Long-term effects of neonatal MK-801 treatment on prepulse inhibition in young adult rats
- 200 Downloads
Blockade of N-methyl-d-asparate (NMDA) receptors has been shown to produce some of the abnormal behaviors related to symptoms of schizophrenia in rodents and human. Neonatal treatment of rats with non-competitive NMDA antagonists has been shown to induce behavioral abnormality in a later period.
The aim of this study was to determine whether brief disruption of NMDA receptor function during a critical stage of development is sufficient to produce sensorimotor-gating deficits in the late adolescence or early adulthood in the rat.
Male pups received the NMDA receptor blocker MK-801 (0.13 or 0.20 mg/kg), or an equal volume of saline on postnatal day (PD) 7 through 10. The animals were tested twice for prepulse inhibition (PPI) and locomotor activity in pre- (PD 35-38) and post- (PD 56-59) puberty.
Neonatal exposure to both doses MK-801 disrupted PPI in the adolescence and early adulthood. Low-dose MK-801 elicited long-term effects on startle amplitudes, whereas high-dose MK-801 did not. Neither dose of MK-801 showed a significant effect on spontaneous locomotor activity, whereas the high dose attenuated rearing.
The results of this study suggest neonatal exposure to MK-801 disrupted sensorimotor gating in the adolescence and early adulthood stages. These findings indicate that rats transiently exposed to NMDA blockers in neonatal periods are useful for the study of the pathophysiology and treatment of schizophrenia.
KeywordsNMDA receptor MK-801 Neonatal Prepulse inhibition Locomotor activity Rat Animal model Schizophrenia
The authors gratefully acknowledge the insightful comments and criticism by Dr. M. Tsunoda and Dr. K. Tanaka.
This study was supported by a Grant-in-Aid for Scientific Research from Japan Society for the Promotion of Science (No. 20591363).
- Abekawa T, Ito K, Nakagawa S, Koyama T (2007) Prenatal exposure to an NMDA receptor antagonist, MK-801 reduces density of parvalbumin-immunoreactive GABAergic neurons in the medial prefrontal cortex and enhances phencyclidine-induced hyperlocomotion but not behavioral sensitization to methamphetamine in postpubertal rats. Psychopharmacology (Berl) 192:303–316CrossRefGoogle Scholar
- Kawasaki Y, Suzuki M, Nohara S, Hagino H, Takahashi T, Matsui M, Yamashita I, Chitnis XA, McGuire PK, Seto H, Kurachi M (2004) Structural brain differences in patients with schizophrenia and schizotypal disorder demonstrated by voxel-based morphometry. Eur Arch Psychiatry Clin Neurosci 254:406–414PubMedCrossRefGoogle Scholar
- Sumiyoshi T, Tsunoda M, Uehara T, Tanaka K, Itoh H, Sumiyoshi C, Kurachi M (2004) Enhanced locomotor activity in rats with excitotoxic lesions of the entorhinal cortex, a neurodevelopmental animal model of schizophrenia: behavioral and in vivo microdialysis studies. Neurosci Lett 364:124–129PubMedCrossRefGoogle Scholar
- Takahashi M, Kakita A, Futamura T, Watanabe Y, Mizuno M, Sakimura K, Castren E, Nabeshima T, Someya T, Nawa H (2006) Sustained brain-derived neurotrophic factor up-regulation and sensorimotor gating abnormality induced by postnatal exposure to phencyclidine: comparison with adult treatment. J Neurochem 99:770–780PubMedCrossRefGoogle Scholar
- Uehara T, Sumiyoshi T, Itoh H, Kurachi M (2004) Inhibition of dopamine synthesis with alpha-methyl-p-tyrosine abolishes the enhancement of methamphetamine-induced extracellular dopamine levels in the amygdala of rats with excitotoxic lesions of the entorhinal cortex. Neurosci Lett 356:21–24PubMedCrossRefGoogle Scholar
- Weinberger DR (1995) Neurodevelopmental perspectives on schizophrenia. In: Bloom FE, Kupfer DJ (eds) Psychopharmacology; the fourth generation of progress. Raven, New York, pp 1171–1183Google Scholar