Direct intracerebral administration of N-methyl-D-aspartate typically produces focal brain injury. (+)-5-Methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-immi ne maleate (MK-801), a non-competitive N-methyl-D-aspartate antagonist, can protect against N-methyl-D-aspartate-mediated brain injury when administered shortly before or after an intracerebral injection of N-methyl-D-aspartate. However, in this study we report that in perinatal rats if MK-801 (1 mg/kg) is administered intraperitoneally 24 h prior to a unilateral intrastriatal N-methyl-D-aspartate injection, N-methyl-D-aspartate-mediated brain injury is paradoxically enhanced. The severity of resulting brain injury is 15-25% greater in groups that received MK-801 in comparison with saline-treated controls (P less than 0.001, linear regression analysis). In contrast, the severity of brain injury resulting from intrastriatal injection of the glutamate agonist quisqualate is not altered by a similar 24 h MK-801 pretreatment. Furthermore, the enhanced toxicity of N-methyl-D-aspartate produced by a 24 h pretreatment with MK-801 is completely blocked if a second dose of MK-801 is administered 15 min after the intrastriatal injection of N-methyl-D-aspartate. To determine if MK-801 produced alterations in glutamate receptor pharmacology co-incident with the enhanced toxicity of N-methyl-D-aspartate, in vitro quantitative autoradiography for excitatory amino acid receptor subtypes was performed with [3H]glutamate and [3H]N-1-(2-thienyl)cyclohexyl-3,4-piperidine in seven-day-old rats killed 2 or 24 h after MK-801 (1 mg/kg) administration. A 2 h MK-801 pretreatment produced a 30-50% increase in [3H]glutamate binding at N-methyl-D-aspartate preferring recognition sites in all four brain regions examined (areas CA1 and CA3 of the hippocampus, corpus striatum, cingulate cortex) in comparison with saline-treated controls (P less than 0.05, ANOVA). [3H]N-1-(2-Thienyl)cyclohexyl-3,4-piperidine binding to the phencyclidine site associated with the N-methyl-D-aspartate receptor was reduced by 60-80% in all brain regions examined (P less than 0.001). Quisqualate-sensitive [3H]glutamate binding was not altered by a 2 h MK-801 pretreatment. In animals that received a 24 h MK-801 pretreatment.(ABSTRACT TRUNCATED AT 400 WORDS)
The activity-dependent mechanism that refines the topography of the retinotectal projection in frogs is mediated by the NMDA receptor. Earlier studies found that chronic treatment of the optic tectum with the NMDA receptor antagonist DL-2-amino-5-phosphonovaleric acid (DL-AP5) desegregated eye-specific stripes in three-eyed frogs, while chronic treatment with NMDA sharpened stripe borders (Cline et al., 1987; Cline and Constantine-Paton, 1990). We now report that this same chronic treatment with NMDA decreases the electro-physiologically measured sensitivity of the optic tectum to applied NMDA: acute application of a given concentration of NMDA decreased the evoked tectal potential to a lesser extent in animals chronically treated with NMDA than it did in normal and sham-treated animals. This is observed as a shift to the right in the NMDA dose-response curves for both the positive and negative postsynaptic components of the evoked tectal response. We believe that this decreased NMDA receptor effectiveness further restricts the intermingling of axon branches from the two eyes by limiting synapse stabilization to areas where afferent activity is most correlated. This would account for the anatomical sharpening of stripe borders (i.e., increased afferent segregation). Quantitative autoradiographic analysis of 3H-glutamate binding to NMDA receptors indicated that binding densities within the tectum did not differ between control groups and NMDA chronically treated groups. We suggest that in the experimental animals the response to NMDA may be decreased by a change in the effectiveness of individual NMDA receptors rather than by decreases in receptor number. This experimentally induced change may be analogous to naturally occurring decreases in receptor function that correlate with the end of some periods of visual plasticity in mammals.
Thyroxine levels in serum of lambs and ewes were measured to determine their usefulness in assessing iodine nutrition of sheep. Lambs born on properties with no history of goitre had serum thyroxine concentrations more than twice that recorded in their mothers. These high values decreased to a level similar to that in the ewes after 8 weeks. In goitrous lambs younger than 2 weeks old, serum thyroxine concentrations were less than their ewe levels. Lambs born to ewes supplemented with iodine during pregnancy had higher thyroxine levels than lambs of control ewes. A survey of 80 flocks of ewes in Victoria showed that 40% had a low mean thyroxine concentration (less than 50 nmol/l), but only one of these properties had reported an outbreak of goitre. It is suggested that serum thyroxine levels in newborn lambs may provide a more sensitive indicator of hypothyroidism associated with iodine deficiency than ewe levels.
A trial was carried out to determine whether selenium responsive unthriftiness existed on a property in the Strathbogie ranges of Central Victoria where unthriftiness of young sheep has been a problem for 10 to 20 years. White muscle disease had been diagnosed on the property in the previous year and on other properties in the area. Eighty Merino ewes and lambs were allotted to one of 4 groups in a 2 x 2 factorial designed trial in which sodium selenite (0.1 mg/kg) was given orally to ewes and/or lambs at marking time and to treated lambs at 3 monthly intervals thereafter. Selenium treatment of the ewes had no significant effect on subsequent lamb performance. Selenium treatment of the lambs produced significant responses: mortality in treated groups was 0% compared with 17.5% in untreated groups; body weight gains were 1.9 kg higher at both weaning and one year of age in treated than in untreated lambs; mean fleece weight was 14.4% higher in treated lambs and they produced 39% more wool than the surviving untreated lambs.
Autoradiographic methods were used to map NMDA- and quisqualate-sensitive glutamate binding sites in the brain of mature and juvenile Rana pipiens frogs. NMDA- and quisqualate-sensitive sites were consistently co-localized in the CNS. The highest glutamate binding occurred in the telencephalon, hypothalamus, and cerebellum. Glutamate binding sites were also specifically localized in visual pathways, including the superficial neuropil of the optic tectum, consistent with glutamate being the retinal ganglion cell neurotransmitter. The distribution of glutamate binding sites in the brain of juvenile postmetamorphic frogs was similar to that in adults. In general, Quis binding increased about twofold in adults compared to juveniles, whereas NMDA binding did not show a comparable developmental increase. To test whether glutamate binding sites are located on retinal axon terminals or on tectal cell dendrites in the optic tectum, juvenile postmetamorphic frogs were enucleated unilaterally, and receptor binding was performed following 1, 3, 7, and 14 days survival. The denervated tectal neuropil showed a delayed decrease in NMDA- and quisqualate-sensitive binding, consistent with the receptors being located on postsynaptic tectal cell dendrites.
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