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

Abstract

Neonatal lesions of the ventral hippocampus in rats lead to post- but not pre-pubertal behavioral changes suggesting adolescent onset of dopaminergic hypersensitivity and providing an animal model of schizophrenia. Neonatal exposure to glutamate receptor antagonists produces accelerated apoptosis leading to neuronal loss in central nervous system structures including the hippocampus. This suggested that neonatal MK-801 might lead to behavioural changes like those reported following ventral hippocampal lesions. Thus, rats received MK-801 (0, 0.5, 1.0 mg/kg ip) on postnatal day 3 (P3) and were tested pre- (P35) and post-pubertally (P56). MK-801 produced an increase in TUNEL staining in the hippocampus and other forebrain structures, confirming the induction of apoptosis. Results showed little difference in locomotor activity between neonatal saline- and MK-801-treated groups during habituation or following saline injection but increased activity was seen in the 0.5 mg/kg MK-801 group following amphetamine (1.5 mg/kg i.p.) at P35 but not P56. In tests of pre-pulse inhibition (PPI), neonatal saline and MK-801 groups showed stable startle amplitudes, minimal responding to the pre-pulse stimuli alone, an increase in PPI with increases in pre-pulse intensity, and reduced PPI with apomorphine (0.1 mg/kg s.c.). At P56, neonatal MK-801 groups tested following vehicle showed less sensitivity to changes in pre-pulse intensity. It was concluded that neonatal MK-801 increases apoptotic cell loss in the hippocampus but does not produce behavioural effects like those seen after neonatal ventral hippocampal lesions. However, neonatal MK-801 did lead to increases in locomotor activity in juveniles but not adults and reduced sensitivity to pre-pulse intensity in PPI tests in adulthood.

Long-term effects of neonatal MK-801 treatment on prepulse inhibition in young adult rats

“…MK-801 treatment (0.5 or 1.0 mg/kg, i.p.) on PD 3 did not affect PPI on PD 35 and 56, whereas it reduced sensitivity to prepulse intensity changes on PD 56 (post-puberty), but not on PD 35 (Beninger et al 2002). On the other hand, MK-801 (0.5 mg/kg, s.c.) treatment on PD 7 did not affect PPI on PD 56 (Harris et al 2003).…”

“…Several researchers have attempted to develop animal models of schizophrenia using rats based on the neurodevelopmental hypothesis or the NMDA-receptordysfunction hypothesis (Beninger et al 2002;Harris et al 2003;Rasmussen et al 2007;Stefani and Moghaddam 2005;Takahashi et al 2006;Wang et al 2001). Treatment of neonatal rats with non-competitive NMDA antagonists (e.g., MK-801, phencyclidine) led to behavioral abnormalities related to clinical symptoms of schizophrenia (e.g., locomotor activity, prepulse inhibition; Prepulse inhibition (PPI), spatial memory test) in the adult stage.…”

Novel mechanisms and approaches in the study of neurodegeneration and neuroprotection. A review

“…As an extension of those studies they have additionally lesioned neonatal mice with the NMDA antagonists MK-801, ketamine, and ethanol (see Beninger et al, 2002;Olney et al, 2002;Zhou et al, 2002) to produce amphetamine-attenuated locomotor hyperactivity in adulthood . The import of these findings is that druginduced toxicity to the brain can produce abnormalities that are apparently life-long, and affecting a phenotypic system different from the one originally injured.…”

Development of neurological reflexes and motor coordination in rats neonatally treated with monosodium glutamate

“…A number of neurotoxicants are known to produce a delay or long-lasting impairment in neurobehavioral development, motor and cognitive functioning in newborn rats (Harry, 1998;Archer et al, 2002;Beninger et al, 2002;Reddy et al, 2002;Palomo et al, 2003). Glutamate, the major excitatory neurotransmitter in the brain, is also categorized as an excitotoxin (Segura-Aguilar and Kostrzewa, 2004).…”