By R. Mitch. Massachusetts College of Pharmacy and Health Sciences.

TH can bring about both these reactions but the extent to which this happens in vivo is uncertain order evista 60 mg without a prescription. In all catecholamine-releasing neurons, transmitter synthesis in the terminals greatly exceeds that in the cell bodies or axons and so it can be inferred Figure 8. The hydroxylation of the amino acid, tyrosine, which forms dihydroxyphenylalanine (DOPA) is the rate-limiting step. Conversion of dopamine to noradrenaline is effected by the vesicular enzyme, dopamine-b-hydroxylase (DbH) after uptake of dopamine into the vesicles from the cell cytosol 168 NEUROTRANSMITTERS, DRUGS AND BRAIN FUNCTION that all the factors (enzymes and storage vesicles) which are vital for this process undergo axoplasmic transport after their assembly in the cell body. It was recognised as early as the 1960s that conversion of tyrosine to l-DOPA was the rate-limiting step in the synthesis of noradrenaline. This emerged from experiments showing that incubation of tissues with high concentrations of tyrosine had no effect on the rate of synthesis of noradrenaline, whereas incubation with high concentrations of l-DOPA or dopamine increased it. More evidence came from experiments showing that the rate of conversion of [3H]tyrosine to [3H]DOPA was increased if the sympathetic nerves innervating the test tissue were stimulated, whereas stimulation of nerves innervating tissues incubated in a medium containing [3H]DOPA did not accelerate synthesis of [3H]dopamine or [3H]noradrenaline. Because the enzymes, DOPA decarboxylase and DbH, have a high affinity for their substrates, neither l-DOPA nor dopamine accumulate in noradrenergic nerve terminals under normal conditions. It is thought that DbH can also be rate-limiting during periods of intense or prolonged impulse-evoked release of noradrenaline. This is because a high release rate compromises the supply of vesicles that not only store and release noradrenaline but are also the site of its synthesis after uptake of dopamine from the cytosol. Evidence suggests that vesicular uptake of dopamine is reduced after periods of intense neurotransmission; this results in its accumulation in the cytosol until new vesicles are delivered to the terminals. TH is a mixed-function oxidase with an absolute requirement for reduced pterin co- factor, 6R-tetrahydrobiopterin, molecular oxygen and Fe2‡. The K of the enzyme for m its substrate is thought to be well below tissue concentrations of tyrosine and so the enzyme is probably normally about 80% saturated. This makes it unlikely that the supply of tyrosine limits enzyme activity and synthesis of noradrenaline under normal circumstances. However, it was clear from the earliest studies of noradrenergic neurons that the synthesis of noradrenaline was increased during neuronal activity, whether this is induced pharmacologically (e. Such findings suggested that synthesis and release are coupled in some way.

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In contrast to these excitatory effects elevating brain histamine levels with metoprine generic evista 60mg mastercard, an inhibitor of histamine-N-methyltransferase protects rodents against maximal electroshock although the specificity of the effect remains to be established. Agonists and antagonists at the H3 autoreceptors, which should decrease and increase histamine release, have been shown to augment and reduce slow-wave sleep in rats and cats. There are in fact numerous demonstra- tions of this using tests which require visual±motor coordination such as vigilance tasks and finger tapping. Since the slowing of such function could result from retarding information processing in the visual cortex it is interesting that the latency of com- ponents of the evoked potential, which follows presentation of a changing (reversing) black and white checkerboard pattern, is prolonged significantly in humans by the H1 antagonist diphenhydramine, which enters the brain, but not by terfenedine which does not (Tharion, McMenemy and Rauch 1994). There is also some evidence that histamine may be involved in food and water intake and thermoregulation (see Hough and Green 1983). NEUROSTEROIDS Neurosteroids differ from nearly all the other transmitters and mediators in that they are lipid-soluble and can easily cross the blood±brain barrier. Thus it is necessary to distinguish those steroids that are produced in the brain from those that find their way there from the circulation after being released from the adrenal cortex or gonads. There are many natural and synthetic steroids that have some effect on neuronal function and can be considered neuroactive but few are actually produced in the brain to act on neurons, i. This also applies to tetrahydrodeoxycorticosterone for although it is formed by reduction of deoxycorticosterone within the brain, its synthesis depends on that steroid coming from the blood. The chemical structures and interrelationship of the neurosteroids listed in (b) and (c) above are shown in Fig. PREG and DHEA are known as 3b-hydroxy-D5-steroids and are also found in peripheral glands as intermediaries between cholesterol and active steroids such as PROG and testosterone. It seems that cholesterol may be the starting point of neurosteroid synthesis in the brain. Cytochrome P450scc, the specific hydroxylase needed for cleavage of the cholesterol side-chain to give PREG, has been found widely in white matter and in myelinating oligodendrocytes, but not in neurons. Enzymes are present for the conversion of PREG to PROG and both are reduced in glia and neurons.

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