Approaches To The Manipulation Of Neurotransmitter Function In Humans

Once the malfunction of a particular NT has been established in a disease state, we need to find ways by which its activity can be restored to normal. The approaches used are indicated in Fig. 14.1 and outlined below. It is assumed that no NT crosses the blood-brain barrier and so its activity must be modified indirectly.

METHODS OF INCREASING NT FUNCTION (Fig. 14.1(a))

(1) Increase synthesis. This may be achieved by giving the precursor, if it crosses the blood-brain barrier. Whether this works will depend on (i) how many neurons remain to synthesise the NT, unless this can be performed extraneuronally and (ii) the availability of synthesising enzymes. Thus if synthesis is a complicated multistage process or is controlled by the availability of enzymes that are already reduced or working maximally in remaining neurons, this approach may prove difficult.

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(A) Mechanisms of augmenting f NT functions

Mitochondrion

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Figure 14.1 Caption opposite

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Precursor

Metabolising enzyme

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Metabolites

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Metabolising enzyme

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(B) Mechanisms of reducing^ NT functions

Mitochondrion

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P) Vesicle

^ Metabolising1 synthesising enzyme

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Figure 14.1 continued Diagrammatic representation of a neuronal synapse and the mechanisms by which the action of a neurotransmitter may be either augmented (A) or reduced (B). Augmentation of a NT (A) could involve; providing the precursor (1), increasing release by blocking autoreceptors (2), reducing destruction by blocking its reuptake (3a) or extra- (3b) or intraneuronal (3c) metabolism, or providing appropriate postsynaptic agonists (4). Reduction of NT function (B) follows blocking synthesis (1), reducing release by stimulating autoreceptor (2) or using antagonists (3). For further details see text " c to VO

(2) Increase release. This should follow block of any presynaptic inhibitory auto-receptors. It is not practical at present to increase the vesicular release of a particular NT.

(3) Reduce destruction. This may be achieved by blocking the neuronal or glial uptake (3a) of the NT or its extra- (3b) or intraneuronal metabolism (3c). Its success depends on there still being an adequate, even if reduced, release of the NT, and the protected NT being able to work postsynaptically and not stimulate autoreceptors to reduce the synaptic release of the endogenous NT even further. If the uptake sites are outside the synapse then the protected NT may not easily gain access to the receptors located postsynaptically.

(4) Give an appropriate agonist. Many of the problems associated with the above approaches may be circumvented by administering an appropriate agonist. This could be designed chemically so that it crosses the blood-brain barrier, has a long half-life, and works on the most appropriate subset of receptors, although experience has shown that sometimes more than one effect (receptor action) of the NT may be required. It would be counterproductive if the drug activated the presynaptic autoreceptors unless they happen to augment release. The synaptic action of a NT may also be increased by drugs that have an allosteric action on the receptor to increase its affinity or response to the endogenous NT, e.g. benzodiazapines at the GABA receptor.

Approaches (l)-(3) clearly depend on there being some residual neuronal function and

NT release.

METHODS OF DECREASING NT FUNCTION (Fig. 14.1(b))

(1) Stop synthesis. This may be achieved by inhibiting the appropriate enzyme. Its value depends on all, or at least one stage, of the synthesis being sufficiently specific to the NT involved so that only its synthesis is affected. A good example would be choline acetyltransferase in the synthesis of ACh or glutamic acid decarboxylase in the synthesis of GABA. By contrast, inhibiting amino acid decarboxylase could reduce NA, DA and 5-HT synthesis. It may be possible to reduce the neuronal uptake of a precursor if this requires a specific transport mechanism. Thus the synthesis of ACh can be reduced by blocking the uptake of precursor choline with hemicholinium.

(2) Reduce release. This is most likely to be achieved by stimulating inhibitory pre-synaptic autoreceptors (2a). Some drugs may reduce storage (2b) and hence release, although it is unlikely that this can be targeted at just one NT.

(3) Give an appropriate antagonist. As with agonists, these have the advantage that they can be designed to have a long half-life and act specifically on one type of receptor.

Currently it is not possible to increase the rate of removal (uptake) or metabolism of a NT.

RELATING NT MANIPULATION TO THE CAUSE OF THE DISORDER

To what extent the above approaches can provide successful therapy will depend on both the cause of the disorder and the manner in which the NT is used in normal neuronal function. Thus the disorder could be due to:

(1) An actual degeneration of a NT pathway or

(2) No actual degeneration but a biochemical abnormality or some circuitry failure, leading to inadequate or excessive activity of the NT.

The requirement in respect of NT function may be:

(a) That it must be released physiologically from its nerve terminals by appropriate synaptic activity in order to produce the desired effect or

(b) That it is sufficient merely to provide the NT at the synapse, without the need for it to be released physiologically.

Clearly a disorder combining (1) with (a) would mean that little improvement could be expected by manipulating the lost NT, since the nerves are no longer there to release it physiologically. The main hope then would be to try to replenish the neurons with transplants (regeneration may be possible one day) and hope they become appropriately innervated, or modify the action of some other NT which has become exaggerated (or reduced), as a result of the primary NT loss. By contrast it is easier to treat a disorder, whether characterised by neuronal degeneration ((1) above) or not (2), if it is sufficient just to provide NT (b), as appears to be the case in Parkinsonism.

Of course, the effectiveness and specificity of any of the above manipulations will depend on how widely the NT is distributed and used and whether the malfunction applies only to one area or activity. Thus trying to increase (or decrease) the activity of a NT in only one area will be difficult if it has actions elsewhere which have not been affected by the disorder. The nervous system also has remarkable adaptive powers so the synaptic loss (or increase) of a NT is generally followed by a local compensating increase (decrease) in postsynaptic receptor number. This can be a useful response initially but it will be negated by the therapeutic provision of more (less) NT. Also a change in the activity of one NT can lead to desirable compensating changes in the function of other NTs either working in conjunction with it or normally controlled by it. These will be lost by replenishment of the NT.

It must also be remembered that some NTs, like ACh, NA and 5-HT, have important peripheral as well as central roles and any attempt to modify them centrally will affect those peripheral effects as well. This may be avoided, or reduced, by utilising the blood-brain barrier. Thus if attempts made to increase the central action of a NT result in peripheral effects, these may be counteracted by using an appropriate antagonist that does not cross the blood-brain barrier. It is less easy to overcome peripheral side-effects caused by using a drug that antagonises the action of a NT, although in theory drugs that mimic or augment its action and do not cross the blood-brain barrier could be used. In fact this approach has proved valuable in treating the peripheral neuro-muscular disorder of myasthenia gravis which presents as a muscle weakness caused by insufficient cholinergic activity at skeletal neuromuscular junctions. The function of ACh can be increased and the symptoms alleviated, without central side-effects, by reducing the destruction of ACh by giving the anticholinesterase drug neostigmine, which does not cross the blood-brain barrier. Of course, nothing is perfect and anti-muscarinic drugs may be needed to overcome the accompanying increased peripheral parasympathomimetic effects of ACh.

Despite all these problems there has been considerable progress in the treatment of disease states through NT manipulation. Before the advent of levodopa therapy in Parkinsonism the treatment of neurological and psychiatric disorders had little scientific basis but the initial and striking success with levodopa in Parkinsonism perhaps raised false expectations. In respect of drug therapy, Parkinsonism presented with a number of advantageous features that are unlikely to be repeated in other conditions. It involves a relatively specific degeneration of one particular NT (DA) pathway, DA has a precursor (levodopa) that readily crosses the blood-brain barrier and its peripheral metabolism to DA can be stopped by decarboxylase inhibitors that themselves do not cross the blood-brain barrier. Although DA is used elsewhere in the brain, nowhere is it concentrated to the same extent as in the striatum, where the degeneration occurs, and it has few peripheral effects. Thus side-effects are relatively few. Fortunately DA also appears to be synthesised from levodopa even in the absence of DA neurons and it does not appear to have to be released synaptically in a physiological way in order to control striatal activity and reduce the symptoms of rigidity and akinesia. Even so, long-term therapy with levodopa has not been without its problems and disappointments and highlights the difficulties of replacement therapy.

Neurotransmitters, Drugs and Brain Function.

Edited by Roy Webster Copyright © 2001 John Wiley & Sons Ltd ISBN: Hardback 0-471-97819-1 Paperback 0-471-98586-4 Electronic 0-470-84657-7

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