Drug Effects On Neurotransmitter Function

To establish the role of a particular NT experimentally it is necessary to modify its synaptic activity. This can be done most easily with drugs.

Precursor

Metabolising enzyme

Precursor

Metabolising enzyme

Metabolites *

Presynaptic terminal la

Metabolites *

Metabolising enzyme

Postsyna receptors ptK\\

Neuronal or cellular events

Mitochondrion

Transporter Vesicle

. Metabolising enzyme

Figure 5.5 Diagrammatic representation of a synapse showing the sites at which drugs may act to increase or decrease the concentration and action of a neurotransmitter. Drugs can affect the synthesis (1), storage (2), release (3), action (4) and destruction (5) of the transmitter. The different ways in which they achieve this (a. b. c) are outlined in Table 5.1

Table 5.1 Drug modification of the different aspects of neurotransmitter function in synaptic transmission as illustrated in Fig. 5.5

Aspect Modification Effect on NT function

Table 5.1 Drug modification of the different aspects of neurotransmitter function in synaptic transmission as illustrated in Fig. 5.5

Aspect Modification Effect on NT function

1

Synthesis

(a)

Supplement precursor

+

(i)

(b) (c)

Block precursor uptake Inhibit synthesising enzyme

2

Storage

(a)

Inhibit NT uptake into vesicle

(+)

(ii)

(b)

Inhibit NT binding in vesicle

(+)

3

Release

(a)

Stimulation of negative autoreceptors

(exocytotic)

(b)

Blockade of autoreceptors

+

(iii)

(c)

Disrupt release (exocytotic) mechanism

4

Action

(a)

Mimic effect of NT on receptor

+

(iv)

(b)

Block postsynaptic receptor

5

Destruction

(a)

Block uptake into neuron (and/or glia)

+

(v)

(b)

Inhibit intraneuronal metabolism

+

(c)

Inhibit extracellular metabolism

+

Notes:

(i) Synthesis may have multiple steps within the terminal process which provides more than one site for drug modification and one stage may even be within the vesicle, Providing extra synthesising enzyme is not a practical proposition but altering the availability of certain co-factors can have an influence (e,g, impaired vitamin V6 intake reduces GABA synthesis),

(ii) Drugs affecting storage (e,g, reserpine) are not likely to affect only one NT, Also although any reduction in the vesicular storage of NT will eventually lead to a reduction (—) in its normal exocytotic release by action potential, it is possible that the extra NT will build up sufficiently in the cytoplasm (if not metabolised) to diffuse out of the neuron or even induce its reverse transport out of the neuron through the membrane transporter that normally brings it in from the synapse (+),

(iii) Some terminals may also have receptors which augment release when activated by the NT as well as receptors for NTs other than that being released, Drugs that affect the actual release process, e,g, Ca2+ influx, are unlikely to have a specific effect on just one NT system unless concentrated in particular neurons by specific uptake,

(iv) Most NTs act on more than one postsynaptic receptor, This provides the opportunity to design drugs that will act specifically on just one of them although reproduction of the full effect of the NT may require the participation of more than one of its receptors (e,g, DA function in the basal ganglia), It should also be remembered that even if a drug is specific for just one NT receptor its effects will depend on how numerous and widely distributed that receptor is, This is particularly true of the much-used amino acids glutamate and GABA, Also many different functions could be linked to the same receptor (e,g, the numerous peripheral actions mediated by cholinergic muscarinic receptors),

(v) A NT may be taken up into glia (e,g, GABA) or even nerve terminals other than those from which it is released, As with synthesis, it is difficult to augment the action of the metabolising enzymes,

The concept that a drug is either an agonist or antagonist that acts at a receptor site is a simple one, especially if it is acting at the receptor for a NT that is linked either directly or indirectly through second messenger systems, to the control of ion channel opening and the excitability (discharge) of a neuron, The receptor or perhaps more precisely the receptive site can, however, also be part of an enzyme involved in the synthesis or metabolism of that NT, the transporter responsible for taking the NT (or its precursor) across the membrane of a storage vesicle or axon terminal or even the actual NT binding site within a vesicle, This means that a drug can modify the action of a NT and the function of the synapse where it acts in a number of ways, These will now be outlined in general and then covered in more detail for each particular NT in the following chapters (6-13),

At most synapses a conventional NT is synthesised from an appropriate precursor in the nerve terminal, stored in vesicles, released, acts on postsynaptic receptors and is then destroyed either by extraneuronal metabolism or intraneuronal metabolism after reuptake. Its release is triggered by invading action potentials and controlled by presynaptic autoreceptors. Although some NTs, e.g. peptides, are not synthesised in the terminal and others, e.g. NO, are formed on demand, some features of the 'typical' synapse, as described above, still apply to them. The mechanisms by which drugs may modify synaptic function through their effects on the synthesis, storage, release, action and destruction of a NT are shown in Fig. 5.5 and outlined in Table 5.1. They constitute what may be regarded as a template for how a drug may affect synaptic transmission.

Manipulating the activity of a NT in these ways helps to determine its function either at a synaptic level or in more general behavioural terms. Thus the clearest way of establishing the identity of the NT at a particular synapse is to ascertain which NT receptor antagonist blocks transmission there.

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