Brain cholinergic pathways

Figure 13.2. The major cholinergic pathways of the human brain.

The cholinergic pathways in the mammalian brain are extremely diffuse and arise from cell bodies located in the hindbrain and the midbrain. Of these areas, there has been considerable interest of late in the nucleus basalis magnocellularis of Meynert because this region appears to be particularly affected in some patients with familial Alzheimer s disease. As the projections from this area innervate the cortex, it has been speculated... 

Other cholinergic pathways in the brain include a network of intrinsic neurons in the striatum, and also various nuclei in the lower brain stem which project to the cerebellum are the origins of the cranial nerves. Striatal cholinergic neurons project mainly to spiny neurons which are the principal locus for the relay of cortical information flowthrough the basal ganglia (Calabresi et al.. 

The second section on clinical science has been increased by two chapters to accommodate the increase in the numbers of drugs and advances in knowledge about psychiatric disorders. Three new neurotransmitter systems are introduced and illustrated substance P and the neurokinin family nitric oxide and the endocannabi-noids such as anandamide (the brain s own marijuana ). Also amplified is coverage of the classical neurotransmitter systems, especially intercommunications now illustrated between serotonin and dopamine and between norepinephrine/noradrenaline and serotonin. Also included are numerous new illustrations of noradrenergic and cholinergic pathways. 

Many AD patients have damage to other neurotransmitter pathways as much as to their cholinergic pathways thus, they would not be helped much by manipulating only ACh levels in their brains. 

A similar plant is water hemlock, which contains a different toxin, called cicutoxin. This is very potent and exposure to it is often fatal. One study of poisonings with this plant found that 30 per cent of victims died. It affects primarily the brain and the spinal cord, causing seizures and epileptic fits, possibly by overstimulating certain nerves (cholinergic pathways). 

NGF infusions into the ventral hippocampus promoted axonal regeneration from the septum into the dorsal hippocampal formation, but did not induce sprouting of the nonlesioned cholinergic pathway that projects to the ventral hippocampal formation.164 Thus, as was also mentioned in Section 9.4.1.1, it is possible that NGF or other neurotrophic factors only or predominantly promote regeneration of lesioned axons in the adult brain. If so, the side effects of such treatments may not include or have limited effect on aberrant collateral sprouting of noninjured axons. One important question, which has not been resolved, is whether or how the neurotropic and guidance effects of NGF can be harnessed or even circumvented to allow a normal pattern of reinnervation and the formation of appropriate synaptic reconnections. 

A single common mechanism for producing AD does not exist. Regardless of the source, however, the features remain the same degeneration of neurons in higher brain areas accumulation of NFTs and neuritic plaques profound destruction of cholinergic pathways and an insidious dementia, slowly progressive until death. 

Parkinson s disease was the first neurological disorder to be associated with deficiency of a specific neurotransmitter. In Parkinson s disease, there is a deficiency of dopamine in the basal nuclei, which leads to overactivity of cholinergic pathways and the characteristic hypokinesia, rigidity and tremor. Drugs used to treat Parkinson s disease aim to replace dopamine stimulate dopamine receptors or the release of remaining dopamine reduce breakdown of dopamine or reduce excessive parasympathetic activity. More recently, attempts have been made to replace dopamine-secreting cells by transplantation of fetal brain tssue. 

Seiden, N. R., Gitelman, D. R., Salaiiion-Murayama, N., Parrish. T. B., and Mesulam. M. M. (1998). Trajectories of cholinergic pathways within the cerebral hemispheres of the huinan brain. Brain 121, 2249-2257. 

Histamine receptors were first divided into two subclasses Hi and H2 by Ash and Schild (1966) on the basis that the then known antihistamines did not inhibit histamine-induced gastric acid secretion. The justification for this subdivision was established some years later when Black (see Black et al. 1972) developed drugs, like cimetidine, that affected only the histamine stimulation of gastric acid secretion and had such a dramatic impact on the treatment of peptic ulcers. A recently developed H2 antagonist zolantidine is the first, however, to show significant brain penetration. A further H3 receptor has now been established. It is predominantly an autoreceptor on histamine nerves but is also found on the terminals of aminergic, cholinergic and peptide neurons. All three receptors are G-protein-coupled but little is known of the intracellular pathway linked to the H3 receptor and unlike Hi and H2 receptors it still remains to be cloned. Activation of Hi receptors stimulates IP3 formation while the H2 receptor is linked to activation of adenylate cyclase. 

Fig. 2.20 Efferent pathways into bulb showing (a) cholinergic (ACh) fibres projecting to MOB from basal forebrain nuclei. AON = ant. olfactory nucleus, OT = olfactory tract, DB = diagonal band nuc. (from Davis et al., 1978). (b) Nor-Adrenalin input to AOB, via MFB pathway from brain stem centres (nuclei A1-2, A6) (from Keveme, 1971).

This laboratory, as well as others, has shown unequivocally that PCP affects a variety of parameters related to neurotransmission in several neuronal systems. This paper has focused on evidence for the involvement of dopaminergic, cholinergic, and glutama-tergic pathways, and evidence of their interactions in the rat striatum. However, the effects of PCP undoubtedly involve other neuronal systems in other brain areas. Thus, it must be borne in mind that the data discussed in this paper cannot possibly account for the more complex behavioral effects of PCP. 

---