Effects of chronic forced-swim stress on behavioral properties in rats with neonatal repeated MK-801 treatment

Highlights

• Stress-vulnerability in rats neonatally treated with MK-801 was examined.

• Rats were subjected to chronic forced-swim stress.

• Neonatal MK-801 treatment reduced stress-induced immobility in the forced-swim test.

• Neonatal MK-801 treatment may impair adaptation or coping ability against stress.

• Discussing the results in terms of the two-hit hypothesis of schizophrenia.

Abstract

The two-hit hypothesis has been used to explain the onset mechanism of schizophrenia. It assumes that predisposition to schizophrenia is originally attributed to vulnerability in the brain which stems from genetic or early developmental factors, and that onset is triggered by exposure to later detrimental factors such as stress in adolescence or adulthood. Based on this hypothesis, the present study examined whether rats that had received neonatal repeated treatment with an N-methyl-d-aspartate (NMDA) receptor antagonist (MK-801), an animal model of schizophrenia, were vulnerable to chronic stress. Rats were treated with MK-801 (0.2 mg/kg) or saline twice daily on postnatal days 7–20, and animals in the stress subgroups were subjected to 20 days (5 days/week × 4 weeks) of forced-swim stress in adulthood. Following this, behavioral tests (prepulse inhibition, spontaneous alternation, open-field, and forced-swim tests) were carried out. The results indicate that neonatal repeated MK-801 treatment in rats inhibits an increase in immobility in the forced-swim test after they have experienced chronic forced-swim stress. This suggests that rats that have undergone chronic neonatal repeated NMDA receptor blockade could have a reduced ability to habituate or adapt to a stressful situation, and supports the hypothesis that these rats are sensitive or vulnerable to stress.

Introduction

N-methyl-d-aspartate (NMDA) receptors, a subtype of ionotropic glutamate receptors, have been implicated in many neural processes. Therefore, treatment with NMDA antagonists impairs numerous neural and mental functions. For example, many studies have shown that NMDA receptors are involved in long-term potentiation, which is believed to be one of the physiological bases for learning and/or memory (Abraham and Mason, 1988, Harris et al., 1984, Morris, 1989, Morris et al., 1986, Morris et al., 1989), and that NMDA receptor antagonists induce learning and/or memory impairments (Kawabe et al., 1998a, Kawabe et al., 1998b, Morris, 1989, Morris et al., 1986, Morris et al., 1989, Yoshihara and Ichitani, 2004). Furthermore, it is also well known that NMDA receptor antagonists such as phencyclidine (PCP) and ketamine induce positive and negative schizophrenia-like symptoms in humans and animals (Bubeníková-Valešová et al., 2008, Javitt and Zukin, 1991).

In addition to these findings based mainly on treatment with NMDA receptor antagonists in adulthood, it is also frequently reported that repeated treatment with antagonists such as PCP and MK-801 (dizocilpine; 5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine) during the early developmental stage can cause long-term alterations of anatomical, neurochemical, neurophysiological, behavioral, and other parameters in rats and mice (for example, Facchinetti et al., 1993, Facchinetti et al., 1994, Gorter et al., 1992a, Gorter and de Bruin, 1992, Gorter et al., 1991, Gorter et al., 1992b, Kawabe et al., 2007, Kawabe and Miyamoto, 2008, Nakatani-Pawlak et al., 2009, Niikura et al., 2015, Sircar, 2003, Stefani and Moghaddam, 2005, Wang et al., 2003). Additionally, since blockade of NMDA receptors in early developmental stages induces neural degeneration, and impairs normal development of the neural circuits and the brain (Beninger et al., 2002, Facchinetti et al., 1993, Facchinetti et al., 1994, Ikonomidou et al., 1999, Kawabe and Miyamoto, 2008, Nakatani-Pawlak et al., 2009, O'Donoghue et al., 1993, Wang et al., 2004, Wang et al., 2003), rats or mice that have received this treatment are used as animal models which adhere to the neurodevelopmental hypothesis of schizophrenia. This hypothesis assumes that maldevelopment of the brain, which is caused by genetic defects, viral infection, obstetric problems and other detrimental factors in early developmental stages, contributes to the onset of schizophrenia (Lewis and Levitt, 2002, Weinberger, 1987). Our previous studies showed that neonatal repeated treatment with competitive (CGS 19755; cis-4-phosphonomethyl-2-piperidine carboxylic acid) and noncompetitive (MK-801) NMDA receptor antagonists impaired spatial working memory in the radial-arm maze or the delayed nonmatching-to-position (DNMTP) tasks (Kawabe et al., 2007, Kawabe and Miyamoto, 2008). Since working memory is severely impaired in schizophrenic patients (Goldman-Rakic, 1994, Manoach, 2003), these results validate the use of animals with neonatal NMDA receptor blockade as a preclinical model of schizophrenia.

In addition to genetic and early developmental factors, stress is one of the risk factors associated with a variety of mental disorders. The two-hit hypothesis of schizophrenia assumes that genetic or early developmental defects (first hit) are potential factors in the onset of schizophrenia, and that later detrimental factors in adolescence or adulthood (second hit) trigger this onset (Bayer et al., 1999, Feigenson et al., 2014, Maynard et al., 2001). Since stress is considered to be a major second hit factor, it is valuable to examine whether animal models of schizophrenia are vulnerable to stress. The present study examined whether rats subjected to neonatal repeated treatment with an NMDA receptor antagonist (MK-801), an animal model of schizophrenia, had stress-vulnerability as assessed by several behavioral or cognitive measures; sensorimotor gating, working memory, locomotor activity, and stress coping. These behavioral parameters were tested after chronic forced-swim stress had been applied in adulthood. Forced-swim stress is commonly used in stress studies of rats and mice, and it has been frequently reported to induce stress-related endocrinal, neural, and behavioral alterations (for example, Anisman et al., 2001, de Kloet and Molendijk, 2016, Shishkina et al., 2015). Thus, I considered that it would be an effective second hit factor in the context of the two-hit hypothesis.