Cholinergic Pathways And Function

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Three distinct and basic CNS neuronal systems were referred to in Chapter 1, namely: long-axon neurons, intrinsic short-axon neurons and those in brainstem nuclei with extensively branching and ramifying ascending axons. The ubiquitous nature of ACh as a NT is evidenced by it being employed as such in all three situations to some extent, although for the first it is mainly confined to the periphery where it is released from long-axon preganglionic fibres and somatic motor nerves to skeletal muscle. In the striatum it is released from intrinsic interneurons and in the cortex from the terminals of ascending axons from subcortical neurons in defined nuclei. See Fig. 6.7 for detail.

Cholinergic Pathways The Brain Function Nucleus

Figure 6.7 Cholinergic pathways, (a) Acetylcholine is found in intrinsic neurons within the striatum but the main pathways are the cortical projections from the nucleus basalis magnocellularis (BM) which also sends axons to the thalamus and amygdala. There are other projections from the medial septum (Ms) and the nucleus of the diagonal band, or diagonalis broco (DB), to the hippocampus and from the magnocellular preoptic nucleus (MPO) and DB to the olfactory bulb (OB). The DM and BM are sometimes referred to as the substantia inominata. Collectively all these nuclei are known as the magnocellular forebrain nuclei (FN). Other cholinergic nuclei are found more caudally in the tegmentum. The paramedian (or pendunculo) pontine tegmental nucleus (PPTN) sends afferents to the paramedian pontine reticular formation and cerebellum but more importantly to the thalamus (lateral geniculate nucleus) and the more cephalic cholinergic neurons in MPO. Activation of neurons in PPTN during REM sleep gives rise to the PGO (ponto-geniculo-occipital) waves (see Chapter 22). There is a smaller lateral and dorsal tegmental nucleus (LDTN) with afferents projections like that of the PPTN, especially to the thalamus, but its role is less clear (see Woolf 1991). In the ventral horn of the spinal cord (b) ACh is released from collaterals of the afferent motor nerves to skeletal muscle to stimulate small interneurons, Renshaw cells (R), that inhibit the motoneurons

SPINAL CORD

Since ACh is the transmitter at the skeletal neuromuscular junction one might also expect it to be released from any axon collaterals arising from the motor nerve to it. Such collaterals innervate (drive) an interneuron (the Renshaw cell) in the ventral horn of the spinal cord, which provides an inhibitory feedback onto the motoneuron. Not only is ACh (and ChAT) concentrated in this part of the cord but its release from antidromically stimulated ventral roots has been demonstrated both in vitro and in vivo. Also the activation of Renshaw cells, by such stimulation, is not only potentiated by anticholinesterases but is also blocked by appropriate antagonists. In fact it illustrates the characteristics associated with both ACh receptors. Stimulation produces an initial rapid and brief excitation (burst of impulses), which is blocked by the nicotinic antagonist dihydro-;6-erythroidine, followed, after a pause, by a more prolonged low-frequency discharge that is blocked by muscarinic antagonists and mimicked by muscarinic agonists. Thus in this instance although ACh is excitatory, as in other areas of the CNS, the activation of Renshaw cells actually culminates in inhibition of motoneurons. Pharmacological manipulation of this synapse is not attempted clinically and although administration of nicotinic antagonists that are effective at peripheral autonomic ganglia and can pass into the CNS, such as mecamylamine, may cause tremor and seizures, it cannot be assumed that this results from blocking cholinergic inhibition of spinal motoneurons.

STRIATUM

The concentration of ACh in the striatum is the highest of any brain region. It is not affected by de-afferentation but is reduced by intrastriatal injections of kainic acid and so the ACh is associated with intrinsic neurons. Here ACh has an excitatory effect on other neurons mediated through muscarinic receptors and is closely involved with DA (inhibitory) function. Thus ACh inhibits DA release and atropine increases it, although the precise anatomical connection by which this is achieved is uncertain and the complexity of the interrelationship between ACh and DA is emphasised by the fact that DA also inhibits ACh release. In view of the opposing excitatory and inhibitory effects of ACh and DA in the striatum and the known loss of striatal DA in Parkinsonism (see Chapter 15) it is perhaps not surprising that antimuscarinic agents have been of some value in the treatment of that condition, especially in controlling tremor, and that certain muscarinic agonists, like oxotremorine, produce tremor in animals.

CORTEX

Cholinergic neurotransmission has been most thoroughly studied in the cortex where the role of ACh as a mediator of some afferent input is indicated by the finding that undercutting the cortex leads to the virtual loss of cortical ACh, ChAT and cholinesterase. That it is not the mediator of the primary afferent input has been shown by the inability of atropine to block the excitatory effect of stimulating those pathways and the fact that such stimulation causes a release of ACh over a wide area of the cortex and not just localised to the area of their cortical representation (see Collier and Mitchell 1967). Indeed there have been many experiments which show that the release of ACh in the cortex is proportional to the level of cortical excitability, being increased by a variety of convulsants and decreased by anaesthesia (Fig. 6.8). The origins of this diffuse cholinergic input have been traced in the rat to the magnocellular forebrain nuclei (MFN) by mapping changes in cortical cholinesterase and ChAT after lesioning specific subcortical nuclei. The most important of them appears to be the nucleus basalis magnocellularis, similar to the nucleus of Maynert in humans, which projects predominantly to the frontal and parietal cortex and is thought to be affected

Brain Functions Drugs

Figure 6.8 ACh release and cortical activity. Correlation between acetylcholine release and EEG activity after injections of leptazol (LEPmgkg-1 intravenously) into the urethane anaesthetised rat. ACh was collected in a cortical cup incorporating EEG recording electrodes. Mean values ±SE, n — 6 (unpublished data, but see Gardner and Webster 1977)

Figure 6.8 ACh release and cortical activity. Correlation between acetylcholine release and EEG activity after injections of leptazol (LEPmgkg-1 intravenously) into the urethane anaesthetised rat. ACh was collected in a cortical cup incorporating EEG recording electrodes. Mean values ±SE, n — 6 (unpublished data, but see Gardner and Webster 1977)

in Alzheimer's disease. This nucleus, together with the diagonal band, forms the substantia innominata and the dorsal neurons of this band also join with those in the medial septum to provide a distinct cholinergic input to the hippocampus (Fig. 6.7), which may play a part in memory function (see Chapter 18).

There is a second group of cholinergic neurons more caudally in the pontine tegmentum, the pendunculo pontine tegmental nucleus (PPPTN) and a smaller laterodorsal tegmental nucleus (LDTN). Their role in sleep and waking is discussed below and in Chapter 22.

Despite the excitatory effect of ACh in the cortex and its increased release during convulsive activity, antimuscarinic agents have only a slight sedative action (indeed, as emphasised above, atropine may cause excitation) and no anticonvulsant activity, except possibly in reducing some forms of experimentally induced kindling. ACh appears to exert a background excitatory effect on cortical function and while it may not directly stimulate the firing of pyramidal cells it will sensitise them to other excitatory inputs through its muscarinic activity.

AROUSAL AND SLEEP

Such a diffuse excitatory action of ACh in the cortex could fit it for a role in the maintenance of arousal and in fact the forebrain cholinergic nuclei, described above, appear to be innervated by the ventral part of the so-called ascending reticular system or pathway, which originates in a diffuse collection of brainstem neurons (see Chapter 22). If this pathway is lesioned the cortical EEG becomes quiescent but when stimulated it produces a high-frequency low-voltage desynchronised (aroused) EEG, which can be countered by antimuscarinic and potentiated by anticholinesterase drugs. Unfortunately this does not seem to apply to the actual behavioural arousal produced by such stimulation and suggests that ACh does not have a primary and certainly not a unique role in the maintenance of consciousness or sleep, although the firing of forebrain cholinergic neurons increases during the transition from sleep to waking. ACh does, however, feature prominently in one aspect of sleep behaviour.

As we relax in preparation for and pass into sleep, the active desynchronised 'awake' EEG characterised by the low-amplitude (5-10 high-frequency (10-30 Hz) beta waves becomes progressively more synchronised giving larger (20-30 and slower (8-12 Hz) alpha waves, and then even slower (1-4 Hz) and bigger (30-150 delta waves. This so-called slow-wave sleep is interrupted at intervals of some 1-2 h by the break-up and desynchronisation of the EEG into an awake-like pattern. Since this is accompanied by rapid eye movements, even though sleep persists and can be deeper, the phase is known as rapid eye movement, REM or paradoxical, sleep. It is a time when dreaming occurs and when memory may be secured.

Such REM sleep may occur some four or five times during a night's sleep and can occupy 20% of sleep time. More importantly, for this discussion, it can be intensified by anticholinesterases and reduced by antimuscarinics and it is accompanied, and in fact preceded, by burst firing of a group of cholinergic neurons in the pedunculo pontine tegmental nucleus (PPTN). Neurons from this nucleus, which is quite distinct from the nucleus basalis, project to the paramedian pontine reticular formation, the thalamic lateral geniculate body and thus to the occipital cortex, all of which show increased activity during REM sleep to give PGO (ponto-geniculo-occipital) waves. Clearly sleep is not just a passive event and while cholinergic activity may be important in the production of REM sleep it does not appear to be responsible for turning it off or for actually inducing sleep. Many other NTs and neuronal networks come into this (see Chapter 22).

COGNITION AND REWARD

Not only is REM sleep a time for dreaming but it is also believed to be a time for the laying down (consolidation) of memory. This is only one observation among many that implicates ACh in the memory process. Certainly antimuscarinic drugs like atropine are well known to impair cognitive function in both animals and humans. In the former antimuscarinic drugs appear to impair both the acquisition and retention of some learned tasks, as in the Morris water maze. This involves placing a rat in a circular tank of water containing a stand with a platform just below the surface but which is not clearly visible because the vessel walls or water have been made opaque. Generally the rat quickly learns (2-3 trials) to identify the position of and swims to the platform. That ability is impaired by pretreatment with antimuscarinics which increase the number of trials (possibly tenfold) required before the animal swims directly to the platform and can increase the time to achieve it if given after the task has been learnt.

Perhaps the strongest evidence for the role of ACh in cognitive processes comes, however, from the finding that in Alzheimer's disease there is a reasonably selective loss of cholinergic neurons in the nucleus basalis and that augmenting cholinergic function with anticholinesterase and to some extent by appropriate muscarinic agonists can help to restore memory function in the early stages of the disease. How cholinergic function can facilitate the memory process is uncertain. It is generally thought that the laying down of memory is in some way dependent on the high-frequency discharge of hippo-campal neurons in which long-term potentiation or LTP (the persisting potentiated response to a normal afferent input after a prior and short intense activation) plays an important part (see Chapter 18). Unfortunately while NMDA antagonists impair LTP, antimuscarinics do not. Of course, ACh will, by blocking K+ efflux, increase the likelihood of neurons discharging repetitively.

While it is the muscarinic receptor which is primarily concerned with the cognitive effects of ACh it has recently been shown that part of the cholinergic septal input to the hippocampus innervates excitatory nicotinic receptors on GABA interneurons. Since these appear to synchronise the activity of the main hippocampal glutamate neurons their stimulation could influence hippocampal function and memory process (see Jones, Sudweeks and Yakel 1999). The fact that there is a cholinergic projection from the pedunculo pontine tegmental nucleus to the dopomine neurons of the ventral tegmental area (VTA) and that its excitatory effect is mediated through nicotinic receptors could also implicate them and so ACh, in the reward process. This is thought to be mediated in part through the mesolimbic and mesocortical dopamine pathways arising from the VTA and may offer an explanation for the addictive nature of nicotine and smoking.

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