Inhibitory transmitters

Nevertheless, useful information can be deduced from patterns of distribution. Glycine is concentrated more in the cord than cortex and in ventral rather than dorsal grey or white matter. This alone would be indicative of a NT role for glycine in the ventral horn, where it is now believed to be the inhibitory transmitter at motoneurons. GABA, on the other hand, is more concentrated in the brain than in the cord and in the latter it is predominantly in the dorsal grey so that although it is an inhibitory transmitter like glycine it must have a different pattern of activity. 

Many lines of evidence. .. make it seem probable that GABA is a major inhibitory transmitter in the vertebrate central nervous system . 

This hypothesis, similarly, proposes that physical activity increases tryptophan transport into the presynaptic neurone, where it is used to synthesise 5-hydroxytryptamine. Hence, when the nerve is stimulated, more 5-hydroxytryptamine is released into the synapse and, if this is another inhibitory transmitter in the motor control pathway, it will inhibit contraction (Figure 13.28). This is one of several effects of 5-hydroxytryptamine in the brain which are probably achieved via different receptors on different neurones. All three hypotheses are summarised in Figure 13.29. 

Neurotransmitters can either excite or inhibit the activity of a cell with which they are in contact. When an excitatory transmitter such as acetylcholine, or an inhibitory transmitter such as GABA, is released from a nerve terminal it diffuses across the synaptic cleft to the postsynaptic membrane, where it activates the receptor site. Some receptors, such as the nicotinic receptor, are directly linked to sodium ion channels, so that when acetylcholine stimulates the nicotinic receptor, the ion channel opens to allow an exchange of sodium and potassium ions across the nerve membrane. Such receptors are called ionotropic receptors. 

The side effects of the MAOIs include, somewhat surprisingly, orthostatic h)rpotension. This is thought to be due to the accumulation of dopamine in the sympathetic cervical ganglia where it acts as an inhibitory transmitter. 

So far attention has concentrated on the effects of lithium on excitatory transmitters. There is evidence that the drug can also facilitate inhibitory transmission, an effect that has been attributed to a desensitization of the pres)maptic gamma-aminobutyric acid (GABA) receptors, which results in an increase in the release of this inhibitory transmitter. The increased conversion of glutamate to GABA may also contribute to this process. Thus it would appear that lithium has a varied and complex action on central neurotransmission, the net result being a diminution in the activity of excitatory transmitters and an increase in GABAergic function. 

The mechanism of action of valproate is complex and still the subject of uncertainty. The drug appears to act by enhancing GABAergic function. Thus it increases GABA release, inhibits catabolism and increases the density of GABA-B receptors in the brain. There is also evidence that it increases the sensitivity of GABA receptors to the action of the inhibitory transmitter. Other actions that may contribute to its therapeutic effects include a decrease in dopamine turnover, a decrease in the activity of the NMDA-glutamate receptors and also a decrease in the concentration of... 

GABA acts as an inhibitory transmitter in many different CNS pathways. It is subsequently destroyed by a transamination reaction (see Section 15.6) in which the amino group is transferred to 2-oxoglutaric acid, giving glutaric acid and succinic semialdehyde. This also requires PLP as a cofactor. Oxidation of the aldehyde group produces succinic acid, a Krebs cycle intermediate. 

Ionotropic receptors (bottom left) are ligand-gated ion channels. When they open as a result of the transmitter s influence, ions flow in due to the membrane potential (see p. 126). If the inflowing ions are cations (Na"", C, Ca ""), depolarization of the membrane occurs and an action potential is triggered on the surface of the postsynaptic cell. This is the way in which stimulatory transmitters work (e.g., acetylcholine and glutamate). By contrast, if anions flow in (mainly Cl ), the result is hyperpolarization of the postsynaptic membrane, which makes the production of a postsynaptic action potential more dif cult. The action of inhibitory transmitters such as glycine and GABA is based on this effect. 

Biogenic amines arise from amino acids by decarboxylation (see p. 62). This group includes 4-aminobutyrate (y-aminobutyric acid, GABA), which is formed from glutamate and is the most important inhibitory transmitter in the CNS. The catecholamines norepinephrine and epinephrine (see B), serotonin, which is derived from tryptophan, and histamine also belong to the biogenic amine group. All of them additionally act as hormones or mediators (see p. 380). 

Pharmacology Benzodiazepines appear to potentiate the effects of gamma-aminobutyrate (GABA) (ie, they facilitate inhibitory GABA neurotransmission) and other inhibitory transmitters by binding to specific benzodiazepine receptor sites. 

GABA is the principal inhibitory transmitter in the brain exerting a direct depressant effect on neurons by hyperpolarization and reducing release... 

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