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Neonatal exposure to MK-801, an N-methyl-D-aspartate receptor antagonist, enhances methamphetamine-induced locomotion and disrupts sensorimotor gating in pre- and postpubertal rats

Department of Neuropsychiatry, University of Toyama Graduate School of Medicine and Pharmaceutical Sciences, Sugitani, Toyama, Japan.
Brain research (Impact Factor: 2.84). 09/2010; 1352:223-30. DOI: 10.1016/j.brainres.2010.07.013
Source: PubMed

ABSTRACT

Administration of non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists (e.g. phencyclidine, MK-801) has been shown to elicit behavioral abnormalities related to symptoms of schizophrenia, such as spontaneous locomotor activity and impaired sensorimotor gating, as represented by deficits of prepulse inhibition (PPI). We sought to determine whether transient blockade of NMDA receptors at the neonatal stage would produce dopamine supersensitivity around puberty, as manifested by these behavioral measures. For this purpose, we examined methamphetamine (MAP; 1.0mg/kg, i.p.)-induced locomotor activity and PPI in pre- (postnatal day; PD 36-38) or post- (PD 64-66) puberty in rats administered MK-801 (0.2mg/kg/day, s.c.) between PD 7 and PD 10. Neonatal MK-801 treatment augmented MAP-induced hyperlocomotion especially in the early adulthood, whereas spontaneous locomotor activity and rearing were not changed. MK-801 administration also disrupted PPI without affecting startle amplitudes around puberty. These findings suggest that transient exposure to MK-801 in the neonatal stage causes exaggerated dopamine transmission and cognitive deficits, particularly in the post-puberty stage.

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    • "These findings point to functional abnormalities of mGluR3 in the PFC of patients with schizophrenia, consistent with the observations reported here (Fig. 2A) The results of this study are partly consistent with our previous findings from neonatal MK-801-treated rats. MK-801 administration on PD 7 through 10 resulted in increased locomotion on PD 56 (Uehara et al., 2010). Inhibitors of GCP II, such as ZJ43 and 2-PMPA, have been reported to attenuate PCP-or damphetamine (AMPH)-induced hyperactivity, which is blocked by coadministration of the mGluR2/3 antagonist LY341495 (Olszewski et al., 2008, 2012; Zuo et al., 2012). "

    Full-text · Dataset · Jul 2015
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    • "These findings point to functional abnormalities of mGluR3 in the PFC of patients with schizophrenia, consistent with the observations reported here (Fig. 2A) The results of this study are partly consistent with our previous findings from neonatal MK-801-treated rats. MK-801 administration on PD 7 through 10 resulted in increased locomotion on PD 56 (Uehara et al., 2010). Inhibitors of GCP II, such as ZJ43 and 2-PMPA, have been reported to attenuate PCP-or damphetamine (AMPH)-induced hyperactivity, which is blocked by coadministration of the mGluR2/3 antagonist LY341495 (Olszewski et al., 2008, 2012; Zuo et al., 2012). "

    Full-text · Dataset · Jul 2015
    • "Accordingly, some animal models of schizophrenia that induce dysfunction in the GABAergic neurons in the PFC and hippocampus also show amphetamine-or novelty-induced hyperlocomotion [40] [104] [107], but not others [27]. The lack of amphetamine-induced psychomotor effects that we describe here versus those previously shown with developmental MK-801 treatment [107], suggests either crucial differences in the mechanisms of action between MK-801 and ketamine, or that ketamine blockade of NMDARs on corticolimbic GABAergic neurons during early postnatal development may permanently induce a brain state akin to that of amphetamine-sensitized mice, thereby resulting in the occlusion of amphetamine-induced hyperlocomotion (cf. [27]). "
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    ABSTRACT: Dysfunctions in the GABAergic system are considered a core feature of schizophrenia. Pharmacological blockade of NMDA receptors (NMDAR), or their genetic ablation in parvalbumin (PV)-expressing GABAergic interneurons can induce schizophrenia-like behavior in animals. NMDAR mediated currents shape the maturation of GABAergic interneurons during a critical period of development, making transient blockade of NMDARs during this period an attractive model for the developmental changes that occur in the course of schizophrenia's pathophysiology. Here, we examined whether developmental administration of the non-competitive NMDAR antagonist ketamine results in persistent deficits in PFC-dependent behaviors in adult animals. Mice received injections of ketamine (30mg/kg) on postnatal days (PND) 7, 9 and 11, and then tested on a battery of behavioral experiments aimed to mimic major symptoms of schizophrenia in adulthood (between PND 90 and 120). Ketamine treatment reduced the number of cells that expressed PV in the PFC by ∼60% as previously described. Ketamine affected performance in an attentional set-shifting task, impairing the ability of the animals to perform an extradimensional shift to acquire a new strategy. Ketamine-treated animals showed deficits in latent inhibition, novel-object recognition and social novelty detection compared to their SAL-treated littermates. These deficits were not a result of generalized anxiety, as both groups performed comparably on an elevated plus maze. Ketamine treatment did not cause changes in amphetamine-induced hyperlocomotion that are often taken as measures for the positive-like symptoms of the disorder. Thus, ketamine administration during development appears to be a useful model for inducing cognitive and negative symptoms of schizophrenia. Copyright © 2015. Published by Elsevier B.V.
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