Introduction

As outlined in Chapter 1, acetylcholine was the first neurotransmitter to be discovered and isolated. Its mode of action at peripheral synapses and in particular at the neuromuscular junction has been extensively studied and it is clearly the NT at all first synapses outside the CNS, whether this be at sympathetic or parasympathetic ganglia of the autonomic nervous system, the adrenal medulla or neuromuscular junctions in skeletal muscle. In these instances it transmits fast excitation through nicotinic receptors linked directly to the opening of Na+ channels. At parasympathetic nerve endings, such as those of the vagus on smooth and cardiac muscle and secretary cells, as well as just those few sympathetic nerve endings to sweat glands, it is also the neuro-transmitter. In these instances it has much slower excitatory or inhibitory effects mediated through muscarinic receptors utilising second messenger systems.

By contrast, the central actions of ACh are perhaps still less well understood than those of some more recently discovered NTs like dopamine and GABA. It does not appear to have a clear primary function but often an important supporting role. Attempts to understand its central actions were not encouraged by the knowledge that even those anticholinergic drugs that clearly cross the blood-brain barrier have few marked central effects and handicapped by the difficulty in measuring its release and turnover, or mapping its pathways.

Until the recent development of appropriate HPLC techniques capable of detecting pmol amounts (see Flentge et al. 1997) ACh could only be measured chemically by relatively lengthy and expensive procedures (e.g. gas chromotography), which were not always very sensitive, or by bioassays. Although the latter, using muscle preparations that responded to ACh, such as the dorsal muscle of the leech, the rectus abdominus of the frog or certain clam hearts, were reasonably sensitive they were tiresome and not easily mastered. Thus studies on the release and turnover of ACh have not been as easy as for the monoamines.

Similarly, cholinergic nerves could only be visualised indirectly. Staining for cho-linesterase, the metabolising enzyme for ACh, gave some information on the location of cholinergic synapses, where it is found postsynaptically rather than in nerve terminals, but it is not specific to cholinergic nerves. Fortunately choline acetyltransference (ChAT), which acetylates choline in the synthesis of acetylcholine, is specific to cholinergic nerve terminals and its labelling by immunochemistry has much facilitated the mapping of cholinergic pathways (Fig. 6.7).

Neurotransmitters, Drugs and Brain Function. Edited by R. A. Webster ©2001 John Wiley & Sons Ltd

Figure 6.1 Synthesis and metabolism of acetylcholine. Choline is acetylated by reacting with acetyl-CoA in the presence of choline acetyltransferase to form acetylcholine (1). The acetylcholine binds to the anionic site of cholinesterase and reacts with the hydroxy group of serine on the esteratic site of the enzyme (2). The cholinesterase thus becomes acetylated and choline splits off to be taken back into the nerve terminal for further ACh synthesis (3). The acetylated enzyme is then rapidly hydrolised back to its active state with the formation of acetic acid (4)

Figure 6.1 Synthesis and metabolism of acetylcholine. Choline is acetylated by reacting with acetyl-CoA in the presence of choline acetyltransferase to form acetylcholine (1). The acetylcholine binds to the anionic site of cholinesterase and reacts with the hydroxy group of serine on the esteratic site of the enzyme (2). The cholinesterase thus becomes acetylated and choline splits off to be taken back into the nerve terminal for further ACh synthesis (3). The acetylated enzyme is then rapidly hydrolised back to its active state with the formation of acetic acid (4)

In contrast to all this negativity, it must be acknowledged that more is known about the structure and function of cholinergic receptors and synapses, especially the nicotinic ones, than for the receptors of any other NT. It is unfortunate that nicotinic synapses are not very common in the CNS.

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