Ho

chohchgoh chohchgoh

3-hydroxy-4-methoxyphenyl glycol (MOPEG)

Dopamine

Dopamine

Dlhydroxyphenylacatic acid ho ho chgcoc u h3c ho

Homovanillic acid (HVA)

Homovanillic acid (HVA)

Figure 2.16. Pathways for the synthesis and metabolism of the catecholamines. A=phenylalanine hydroxylase+pteridine cofactor+O2; B=tyrosine hydroxylase+ tetrahydropteridine+Fe+++O2; C=dopa decarboxylase+pyridoxal phosphate; D= dopamine beta-oxidase+ascorbate phosphate+Cu+++O2; E=phenylethanolamine n-methyltransferase+s-adenosylmethionine; 1=monoamine oxidase and aldehyde dehydrogenase; 2=catechol-o-methyltransferase+s-adenosylmethionine.

prevent the peripheral catabolism of L-dopa (levodopa) in patients being treated for parkinsonism. As these drugs do not penetrate the blood-brain barrier they will prevent the peripheral decarboxylation of dopa so that it can enter the brain and be converted to dopamine by dopamine beta-oxidase (also called dopamine beta-hydroxylase).

Dopamine beta-oxidase inhibitors are only of limited clinical use at the present time, probably due to their relative lack of specificity. Diethyldithio-carbamate and disulfiram are examples of drugs that inhibit dopamine beta-oxidase by acting as copper-chelating agents and thereby reducing the availability of the cofactor for this enzyme. Whether their clinical use in the treatment of alcoholism is in any way related to the reduction in brain catecholamine concentrations is uncertain. The main action of these drugs is to inhibit liver aldehyde dehydrogenase activity, thereby leading to an accumulation of acetaldehyde, and the onset of nausea and vomiting, should the patient drink alcohol.

Two enzymes are concerned in the metabolism of catecholamines, namely monoamine oxidase, which occurs mainly intraneuronally, and catechol-O-methyltransferase, which is restricted to the synaptic cleft. The importance of the two major forms of monoamine oxidase, A and B, will be considered elsewhere.

The process of oxidative deamination is the most important mechanism whereby all monoamines are inactivated (i.e. the catecholamines, 5-HT and the numerous trace amines such as phenylethylamine and tryptamine). Monoamine oxidase occurs in virtually all tissues, where it appears to be bound to the outer mitochondrial membrane. Whereas there are several specific and therapeutically useful monoamine oxidase inhibitors, inhibitors of catechol-O-methyltransferase have found little application. This is mainly due to the fact that at most only 10% of the monoamines released from the nerve terminal are catabolized by this enzyme. The main pathways involved in the catabolism of the catecholamines are shown in Figure 2.16.

Anatomical distribution

One of the first demonstrations of the central monoamine pathways in the mammalian brain was by a fluorescence technique in which thin sections of the animal brain were exposed to formaldehyde vapour which converted the amines to their corresponding fluorescent isoquinolines. The distribution of these compounds could then be visualized under the fluorescent microscope. Using this technique it has been possible to map the distribution of the noradrenergic, dopaminergic and serotonergic pathways in the animal and human brain.

The central noradrenergic system. This is not so diffusely distributed as the cholinergic system. In the lower brainstem, the neurons innervate the medulla oblongata and the dorsal vagal nucleus, which are thought to be important in the central control of blood pressure. Other projections arising from cell bodies in the medulla descend to the spinal cord where they are believed to be involved in the control of flexor muscles. However, the most important noradrenergic projections with regard to psychological functions arise from a dense collection of cells in the locus coeruleus and ascend from the brainstem to innervate the thalamus, dorsal hypothalamus, hippocampus and cortex. The ventral noradrenergic bundle occurs caudally and ventrally to the locus coeruleus and terminates in the hypothalamus and the subcortical limbic regions. The dorsal bundle arises from the locus coeruleus and innervates the cortex. Both the dorsal and ventral noradrenergic systems appear to be involved psychologically in drive and motivation, in mechanisms of reward and in rapid eye movement (REM) sleep. As such processes are severely deranged in the major affective disorders it is not unreasonable to speculate that the central noradrenergic system is defective in such disorders. The distribution of the noradrenergic tracts in the human brain is shown in Figure 2.17.

The central dopaminergic systems. These are considerably more complex than the noradrenergic system. This may reflect the greater density of dopamine-containing cells, which have been estimated to be 30-40000 in number compared with 10 000 noradrenaline-containing cells. There are several dopamine-containing nuclei as well as specialized dopaminergic neurons localized within the retina and the olfactory bulb. The dopaminergic system within the mammalian brain can be divided according to the length of the efferent fibres into the intermediate and long length systems.

The intermediate length systems include the tuberoinfundibular system, which projects from the arcuate and periventricular nuclei into the intermediate lobe of the pituitary and the median eminence. This system is responsible for the regulation of such hormones as prolactin. The interhypothalamic neurons send projections to the dorsal and posterior hypothalamus, the lateral septal nuclei and the medullary periventricular group, which are linked to the dorsal motor nucleus of the vagus; such projections may play a role in the effects of dopamine on the autonomic nervous system.

The long length fibres link the ventral tegmental and substantia nigra dopamine-containing cells with the neostriatum (mainly the caudate and the putamen), the limbic cortex (the medial prefrontal, cingulate and entorhinal areas) and with limbic structures such as the septum, nucleus accumbens, amygdaloid complex and piriform cortex. These projections are usually called the mesocortical and mesolimbic dopaminergic systems, respectively, and are functionally important in psychotic disorders and in the therapeutic effects of neuroleptic drugs. Conversely, changes in the functional activity of the dopaminergic cells in the neostriatum are primarily responsible for movement disorders such as Parkinsonism and Huntington's chorea.

The central adrenergic system. It is only recently that immunohistochemical methods have been developed to show that adrenaline-containing cells occur in the brain. Some of these cells are located in the lateral tegmental area, while others are found in the dorsal medulla. Axons from these cells innervate the hypothalamus, the locus coeruleus and the dorsal motor nucleus of the vagus nerve. While the precise function of adrenergic system within the brain is uncertain, it may be surmized that adrenaline could play a role in endocrine regulation and in the central control of blood pressure. There is evidence that the concentration of this amine in cerebrospinal fluid

Figure 2.17. Diagrammatic representation of central noradrenergic pathways.

is reduced in depression, which might imply that it is also concerned in the control of mood.

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