Acetylcholine (ACh) is phylogenetically a very old molecule that is widely distributed in eukaryotic as well as prokaryotic cells. Furthermore, ACh is found in many non-neuronal tissues, in which it appears to modulate basic cellular actions. ACh is formed by the synthesis of acetyl coenzyme A and choline via the enzyme choline acetyltransferase. Acetyl coenzyme A is available from mitochondria, and choline is obtained through the diet. ACh is rapidly inactivated in the synaptic cleft by the enzyme acetylcholinesterase. The activity of both choline acetyltransferase and acetylcholinesterase is reduced in the frontal and temporal cortices of patients with Alzheimer's disease, and the decrease in choline acetyltransferase activity is associated with the presence of the apolipoprotein epsilon 4 (ApoE-i4) allele (Lai et al. 2006).
The presence of ACh-containing cell bodies and axons has been demonstrated by the use of histochemical procedures to visualize the acetylcholinesterase molecule, as well as by the use of specific antibodies directed against choline acetyltransferase. Immunocytochemical identification of ACh-containing axons using choline acetyltransferase antibodies is the preferred method, because acetylcholinesterase may not be a specific marker of cholinergic structures. A detailed review of the primate cholinergic system can be found in De Lacalle and Saper (1997).
ACh-containing neurons are located in two main groups in the brain (see Figure 4-1). The basal forebrain cholinergic complex is located near the inferior surface of the telencephalon, between the hypothalamus and orbital cortex. This complex includes the medial septal nucleus, the diagonal band of Broca, the nucleus basalis (also known as the basal nucleus of Meynert), the magnocellular preoptic area, and the substantia innominata. All of these regions are characterized by the presence of large ACh-containing multipolar neurons (Semba and Fibiger 1989).
The pontomesencephalotegmental cholinergic complex consists of the pedunculopontine nucleus, which is located along the dorsolateral aspect of the superior cerebellar peduncle, and the laterodorsal tegmental nucleus in the ventral part of the periaqueductal gray. Similar to the cells in the basal forebrain complex, the pontomesencephalotegmental complex is also characterized by the presence of large ACh-containing cells (Semba and Fibiger 1989).
In addition to these cell groups, ACh-containing neurons are also present in all nuclei of the striatum (i.e., the caudate, putamen, and nucleus accumbens). However, these cholinergic cells are interneurons and thus do not project out of the striatum (Cooper et al. 1996).
The cerebral cortex is a major recipient of cholinergic projections, which originate predominantly from the basal forebrain complex. The organization of these projections in the primate is similar to that in the rodent. In general, these projections are topographically organized, with a distinct population of neurons projecting to a particular location in the cortex.
The distribution of ACh-containing axons in the cerebral cortex is heterogeneous, with paralimbic areas having the greatest density of ACh-containing axons. The sensory and association regions of neocortex are less densely innervated by cholinergic axons than are the paralimbic areas. For example, in human brain, the density of cholinergic axons is lowest in the primary visual cortex; moderate in association areas, including parts of the prefrontal (see Figure 4-3) and parietal cortices; and highest in the paralimbic entorhinal and cingulate cortices (Mesulam et al. 1992). The density of cholinergic axons also differs within a cortical region. In monkey prefrontal cortex, there is a rostral to caudal increase in the density of ACh-containing axons, so that area 10 at the frontal pole has a lower density of cholinergic axons than does area 9, which is less densely innervated than the more caudal area 8B. Furthermore, the more caudal premotor (area 6) and motor (area 4) cortices have the highest density of ACh-containing axons in the frontal lobe (Lewis 1991). However, cholinergic axons are distributed homogeneously across prefrontal areas at the same rostrocaudal level (see Figure 4-4).
The distribution of ACh-containing axons across the cortical layers is also heterogeneous. In general, layers 1-2 and 5 have the highest density of cholinergic axons, whereas layer 4 has the lowest density of ACh-containing axons (Lewis 1991; Mesulam et al. 1992).
The hippocampus is also densely innervated by cholinergic axons. These projections arise from the medial septal and diagonal band of Broca nuclei of the basal forebrain complex (Kitt et al. 1987). The molecular layer of the dentate gyrus and the CA2, CA3, and CA4 subsectors of the hippocampus contain the highest densities of ACh-containing axons (Mesulam et al. 1992). Although the densities of ACh-containing fibers in the CA1 subsector and subiculum are lower than those in the other portions of the hippocampus, they are still more densely innervated than most cortical areas (Mesulam et al. 1992).
The amygdala also receives projections from the basal forebrain cholinergic complex. Within the amygdala, all nuclei are densely innervated by ACh-containing axons, with the basolateral nucleus having the highest density (Mesulam et al. 1992). Retrograde tracing has demonstrated that this projection principally arises from the nucleus basalis (Kitt et al. 1987).
In the rodent, the reticular nucleus of the thalamus and the interpeduncular nucleus are densely innervated by cholinergic axons originating from the nucleus of the diagonal band of Broca and the nucleus basalis, respectively. These projections have not been investigated in the primate (Semba and Fibiger 1989).
The thalamus is densely innervated by cholinergic axons, which originate from the pedunculopontine and laterodorsal tegmental nuclei (Semba and Fibiger 1989). In addition, acetylcholinesterase activity and immunoreactivity for choline acetyltransferase have revealed a heterogeneous distribution of cholinergic axons within the thalamus. For example, in the primate, the midline, intralaminar, anterodorsal, lateral mediodorsal, and medial pulvinar nuclei contain very high levels of cholinergic axons (Barbas et al. 1991; Cavada et al. 1995). A similar pattern of cholinergic axons is found in the rodent (Levey et al. 1987).
The pedunculopontine and laterodorsal tegmental nuclei project to other subcortical structures, including the lateral hypothalamus, the superior colliculus, and the lateral preoptic area. However, these projections have only been investigated in rodents (Semba and Fibiger 1989).
ACh receptors have been divided into two main classes, the muscarinic and nicotinic receptors. There are five (M1-M5) subtypes of the muscarinic receptor, all of which are coupled to G proteins and linked to a variety of second-messenger systems. Neuronal nicotinic receptors are formed from five membrane-
spanning subunits situated around a central pore. The neuronal nicotinic receptor has two subunits, r: and (3; the ct subunit has seven different forms, and the subunits that form cxf3 combinations include CX2-GC6 and &2—$4 (Dani and Bertrand 2007). Homomeric and heteromeric nicotinic receptors can be formed from the 1X7-0:10 subunits. The nicotinic receptors are ionotropic, acting directly on sodium channels.
Most of the studies investigating the localization of ACh receptors in the brain have employed autoradiography, utilizing tritiated nicotine or receptor subtype-specific ligands. For example, the M1 and M2 receptor subtypes have been shown to be present in many regions of the cerebral cortex, including the frontal, parietal, and occipital cortices (Flynn and Mash 1993). Specifically, the overall densities of the M1 and M2 receptor subtypes are similar, but the laminar distributions vary across the cortex (Lidow et al. 1989). In parietal, occipital, and motor cortices, both receptor subtypes are concentrated in the superficial layers. In contrast, the M1 and M2 subtypes are evenly distributed across the cortical layers in the prefrontal cortex. Subcortical structures show a varied distribution of muscarinic receptors. The striatum has a high density of M1, M2, and M3 receptors, with M3 receptors localized to the anterior and dorsal caudate nucleus and M1 receptors more prevalent in the ventromedial caudate and medial globus pallidus (Flynn and Mash 1993). Low levels of M1 and M3 receptors are found in the thalamus, hypothalamus, and brain stem. In Alzheimer's disease, M1 and M2 receptors, as measured by autoradiography, are reduced in the frontal cortex and hippocampus, respectively, whereas M3 and M4 receptors appear to be unaffected (Rodriguez-Puertas et al. 1997).
The distribution of tritiated nicotine binding sites is similar in both rat and monkey brains. For example, in both species, dense labeling occurs in sensory-and motor-related thalamic nuclei, the dentate gyrus of the hippocampus, and layer 3 of the cerebral cortex (Clarke 1989). Furthermore, the anatomical distributions of mRNA for the nicotinic ACh receptor subunits have been investigated in the monkey brain. The 04 and [ 2 receptor subunits are the most widely distributed, with highest densities in the dorsal thalamus and the DA-containing nuclei of the mesencephalon (Han et al. 2000). Consistent with the well-known involvement of the cholinergic system in Alzheimer's disease, the densities of «4 and $2 nicotinic receptors are reduced in the temporal and frontal cortices of patients with this disease (Lai et al. 2006).
Several lines of evidence support a role for the 1X7 receptor subunit in the pathophysiology of sensory gating deficits in schizophrenia. For example, a postmortem study has shown that binding of a:-bungarotoxin, which most likely corresponds to nicotinic receptors containing the 1X7 subunit (Leonard et al. 2000), is reduced in the hippocampus of patients with schizophrenia (Freedman et al. 1995). In addition, sensory gating deficits are improved by nicotine in subjects with schizophrenia as well as in their unaffected family members (Adler et al. 1998). Interestingly, unlike control subjects, who show an upregulation of nicotinic receptors in association with smoking, individuals with schizophrenia exhibit lower binding of nicotinic receptors at every level of smoking history (Breese et al. 2000).
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