ACh is the only major low-molecular-weight neurotransmitter substance that is not derived from an amino acid (Kandel et al. 2000). ACh is synthesized from acetyl coenzyme A and choline in nerve terminals via the enzyme choline acetyltransferase (ChAT). Choline is transported into the brain by uptake from the bloodstream and enters the neuron via both high-affinity and low-affinity transport processes (Cooper et al. 2001). In addition to the "standard"
ChAT pathway, there are several additional possible mechanisms by which ACh can be synthesized; the precise roles of these additional pathways and their physiological relevance in the CNS remain to be fully elucidated (Cooper et al. 2001). The highest activity of ChAT is observed in the interpeduncular nucleus, caudate nucleus, corneal epithelium, retina, and central spinal roots. In contrast to the other transmitters discussed thus far (which are most dependent on reuptake mechanisms), ACh has its signal terminated primarily by the enzyme acetylcholine esterase, which degrades ACh (Figure 1-6B). Not surprisingly, therapeutic strategies to increase synaptic ACh levels (e.g., for the treatment of Alzheimer's disease) have focused on inhibiting the activity of cholinesterases.
FIGURE 1-6. The cholinergic system.
FIGURE 1-6. The cholinergic system.
This figure depicts the cholinergic pathways in the brain (A) and various regulatory processes involved in cholinergic neurotransmission (B). Choline crosses the blood-brain barrier to enter the brain and is actively transported into cholinergic presynaptic terminals by an active uptake mechanism (requiring ATP). This neurotransmitter is produced by a single enzymatic reaction in which acetyl coenzyme A (AcCoA) donates its acetyl group to choline by means of the enzyme choline acetyltransferase (ChAT). AcCoA is primarily synthesized in the mitochondria of neurons. Upon its formation, acetylcholine (ACh) is sequestered into secretory vesicles by vesicle ACh transporters (VATs), where it is stored. Vesamicol effectively blocks the transport of ACh into vesicles. An agent such as B-bungarotoxin or AF64A is capable of increasing synaptic concentration of ACh by acting as a releaser and a noncompetitive reuptake inhibitor, respectively. In turn, agents such as botulinum toxin are able to attenuate ACh release from nerve terminals. Once released from the presynaptic terminals, ACh can interact with a variety of presynaptic and postsynaptic receptors. In contrast to many other monoaminergic neurotransmitters, the ACh signal is terminated primarily by degradation by the enzyme acetylcholinesterase (AChE) rather than by reuptake. Interestingly, AChE is present on both presynaptic and postsynaptic membranes and can be inhibited by physostigmine (reversible) and soman (irreversible). Currently, AChE inhibitors such as donepezil and galantamine are the only classes of agents that are FDA approved for the treatment of Alzheimer's disease. ACh receptors are of two types: muscarinic (G proteincoupled) and nicotinic (ionotropic). Presynaptic regulation of ACh neuron firing activity and release occurs through somatodendritic (not shown) and nerve terminal M2 autoreceptors, respectively. The binding of ACh to G protein-coupled muscarinic receptors that are negatively coupled to adenylyl cyclase (AC) or coupled to phosphoinositol hydrolysis produces a cascade of second-messenger and cellular effects (see diagram). ACh also activates ionotropic nicotinic receptors (nAChRs). ACh has it action terminated in the synapse through rapid degradation by AChE, which liberates free choline to be taken back into the presynaptic neuron through choline transporters (CTs). Once inside the neuron, it can be reused for the synthesis of ACh, can be repackaged into vesicles for reuse, or undergoes enzymatic degradation. There are some relatively new agents that selectively antagonize the muscarinic receptors, such as CI-1017 for Mi, methoctramine for M2, 4-DAMP for M3, PD-102807 for M4, and scopolamine (hardly a new agent) for M5 (although it also has affinity for M3 receptor). nAChR or nicotine receptors are activated by nicotine and the specific alpha(4)beta(2*) agonist metanicotine. Mecamylamine is an AChR antagonist. DAG = diacylglycerol; IP3 = inositol-1,4,5-triphosphate.
Source. Adapted from Cooper JR, Bloom FE, Roth RH: The Biochemical Basis of Neuropharmacology, 7th Edition. New York, Oxford University Press, 2001. Copyright 1970, 1974, 1978, 1982, 1986, 1991, 1996, 2001 by Oxford University Press, Inc. Used by permission of Oxford University Press, Inc. Modified from Nestler et al. 2001.
Several cholinergic pathways have been proposed, but until recently the circuits had not been worked out in the brain because of the lack of appropriate techniques. The development of tract tracing and histochemical techniques has provided a clearer picture of the cholinergic pathways. In brief, cholinergic neurons can act as local circuit neurons (interneurons) and are found in the caudate putamen, nucleus accumbens, olfactory tubercle, and islands of Calleja complex (Cooper et al. 2001). They do, however, also serve to function as projection neurons that connect different brain regions; one fairly well-characterized pathway runs from the septum to the hippocampus (Figure 1-6A). The basal forebrain cholinergic complex is composed of cholinergic neurons originating from the medial septal nucleus, diagonal band nuclei, substantia innominata, magnocellular preoptic field, and nucleus basalis. These nuclei project cholinergic neurons to the entire nonstriatal telencephalon, pontomesencephalotegmental cholinergic complex, thalamus, and other diencephalic loci (see Figure 1-6A). Descending cholinergic projections from these nuclei also innervate pontine and medullary reticular formations, deep cerebellar and vestibular nuclei, and cranial nerve nuclei (Cooper et al. 2001).
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