It has been particularly difficult to prove that amino acids are true neurotransmitters; they are present in high concentrations because of their other metabolic roles, and therefore simple measurement of their concentrations did not provide conclusive evidence. Pharmacologic studies of responses to different analogs and the cloning of specific receptors finally provided the proof.
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| Glutamate is the most important excitatory transmitter in the CNS
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| It acts on both ionotropic and metabotropic receptors. Clinically, the receptor characterized in vitro by N-methyl- d-aspartate (NMDA) binding is particularly important (Fig. 40.5).
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| Figure 40.5 The NMDA glutamate receptor. The glutamate receptor that binds N-methyl-l-aspartate (NMDA) is complex. This receptor is clinically important because it may cause damage to neurons after stroke (excitotoxicity, see following page). It contains several modulatory binding sites, so it may be possible to develop drugs that could alter its function. Glycine is an obligatory cofactor, as are polyamines such as spermine. Magnesium physiologically blocks the channel at the resting potential, so the channel can open only when the cell has been partially depolarized by a separate stimulus. It therefore causes a prolongation of the excitation. This receptor also binds phencyclidine (PCP). Because this drug of abuse can cause psychotic symptoms, it is possible that dysfunction of pathways involving NMDA receptors causes some of the symptoms of schizophrenia. |
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| Figure 40.6 Limbic system. The limbic system of the brain is involved in emotions and memory. It consists of various areas surrounding the upper brain stem, including the hippocampus, the amygdaloid body, and the cingulate gyrus. Removal of the hippocampus prevents the laying down of short-term memory, whereas intact amygdaloid function is required for the emotion of fear. |
| The hippocampus (Fig. 40.6) is an area of the limbic system of the brain that is involved in emotion and memory. Certain synaptic pathways there become more active when chronically stimulated - a phenomenon known as long-term potentiation. This represents a possible model of how memory is laid down, and it requires activation of the NMDA receptor and the consequent influx of calcium.
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| Glutamate is recycled by high-affinity transporters into both neurons and glial cells. The glial cells convert it into glutamine, which then diffuses back into the neuron. Mitochondrial glutaminase in the neuron regenerates glutamate for reuse.
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| Glutamate and Excitotoxicity
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| Extracellular glutamate concentration is increased after trauma and stroke, during severe convulsions, and in some organic brain diseases such as Huntington's chorea, AIDS-related dementia, and Parkinson's disease, because of release of glutamate from damaged cells and damage to the glutamate uptake pathways.
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| Excess glutamate is toxic to nerve cells
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| The NMDA receptor is activated, which allows calcium entry into cells. This activates various proteases, which in turn initiate the pathway of programmed cell death, or apoptosis (see also Chapter 29). There may, in addition, be changes in other ionotropic glutamate receptors that also cause aberrant calcium uptake. Uptake of sodium ions is also implicated, and causes swelling of cells. Activation of NMDA receptors also increases the production of nitric oxide, which may in itself be toxic. Cell death in some models of excitotoxicity can be prevented by inhibitors of nitric oxide production, but the mechanism of toxicity is not clear.
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| Attempts are being made to develop drugs to inhibit NMDA activation and suppress excitotoxicity. The hope is that damage caused by stroke can be limited or even reversed. Unfortunately, many of the drugs have side effects because they bind to the phencyclidine-binding site and have unpleasant psychologic effects such as paranoia and delusions.
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| γ-Amino butyric acid (GABA)
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| GABA is synthesized from glutamate by the enzyme glutamate decarboxylase (Fig. 40.7)
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| It is the major inhibitory transmitter in the brain. There are two known GABA receptors: the GABAA receptor is ionotropic, and the GABAB receptor is metabotropic. The GABAA receptor consists of five subunits that arise from several gene families, giving an enormous number of potential receptors with different binding affinities. This receptor is the target for several useful therapeutic drugs. Benzodiazepines bind to it and cause a potentiation of the response to endogenous GABA; these drugs reduce anxiety and also cause muscle relaxation. Barbiturates also bind to the GABA receptor and stimulate it directly in the absence of GABA; because of this lack of dependence on endogenous ligand, they are more likely to cause toxic side effects in overdose.
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| Glycine is primarily found in inhibitory interneurons in the spinal cord, where it blocks impulses traveling down the cord in motor neurons to stimulate skeletal muscle. The glycine receptor on motor neurons is ionotropic and is blocked by strychnine; motor impulses can then be passed without negative control, which accounts for the rigidity and convulsions caused by this toxin.
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