vivo and resulting in hyperactivity, poor motor coordination and impaired cue-based learning. 3 In addition, transcriptional profiling studies have revealed that GPR88 expression is altered in a number of CNS related diseases, [4][5][6][7][8] providing additional evidence that GPR88 is an essential modulator of CNS signaling pathways related to psychiatric disease. All these data suggest that modulating GPR88 activity should have therapeutic utilities in the treatment of a number of CNS related diseases, such as schizophrenia.…”

Animal models of cognitive dysfunction and negative symptoms of schizophrenia: Focus on NMDA receptor antagonism

“…Interestingly, monkeys with amygdala lesions show several social deficits and are expelled from the social group. Another study by Matsuoka et al (2008) demonstrated a down-regulation in 23 genes and up-regulation in 16 genes, with the gene encoding arginine-vasopressin being most down-regulated, and that for transthyretin (Ttr) most up-regulated in the amygdala following MK-801 (0.13 mg/kg for 14 days) treatment in adult male rats. Indeed it has been suggested that there is a close relationship between dysfunction of the amygdala and social behaviour deficits seen in patients with schizophrenia.…”