Neurotransmitter Organisation And Utilisation

In the periphery at the mammalian neuromuscular junction each muscle fibre is generally influenced by only one nerve terminal and the one NT acts on one type of receptor localised to a specific (end-plate) area of the muscle. The system is fitted for the induction of the rapid short postsynaptic event of skeletal muscle fibre contraction and while the study of this synapse has been of immense value in elucidating some basic concepts of neurochemical transmission it would be unwise to use it as a universal template of synaptic transmission since it is atypical in many respects.

In smooth muscle, by contrast, one sympathetic nerve fibre can influence a number of muscle fibres by releasing noradrenaline from varicosities along its length without there being any defined 'end-plate' junctions. The result of receptor activation is a slow change in potential and inactivation of the NT is initially by uptake and then metabolism. In other words, the NT function is geared to the slower phasic changes in tone characteristic of smooth muscle.

In the CNS there are many forms of neuronal organisation. One neuron can have many synaptic inputs and a multiplicity of NTs and NT effects are utilised within a complex interrelationship of neurons. There are also positive and negative feedback circuits as well as presynaptic influences all designed to effect changes in excitability and frequency of neuronal firing, i.e. patterns of neuronal discharge.

While we should try to exploit such differences between NT systems in developing drugs, rather than adopting a blanket concept of neurotransmission, it is still worth while trying to characterise different types of NT systems in the CNS in order to build up a functional framework and concept. The following patterns are suggested (see Fig. 1.8).

Figure 1.8 Some basic neuronal systems. The three different brain areas shown (I, II and III) are hypothetical but could correspond to cortex, brainstem and cord while the neurons and pathways are intended to represent broad generalisations rather than recognisable tracts. 'A' represents large neurons which have long axons that pass directly from one brain region to another, as in the cortico spinal or cortico striatal tracts. Such axons have a restricted influence often only synapsing on one or a few distal neurons. 'B' are smaller inter or intrinsic neurons that have their cell bodies, axons and terminals in the same brain area. They can occur in any region and control (depress or sensitise) adjacent neurons. 'C' are neurons that cluster in specific nuclei and although their axons can form distinct pathways their influence is a modulating one, often on numerous neurons rather than directly controlling activity, as with 'A'. Each type of neuron and system uses neurotransmitters with properties that facilitate their role

Figure 1.8 Some basic neuronal systems. The three different brain areas shown (I, II and III) are hypothetical but could correspond to cortex, brainstem and cord while the neurons and pathways are intended to represent broad generalisations rather than recognisable tracts. 'A' represents large neurons which have long axons that pass directly from one brain region to another, as in the cortico spinal or cortico striatal tracts. Such axons have a restricted influence often only synapsing on one or a few distal neurons. 'B' are smaller inter or intrinsic neurons that have their cell bodies, axons and terminals in the same brain area. They can occur in any region and control (depress or sensitise) adjacent neurons. 'C' are neurons that cluster in specific nuclei and although their axons can form distinct pathways their influence is a modulating one, often on numerous neurons rather than directly controlling activity, as with 'A'. Each type of neuron and system uses neurotransmitters with properties that facilitate their role

LONG-AXON (CLASSICAL) PATHWAYS (Pl)

These include not only pathways with very long axons, such as the cortico-spinal and spino-thalamic tracts but also numerous shorter interconnecting systems, e.g. thalamus to cortex, etc. They may be regarded as the backbone of the CNS. The axons, especially the very long ones, show little divergence and have a relatively precise localisation, i.e. activation of particular motoneurons by stimulating a precise part of the motor cortex. Their influence on neurons is phasic and generally rapid with conventional EPSPs. Distinct axo-dendritic type I asymmetric synapses utilising glutamate acting on receptors (ionotropic) directly linked to the opening of N£ channels are common and these systems form the basic framework for the precise control of movement and monitoring of sensation. Such pathways are well researched and understood by neuro-anatomists and physiologists, but their localised organisation makes them, perhaps fortunately, somewhat resistant to drug action.

INTRINSIC CONTROLLING SYSTEMS (P2)

These are basically neurons whose cell body and axon terminals are both found in the same part of the CNS (Fig. l.2). They are not concerned with transmitting information from one part of the CNS to another but in controlling activity in their own area. They can be excitatory but are more often inhibitory. They may act postsynaptically through conventional IPSPs (or slower potential changes) or presynaptically by modifying NT

release. The former systems are generally thought to use amino acids as NTs, e.g. GABA or glycine acting on ionotropic receptors linked to Cl_ channels, while the latter systems may use GABA (presynaptic inhibition in cord) or peptides (enkephalin neurons). Excitatory interneurons may use ACh or an amino acid, like aspartate.

Since these interneurons exert a background control of the level of excitability in a given area or system their manipulation by drugs is of great interest (e.g. attemps to increase GABA function in epilepsy), especially if this can be achieved without adversely affecting important primary activity in the area. Although intrinsic neurons can only have a localised action they may be influenced by long-axon inputs to them and so incorporated into long pathway effects (Fig. 1.3(d)), such as the cortical inhibition of motoneurons.

MODULATING SYSTEMS (P3)

These have relatively long axons that originate from neurons that are grouped together in subcortical nuclei of perhaps a few hundred cell bodies but spread to vast areas of the brain and cord. The NTs, generally the monoamines noradrenaline, dopamine and 5-HT, are released at various sites along considerable lengths of the axon and distinct synaptic contacts may not always be seen. They may act either postsynaptically or presynaptically to produce slow changes in activity or modify NT release generally through secondary messenger systems. The tonic background influence of these systems and their role in behaviour have instigated the development and study of many drugs to manipulate their function. It also seems that the cholinergic input into the cortex from subcortical nuclei can also be included in this category (see Chapter 5).

Of course, while the identification of these distinct systems may be useful there are many neural pathways that would not fit easily into one of them. Thus some inhibitory pathways, such as that from the caudate nucleus to substantia nigra, utilising GABA, are not intrinsic neurons. The dopamine pathway from the substantia nigra to striatum may start from a small nucleus but unlike other monoamine pathways it shows little ramification beyond its influence on the striatum. The object of the above classification is not to fit all neural pathways and mechanisms into a restricted number of functional categories but again to demonstrate that there are different forms of neurotransmission.

CO-EXISTENCE (P4)

Although it may be argued that this is not a pattern of NT organisation but merely a feature of some (or possibly all) neurotransmitter systems, it justifies separate consideration. Since there is already good evidence for the existence of a fairly large number of different NTs, which it is assumed are released from their own specific neurons, and as they can produce a diversity of postsynaptic events one might consider the release of more than one NT from one terminal a somewhat unnecessary complication. Nevertheless since co-existence is established, its significance must be evaluated in respect of NT function and drug action. This is considered in more detail later (Chapter 12) but it is important to know which NTs co-exist and whether there is a definite pattern, i.e. does neurotransmitter A always occur with B and never with C and is the ratio A:B always the same? Also what effects do the NTs produce, how do they interact and are they both necessary for full synaptic transmission? The latter is a vital question for drug therapy based on NT replacement.

Thus it may be that a full understanding of how one NT works at a synapse will require knowledge of how that function depends on the actions of its co-released NT(s). It could unfold a whole new requirement and dimension to our understanding of synaptic physiology and pharmacology and the use of drugs. On the other hand, it may be of little significance in some cases for although cholinergic-mediated nicotinic and muscarinic responses as well as dopamine and peptide effects are observed in sympathetic ganglia, it is only nicotinic antagonists that actually reduce transmission, acutely anyway.

The brain could be likened to a television set in which the amino acids are providing the basic positive and negative power lines, while the other NTs (the multi-coloured wires) control the colour, contrast and brightness. All are required for a perfect picture but some are obviously more important than others.

FUNCTIONAL SYNAPTIC NEUROCHEMISTRY

To achieve their different effects NTs are not only released from different neurons to act on different receptors but their biochemistry is different. While the mechanism of their release may be similar (Chapter 4) their turnover varies. Most NTs are synthesised from precursors in the axon terminals, stored in vesicles and released by arriving action potentials. Some are subsequently broken down extracellularly, e.g. acetylcholine by cholinesterase, but many, like the amino acids, are taken back into the nerve where they are incorporated into biochemical pathways that may modify their structure initially but ultimately ensure a maintained NT level. Such processes are ideally suited to the fast transmission effected by the amino acids and acetylcholine in some cases (nicotinic), and complements the anatomical features of their neurons and the recepter mechanisms they activate. Further, to ensure the maintenance of function in vital pathways, glutamate and GABA are stored in very high concentrations (10 ^ol/mg) just as ACh is at the neuromuscular junction.

By contrast, the peptides are not even synthesised in the terminal but are split from a larger precurser protein in the cell body or during transit down the axon. They are consequently only found in low concentrations (100 pmol/g) and after acting are broken down by peptidases into fragments that cannot be re-used. It is perhaps not surprising that they have a supporting rather than a primary role.

In between the above two extremes are the monoamines (1-10 nmol/g) which are preformed and stored in terminals but at much lower concentrations than the amino acids and when released are removed primarily by reuptake for re-use, or intraneuronal metabolism to inactive metabolites. Thus the appropriate synaptic organisation, biochemistry and receptor pharmacology of the NTs also varies in keeping with their function. It is often assumed, incorrectly, that the NTs found in the highest concentration are the most potent. In fact the opposite is true. Those like the amino acids while having high affinity for their receptors have low potency while the peptides found at much lower concentration have high potency but low affinity.

Continue reading here: Neurotransmitter Identification

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