Up-regulation of hippocampal glutamate transport during chronic treatment with sodium valproate.

Excessive glutamatergic neurotransmission has been implicated in some neurodegenerative disorders. It would be of value to know whether glutamate transport, which terminates the glutamate signal, can be up-regulated pharmacologically. Here we show that chronic treatment of rats with the anti-epileptic drug sodium valproate (200 mg or 400 mg/kg bodyweight, twice per day for 90 days) leads to a dose-dependent increase in hippocampal glutamate uptake capacity as measured by uptake of [(3)H]glutamate into proteoliposomes. The level of glutamate transporters EAAT1 and EAAT2 in hippocampus also increased dose-dependently. No effect of sodium valproate on glutamate transport was seen in frontal or parietal cortices or in cerebellum. The hippocampal levels of glial fibrillary acidic protein and glutamine synthetase were unaffected by valproate treatment, whereas the levels of synapsin I and phosphate-activated glutaminase were reduced by valproate treatment, suggesting that the increase in glutamate transporters was not caused by astrocytosis or increased synaptogenesis. A direct effect of sodium valproate on the glutamate transporters could be excluded. The results show that hippocampal glutamate transport is an accessible target for pharmacological intervention and that sodium valproate may have a role in the treatment of excitotoxic states in the hippocampus.

Modulatory treatment of NMDA receptors in neonatal rats affects cognitive behavior in adult age.

The glutamatergic NMDA receptor is probably involved in establishing functional connections during development, and interference may promote or impair cognitive functions in adult age. In the present study, rat pups received one daily injection of the NMDA receptor partial agonist D-cycloserine in various concentrations (3, 10, 50 mg/kg), the NMDA receptor antagonist (+/-)-HA-966 (30 mg/kg), or saline throughout postnatal days 10-20 (Experiment 1). In Experiment 2, effects of the (+)-enantiomer of HA-966 were similarly examined. The rats were tested in a novelty task in adult age (postnatal days 98-112). The results from Experiment 1 show that injections of D-cycloserine in the concentration of 10 mg/kg or (+/-)-HA-966 caused a slight increase in locomotor activity only. The results from Experiment 2 show that (+)-HA-966-treated rats displayed reduced preference for novelty, a slight reduction in exploratory activity and locomotor behavior, and increased rate of grooming. These results suggest that neonatal treatment with (+)-HA-966 can impair cognitive behavior in adult life. It was not possible to record any effects on cognitive function after neonatal administration of the glutamatergic agonist D-cycloserine.

Neurotoxicity of albumin in vivo.

The neurotoxicity of albumin was studied in the rat. Solutions of rat albumin (3, 10 and 30 mg/ml) essentially free of fatty acids and globulins were injected into one neostriatum, physiological saline into the other. Injections were also performed with sodium glutamate (10 and 30 mM). Both albumin and glutamate produced lesions in a concentration-dependent manner. Thus 3, 10 and 30 mg/ml albumin produced lesions in excess of saline of 22 +/- 24 microns3, 67 +/- 25 microns3 and 170 +/- 44 microns3, (P = 0.82, 0.03 and 0.0005, respectively). 10 and 30 mM sodium glutamate caused lesions of 45 +/- 14 microns3 and 315 +/- 56 microns3 in excess of saline (P = 0.04 and 0.0004, respectively). Injection of 10 mg/ml albumin together with 10 mM sodium glutamate caused lesions of 70 +/- 11 microns3 in excess of saline (P = 0.005). This was not significantly different from the lesions caused by any of the two substances alone. Thus no potentiating effect of one substance on the toxicity of the other was seen in this study. The neurotoxicity of albumin could be of importance in disease states which are accompanied by leakiness of the blood-brain barrier.

Differential rearing conditions in rats: effects on neurochemistry in neocortical areas and cognitive behaviors.

Previous studies have shown that environmental factors can influence several aspects of the central nervous system that are associated with behavioral changes. In the present study, an attempt was made to investigate how cholinergic and glutamergic transmission systems in neocortical areas might respond to differential rearing conditions and how potential neurochemical changes might be accompanied by alterations in behavior. The results show that only glutamergic levels in the lateral entorhinal cortex (LEC) responded to differential environmental stimulation. The levels of glutamergic activity in LEC correlated significantly with learning and retention of a visual discrimination task and total time exploring objects in a novelty test. A comparatively complex pattern of neurochemical relations was seen in terms of differences across brain structures and hemispheres for both glutamergic and cholinergic activity. The results are interpreted as supporting the glutamergic hypothesis of Alzheimer's disease.

Inhibition of L-glutamate uptake into synaptic vesicles.

The effects of different agents similar in structure to glutamate were tested for inhibition of the vesicular uptake of L-glutamate. Kainate and L-homocysteate turned out to be non-competitive inhibitors of the L-glutamate uptake. Kainate was not taken up by the vesicle fraction. The vesicular uptake of gamma-aminobutyric acid (GABA) was also inhibited by kainate and L-homocysteate. Kynurenate, on the other hand, strongly inhibited the uptake of L-glutamate, whereas the uptake of GABA was hardly affected. L-alpha-Aminoadipate and D-glutamate inhibited the uptake of L-glutamate, whereas L- and D-aspartate and L-cysteate only weakly inhibited the uptake of L-glutamate. GABA, glycine, L-serine and taurine did not inhibit the uptake of L-glutamate.

Changes in retention of a visual discrimination task following unilateral and bilateral transections of temporo-entorhinal connections in rats.

In a previous study, it was shown that the lateral entorhinal cortex (LEC) in the left hemisphere contains higher concentration of glutamate than in the right hemisphere. The purpose of the present study was to examine potential relationship between this neurochemical asymmetry and behavior. Rats with either left, right, or bilateral transections of the fiber connections between the temporal cortex and LEC were tested for postoperative retention of a visual discrimination task. Because histological verification of lesions was crucial in this study, analyses of neurochemistry had to be omitted. The results showed that both left and bilateral lesions resulted in impaired retention, but the bilateral group was even more impaired than the left group. The rats with lesions in the right hemisphere, however, used fewer trials to reach the learning criterion than the control group, but they did not make fewer errors than the controls. The results are discussed in terms of lateralization of mnemonic processes.

Impaired reference memory and reduced glutamergic activity in rats with temporo-entorhinal connections disrupted.

The purpose of the present study was to investigate whether effects of temporo-entorhinal disconnections on acquisition and retention of a visual discrimination task might be associated with neurochemical dysfunctions. The results revealed that the present lesions impaired both acquisition and retention of the discrimination task. This impairment was accompanied by decreased glutamergic activity in both temporal and entorhinal cortices. No changes were seen in levels of acetylcholine or GABA. Further, the distribution of glutamate/aspartate was related to both regional and hemispheric differences. The results are discussed in terms of a highly integrative role of the lateral entorhinal cortex and in terms of other putative neurotransmitter systems involved in the function of memory.