Glutamate system function

Abnormalities of the glutamate system have also been documented in neuropsychiatric disorders. For example, compounds such as PCP and ketamine, which block the NMDA receptor, can induce psychotic symptoms. By contrast, compounds such as d-cycloserine or glycine, which increase NMDA receptor function via the glycine binding site, can decrease psychotic and/or negative symptoms in schizophrenia (Farber et ah, 1999 Goff et ah, 1999, Fleresco-Levy et ah, 1999). 

Ibotenic acid is structurally similar to glutamic acid, whereas muscimol closely resembles gamma-aminobutyric acid (GABA). Muscimol has an affinity for GABA receptors in the central nervous system, functioning as a false neurotransmitter, and appears to mimic the effects of GABA. 

Canaline is the product of the hydrolytic cleavage of canavanine with the simultaneous formation of urea. Canaline is an ornithine analogue which also shows neurotoxicity in the adult sexta where it adversely affects central nervous system functions (jj ). It also is a potent inhibitor of vitamin B -containing enzymes (20-22). It forms a stable Schiff base with the pyridoxal phosphate moiety of the enzyme and drastically curtails enzymatic activity. Pyridoxal phosphate-containing enzymes are vital to insects because they function in many essential transamination and decarboxylation reactions. Ornithine is an important metabolic precursor for insect production of glutamic acid and proline (23). 

To imderstand the actions of domoic acid in the nervous system, we must recognize its structural similarities with glutamic acid (see Figure 1). While most people not familiar with nervous system function think of glutamate as a simple amino acid that participates in biochemical pathways (e.g. feeding carbon atoms into the... 

Wu J -Y (1976) Purification and properties of L-glutamate decarboxylase (GAD) and GABA-aminotransferase (GABA-T), in GABA m Nervous System Function (Roberts E, Chase T. and Tower D., eds.), pp 7-55. Raven Press, New York, N Y. 

A special case of stepwise amino acid addition is repeated condensation to arrive at polymer structures. Such systems functioning in analogy to. for example, polyhydroxybu-tyrate-forming enzymes produce, for example, poly-D-glutamic acids (40,41), and they presumably are related to the polyenzyme type of peptide synthetases. These enzymes, condensing 3-carboxyl-groups, produce a size-defined polymer of about 10 Da. Other systems may produce poly-Lys chains of much smaller size, 25 residues (42). Even branched peptide-forming systems have been reported (43). None of these systems has been characterized in detail. 

The ammonia produced by enteric bacteria and absorbed into portal venous blood and the ammonia produced by tissues are rapidly removed from circulation by the liver and converted to urea. Only traces (10—20 Ig/dL) thus normally are present in peripheral blood. This is essential, since ammonia is toxic to the central nervous system. Should portal blood bypass the liver, systemic blood ammonia levels may rise to toxic levels. This occurs in severely impaired hepatic function or the development of collateral links between the portal and systemic veins in cirrhosis. Symptoms of ammonia intoxication include tremor, slurred speech, blurred vision, coma, and ultimately death. Ammonia may be toxic to the brain in part because it reacts with a-ketoglutarate to form glutamate. The resulting depleted levels of a-ketoglutarate then impair function of the tricarboxylic acid (TCA) cycle in neurons. 

After an overview of neurotransmitter systems and function and a consideration of which substances can be classified as neurotransmitters, section A deals with their release, effects on neuronal excitability and receptor interaction. The synaptic physiology and pharmacology and possible brain function of each neurotransmitter is then covered in some detail (section B). Special attention is given to acetylcholine, glutamate, GABA, noradrenaline, dopamine, 5-hydroxytryptamine and the peptides but the purines, histamine, steroids and nitric oxide are not forgotten and there is a brief overview of appropriate basic pharmacology. 

Normally (Fig. 15.2(a)) DA inhibits the Ind Path to GPext so that this is then free to inhibit the SThN. This latter system can then no longer drive, through glutamate release, the SNr or GPint whose inhibitory outputs are reduced. The assumption is that the thalamo-cortical pathway can then function properly and movement is normal. 

Apart from dopamine many NTs such as glutamate, GABA, various peptides, adenosine and ACh are all involved in striatal function but their wide distribution in the CNS makes it difficult to restrict any manipulation of their activity to the striatum after systemic drug administration. 

Possibly increased DA function is not the actual cause of schizophrenia and its symptoms are just mediated by normally functioning DA systems that appear overactive because of the loss of some counteracting function or other NT(s). To date there is no evidence to fully implicate any other NT but there is growing interest in 5-HT and glutamate (see below). 

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