Sex-specific restoration of MK-801-induced sensorimotor gating deficit by environmental enrichment

doi:10.1016/j.neuroscience.2015.04.050

Neuroscience

Volume 299, 23 July 2015, Pages 28-34

https://doi.org/10.1016/j.neuroscience.2015.04.050 Get rights and content

Highlights

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Postnatal MK-801 led to a significant deficit in prepulse inhibition (PPI).
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PPI deficit by MK-801 was observed in both sexes on postnatal days 28–30.
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Enriched environment was applied from birth up to the time of PPI testing.
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Enriched environment restored MK-801-induced PPI deficit only in male rats.
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Enriched environment per se had no significant effect on PPI.

Abstract

Despite ample evidence of N-methyl-d-aspartate (NMDA) receptor dysfunction in schizophrenia, no study has addressed the effects of enriched environment (EE) on sensorimotor gating deficits induced by postnatal NMDA receptor blockade. We evaluated the effect of EE on sensorimotor gating (measured by prepulse inhibition, PPI), or on sensorimotor gating deficit induced by the NMDA receptor antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801) in both sexes of Wistar rats. Rats were injected with MK-801 (1 mg/kg) on postnatal days (P) 6–10. EE was provided from birth up to the time of experiments on P28–30 or P58–60. PPI data were collected at three prepulse intensities and then averaged to yield global PPI.

MK-801 treatment reduced PPI significantly in both sexes. While EE per se had no significant effect on PPI, it restored MK-801-induced PPI deficit only in male rats. An extended period of EE did not influence PPI deficit in female rats. Our results indicate that postnatal exposure to MK-801 may exert long-lasting effects on neuronal circuits underlying sensorimotor gating. Sex-specific modulation of such effects by EE suggests sexually dimorphic mechanisms are involved.

Introduction

Prepulse inhibition (PPI) of the startle response is characterized by the attenuation of the startle response caused by an intense audiogenic stimulus shortly preceded by a weaker stimulus (Graham, 1975). PPI is a robust operational measure of sensorimotor gating by which excess or trivial stimuli are screened or “gated out” of awareness. Healthy functioning of this mechanism is crucial for normal cognitive processes and several psychiatric disorders, such as schizophrenia are associated with impaired sensorimotor gating, expressed as reduced PPI (Kohl et al., 2013).

Transient neonatal exposure to (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801), a non-competitive N-methyl-d-aspartate (NMDA) antagonist, causes deficits in sensorimotor gating of male (Uehara et al., 2009, Uehara et al., 2012, Lim et al., 2012) and female rats (Beninger et al., 2002, Harris et al., 2003). Similar changes in PPI have also been reported by acute MK-801 administration in male mice and rats (Long et al., 2006, Khella et al., 2014, Suryavanshi et al., 2014). However, several studies have reported lack of effect of neonatal MK-801 treatment on PPI (Harris et al., 2003, Coleman et al., 2009, Lyall et al., 2009, Su et al., 2011, Su et al., 2014) and there seems to be a sex factor influencing the PPI outcome with neonatal MK-801 treatment (Harris et al., 2003, Zhao et al., 2013).

Enriched environment (EE) refers to housing conditions in which a combination of complex inanimate and social stimulations is provided to stimulate curiosity and exploration. EE has been shown to facilitate brain development and functions, including sensory, cognitive and motor, under both physiological and pathological conditions (Sale et al., 2014). There are a limited number of studies evaluating the effects of EE on PPI. EE has led to an increase (Chen et al., 2010), decrease (Peña et al., 2009) or no change of PPI (Varty et al., 2000, Schneider et al., 2006, Hoffmann et al., 2009, Guo et al., 2013) in male rats or mice. Pietropaolo et al. (2006) have found that PPI is responsive to EE in adult female mice, although the effect has been bidirectional depending critically on the presence of home-cage running wheels. Two other studies on female rodents have shown no effect (Kulesskaya et al., 2011) or a decrease (Peña et al., 2009) in PPI by EE. To clarify the relevance of sex to the observed differences, in this study we used both male and female rats and directly compared the effects of postnatal MK-801 treatment and EE on PPI. We also looked at the potential preventive effects of EE on PPI deficits in response to postnatal MK-801 treatment, a representative animal model of schizophrenia (Stefani and Moghaddam, 2005, Adell et al., 2012, Balu et al., 2013). PPI restoration by EE has not been addressed previously in this model.

Section snippets

Animals

The animals were kept in a room with controlled light (light on at 08:00 a.m. for 12 h) and temperature (21 ± 2 °C) and had free access to food (standard laboratory pellets) and water. All experimental and animal care procedures were performed according to international guidelines on the use of laboratory animals and approved by Kerman University of Medical Sciences Ethics Committee for Animal Research in line with the “NIH Guide for the Care and Use of Laboratory Animals”. Maximum efforts were made

Sex differences in response to MK-801 and EE on P28–30

The three-way ANOVA showed only a significant main effect of prepulse intensity [F(2, 252) = 35.3, p < 0.001] and there was no significant interaction between prepulse intensity × group, prepulse intensity × sex and prepulse intensity × group × sex. Tests between subjects showed the main effect of group [F(3, 126) = 10.534, p < 0.001] and sex [F(1, 126) = 6.756, p < 0.01], but no interaction of group × sex was observed. Since prepulse intensity did not interact with any of the other variables (MK-801 treatment, EE

Discussion

The present study demonstrates that transient, postnatal exposure to MK-801 induces disruption of sensorimotor gating measured by PPI in both sexes. EE restores PPI deficits induced by MK-801 treatment uniquely in male rats.

PPI of the startle response is impaired in certain psychiatric disorders, particularly in schizophrenia. Symptoms of schizophrenia typically begin to emerge at adolescence in most of the patients; therefore we tested animals on P28–30 to assess the sensorimotor gating at

Conclusion

Taken together, an early-life blockade of the NMDA receptors by MK-801 induces behavioral changes that mimic several features of schizophrenia including disrupted PPI which is subject to modulation by EE in a sex-specific way. These data strengthen the importance of taking into account sex differences in animal models of schizophrenia. Future studies should address the mechanisms mediating differential effects of EE on male and female brain circuits.

Conflict of interest statement

The authors declare that there are no conflicts of interest.

Acknowledgment

This research article is part of the first author’s Ph.D. thesis. Funding for this study was provided by Neuroscience Research Center, Neuropharmacology Institute, Kerman University of Medical Sciences, Kerman, Iran.

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Sex-specific restoration of MK-801-induced sensorimotor gating deficit by environmental enrichment

Highlights

Abstract

Introduction

Section snippets

Animals

Sex differences in response to MK-801 and EE on P28–30

Discussion

Conclusion

Conflict of interest statement

Acknowledgment

Neuropharmacology

Behav Brain Res

Pharmacol Biochem Behav

Eur Neuropsychopharmacol

Horm Behav

Neuroscience

Neuroscience

Brain Res

Behav Brain Res

Physiol Behav

J Psychiatr Res

Psychoneuroendocrinology

Neuroscience

Biol Psychiatry

Eur J Pharmacol

J Psychiatr Res

Biol Psychiatry

Neurosci Lett

Is the acute NMDA receptor hypofunction a valid model of schizophrenia?

Schizophr Bull

Characterization of MK-801-induced behavior as a putative rat model of psychosis

J Pharmacol Exp Ther

Effect of age and sex on N-methyl-d-aspartate antagonist-induced neuronal necrosis in rats

Stroke

Multiple limbic regions mediate the disruption of prepulse inhibition produced in rats by the noncompetitive NMDA antagonist dizocilpine

J Neurosci

Multiple risk pathways for schizophrenia converge in serine racemase knockout mice, a mouse model of NMDA receptor hypofunction

Proc Natl Acad Sci U S A

Neonatal exposure to the glutamate receptor antagonist MK-801: effects on locomotor activity and pre-pulse inhibition before and after sexual maturity in rats

Neurotox Res

Estrogen and exercise interact to regulate brain-derived neurotrophic factor mRNA and protein expression in the hippocampus

Eur J Neurosci

Activation of nociceptin/orphanin FQ peptide receptors disrupts visual but not auditory sensorimotor gating in BALB/cByJ mice: comparison to dopamine receptor agonists

Neuropsychopharmacology

Roles of the amygdala and bed nucleus of the stria terminalis in fear and anxiety measured with the acoustic startle reflex. Possible relevance to PTSD

Ann N Y Acad Sci