Biochemical pathways leading to the synthesis and metabolism of the major neurotransmitters in the mammalian brain

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No attempt will be made to give an overview of the main pathways of the several dozen neurotransmitters, neuromodulators and co-transmitters which are possibly involved in the aetiology of mental illness. Instead a summary is given of the relevant pathways involved in the synthesis and metabolism of those transmitters which have conventionally been considered to be involved in the major psychiatric and neurological diseases and through which the psychotropic drugs used in the treatment of such diseases are believed to operate.

Acetylcholine

Acetylcholine has been implicated in learning and memory in all mammals, and the gross deficits in memory found in patients suffering from Alzheimer's disease have been ascribed to a defect in central cholinergic transmission. This transmitter has also been implicated in the altered mood states found in mania and depression, while many different classes of psychotropic drugs are known to have potent anticholinergic properties which undoubtedly have adverse consequences for brain function.

Acetylcholine is synthesized within the nerve terminal from choline (from both dietary and endogenous origins) and acetyl coenzyme A (acetyl CoA) by the enzyme choline acetyltransferase. Acetyl CoA is derived from glucose and other intermediates via the glycolytic pathway and ultimately the pyruvate oxidase system, while choline is selectively transported into the cholinergic nerve terminal by an active transport system. There are believed to be two main transport sites for choline, the high affinity site being dependent on sodium ions and ATP and which is inhibited by membrane depolarization, while the low affinity site operates by a process of passive diffusion and is therefore dependent on the intersynaptic concentration of choline. The uptake of choline by the high affinity site controls the rate of acetylcholine synthesis, while the low affinity site, which occurs predominantly in cell bodies, appears to be important for phospholipid synthesis. As the transport of choline by the active transport site is probably optimal, there seems little value in increasing the dietary intake of the precursor in an attempt to increase acetylcholine synthesis. This could be one of the reasons why feeding choline-rich diets (e.g. lecithin) to patients with Alzheimer's disease has been shown to be ineffective.

As with all the major transmitters, acetylcholine is stored in vesicles within the nerve terminal from which it is released by a calcium-dependent mechanism following the passage of a nerve impulse. The inter-relationship between the intermediary metabolism of glucose, phospholipids and the uptake of choline is summarized in Figure 2.14.

It is well established that acetylcholine can be catabolized by both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE); these are also known as ''true'' and ''pseudo'' cholinesterase, respectively. Such enzymes may be differentiated by their specificity for different choline esters and by their susceptibility to different antagonists. They also differ in their anatomical distribution, with AChE being associated with nervous tissue while BChE is largely found in non-nervous tissue. In the brain there does not seem to be a good correlation between the distribution of cholinergic terminals and the presence of AChE, choline acetyltransferase having been found to be a better marker of such terminals. An assessment of cholinesterase activity can be made by examining red blood cells, which contain only AChE, and plasma,

Die Abstraktionsleiter
Figure 2.14. Inter-relationship between intermediary metabolism of glucose, phospholipids and acetylcholine synthesis. Acetyl CoA=acetyl coenzyme A; CAT=catechol-O-methyltransferase; AChE=acetylcholinesterase.

which contains only BChE. Of the anticholinesterases, the organophosphorus derivatives such as diisopropylfluorophosphonate are specific for BChE, while drugs such as ambenonium inhibit AChE.

Most cholinesterase inhibitors inhibit the enzyme by acylating the esteratic site on the enzyme surface. Physostigmine and neostigmine are examples of reversible anticholinesterases which are in clinical use. Both act in similar ways but they differ in terms of their lipophilicity, the former being able to penetrate the blood-brain barrier while the latter cannot. The main clinical use of these drugs is in the treatment of glaucoma and myasthenia gravis.

Irreversible anticholinesterases include the organophosphorus inhibitors and ambenonium, which irreversibly phosphorylate the esteratic site. Such drugs have few clinical uses but have been developed as insecticides and nerve gases. Besides blocking the muscarinic receptors with atropine sulphate in an attempt to reduce the toxic effects that result from an accumulation of acetylcholine, the only specific treatment for organopho-sphate poisoning would appear to be the administration of 2-pyridine aldoxime methiodide, which increases the rate of dissociation of the organophosphate from the esteratic site on the enzyme surface.

Anatomical distribution of the central cholinergic system

The cholinergic pathways in the mammalian brain are extremely diffuse and arise from cell bodies located in the hindbrain and the midbrain. Of these areas, there has been considerable interest of late in the nucleus basalis magnocellularis of Meynert because this region appears to be particularly affected in some patients with familial Alzheimer's disease. As the projections from this area innervate the cortex, it has been speculated corpus r^»1™'™

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Figure 2.15. Distribution of muscarinic and nicotinic receptors in the human brain. Note the very restricted distribution of the nicotinic receptors. Cholinergic tracts arising from the magnocellular cholinergic nuclei innervate large areas of the cortex and subcortical regions.

that a disruption of the cortical cholinergic system may be responsible for many of the clinical features of the illness. The use of cholinomimetic drugs of various types to treat such diseases is discussed in a later chapter.

Figure 2.15 illustrates the distribution of the main cholinergic receptors in the human brain.

The catecholamines

Much attention has been paid to the catecholamines noradrenaline and dopamine following the discovery that their depletion in the brain leads to profound mood changes and locomotor deficits. Thus noradrenaline has been implicated in the mood changes associated with mania and depression, while an excess of dopamine has been implicated in schizophrenia and a deficit in Parkinson's disease.

Noradrenaline is the main catecholamine in postganglionic sympathetic nerves and in the central nervous system; it is also released from the adrenal gland together with adrenaline. Recently adrenaline has also been shown to be a transmitter in the hypothalamic region of the mammalian brain so, while the terms ''noradrenergic'' and ''adrenergic'' are presently used interchangeably, it is anticipated that they will be used with much more precision once the unique functions of adrenaline in the brain have been established.

The catecholamines are formed from the dietary amino acid precursors phenylalanine and tyrosine, as illustrated in Figure 2.16.

The rate-limiting step in the synthesis of the catecholamines from tyrosine is tyrosine hydroxylase, so that any drug or substance which can reduce the activity of this enzyme, for example by reducing the concentration of the tetrahydropteridine cofactor, will reduce the rate of synthesis of the catecholamines. Under normal conditions tyrosine hydroxylase is maximally active, which implies that the rate of synthesis of the catecholamines is not in any way dependent on the dietary precursor tyrosine. Catecholamine synthesis may be reduced by end product inhibition. This is a process whereby catecholamine present in the synaptic cleft, for example as a result of excessive nerve stimulation, will reduce the affinity of the pteridine cofactor for tyrosine hydroxylase and thereby reduce synthesis of the transmitter. The experimental drug alpha-methyl-para-tyrosine inhibits the rate-limiting step by acting as a false substrate for the enzyme, the net result being a reduction in the catecholamine concentrations in both the central and peripheral nervous systems.

Drugs have been developed which specifically inhibit the L-aromatic amino acid decarboxylase step in catecholamine synthesis and thereby lead to a reduction in catecholamine concentration. Carbidopa and benserazide are examples of decarboxylase inhibitors which are used clinically to

Phenylalanine

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