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The glutamate system is involved in many aspects of neuronal synaptic strength and function during development and throughout life. Synapse formation in early brain development, synapse maintenance, and synaptic plasticity are all influenced by the glutamate system. The number of neurons and the number of their connections are determined by the activity of the glutamate system and its receptors. Malfunctions of the glutamate system affect neuroplasticity and can cause neuronal toxicity. In schizophrenia, many glutamate-regulated processes seem to be perturbed. Abnormal neuronal development, abnormal synaptic plasticity, and neurodegeneration have been proposed to be causal or contributing factors in schizophrenia. Interestingly, it seems that the glutamate system is dysregulated and that N-methyl-D-aspartate receptors operate at reduced activity. Here we discuss how the molecular aspects of glutamate malfunction can explain some of the neuropathology observed in schizophrenia, and how the available treatment intervenes through the glutamate system.
Copyright 2002 Elsevier Science Inc.
This study investigates whether ethanol affects the cardiovascular changes evoked by the excitatory amino acid glutamate in the nucleus of the solitary tract (NTS). Male Sprague-Dawley rats were anesthetized with urethane and instrumented for microinjection of drugs into the NTS. In 28 animals, an initial dose-response curve for glutamate (37, 74, and 148 pmol/60 nL) was obtained. In eight animals (control group), the dose-response curve was unchanged when it was tested after microinjection of 60 nL of saline into the NTS. In contrast, the prior intra-NTS administration of ethanol (25 or 50 mM) consistently inhibited the hypotensive and bradycardic effects of glutamate. The specificity of this inhibitory response was corroborated by the inability of intra-NTS administrations of ethanol (50 mM) to affect the hypotensive and bradycardic responses to nicotine (922 pmol. 1.84 nmol, and 3.96 nmol). These results indicate that the cardiovascular effects of glutamate can be antagonized by ethanol in the NTS. This inhibitory effect, in turn, may provide a basis for the hypertensinogenic action of ethanol in humans.
Metabotropic glutamate receptors (mGluRs) are a novel family of recently cloned G protein-coupled receptors. These receptors are heterogeneous and coupled to multiple second messenger systems that include increases in phosphoinositide hydrolysis, activation of phospholipase D, decreases in cAMP formation, increases in cAMP formation, and changes in ion channel function. Using the selective mGluR agonist 1-aminocyclopentane-1,3-dicarboxylic acid (1s,3R-ACPD), considerable progress has been made towards understanding the role of this glutamate receptor class in the central nervous system. This article reviews the molecular aspects and pharmacology of mGluRs, and recent studies elucidating their role in brain function and pathology.
Electrical stimulation of the lateral septum results in a transient cardiodeceleration which may represent parasympathetic rebound to a brief sympathetic activation. Kainic acid (KA) is a potent neuronal excitant. Stimulation of the lateral septum by KA produced a short-latency tachycardia. Vehicle injections, as well as KA administration to adjacent structures, did not effect significant changes in heart rate. Intraventricular KA, however, did result in a significant tachycardia. Knife cuts of the fornix, interrupting the glutamatergic innervation of the septum, completely blocked the cardiovascular response to KA. Pharmacological treatments reducing sympathetic activity prevented or reversed KA-elicited tachycardia. Thus, it appears that septal administration of KA produces sympathetic activation. KA may serve as a useful tool in studies assessing central regulation of the autonomic nervous system, and the interrelationship between autonomic activity and seizure-induced neuronal loss.
To permit a molecular characterization of neurotransmitter transporter proteins, we have studied uptake activities induced in Xenopus laevis oocytes after injection of adult rat forebrain, cerebellum, brainstem, and spinal cord poly(A)+ RNA. L-Glutamate uptake could be observed as early as 24 hr after injection, was linearly related to the quantity of mRNA injected, and could be induced after injection of as little as 1 ng of cerebellar mRNA. Transport of radiolabeled L-glutamate, gamma-aminobutyric acid, glycine, dopamine, serotonin, and choline could be measured in single microinjected oocytes with a regional profile consistent with the anatomical distribution of particular neurotransmitter synthesizing soma. Forebrain L-glutamate and dopamine uptake, as well as cerebellar L-glutamate transport, were found to be Na+-dependent. Cerebellar mRNA-induced L-glutamate transport was both time and temperature-dependent, was saturable by substrate, suggesting a single activity with an apparent transport Km of 14.2 microM and a Vmax of 15.2 pmol/hr per oocyte, and was sensitive to inhibitors of brain L-glutamate transport. Thus, the oocyte L-glutamate transport induced by injection of adult rat cerebellar mRNA appears essentially identical to the high-affinity, Na+-dependent L-glutamate uptake found in brain slices and nerve terminals. Experiments with size-fractionated cerebellar mRNA reveal single, comigrating peaks for cerebellar L-glutamate and gamma-aminobutyric acid transport, with peak activity obtained in fractions of approximately 2.7 kilobases, suggesting the presence of single or similarly sized mRNAs encoding each of these activities.