Cholinergic systems and schizophrenia: primary pathology or epiphenomena?
Section snippets
Defining schizophrenia
Schizophrenia is an enigmatic illness that most often appears in the second or third decades of life, frequently leading to severe lifelong functional impairment. Although hallucinations and delusions are the most dramatic symptoms, deficits in working memory and other cognitive domains may be the most functionally limiting. While the unequivocal determination of specific factors that contribute to the development of schizophrenia has yet to be realized, the search for consistent brain
Cholinergic cell groups
Although acetylcholine (ACh) was the first neurotransmitter to be discovered, the identification and delineation of central cholinergic systems is ongoing, particularly in human and primate brain. Initially, histochemistry for acetylcholinesterase (AchE), the central degradatory enzyme for ACh, was used to define cholinergic cell bodies and projection pathways. However, this enzyme is also found in non-cholinergic neurons, thereby limiting its specificity. More recently, histochemistry for
Cholinergic projection pathways
Distinct projection patterns characterize the outflow from the cholinergic cell groups described by Mesulam et al., 1983a, Mesulam et al., 1983b. Ch1 and Ch2 neurons project extensively into the hippocampus and hypothalamus. Ch3 is intimately connected with the olfactory bulb and to a lesser extent with the amygdala. Ch4 is the major source of cholinergic input to the amygdala and neocortex (Mesulam et al., 1983a, Mesulam et al., 1983b), with an elaborate topography of projections from
Muscarinic cholinergic receptors
Five highly related but distinct muscarinic receptor subtypes have been identified in the human brain (M1–M5). Each receptor has a select sequence and chromosomal localization. Muscarinic receptors belong to the superfamily of hormone and neurotransmitter G-protein coupled receptors, which evoke slow modulatory second messenger responses. Therefore, as a by-product of working through second messenger systems, muscarinic receptors more slowly effect neuronal activity than ionotropic receptors.
Nicotinic cholinergic receptors
Nicotinic cholinergic receptors belong to the superfamily of ligand-gated ion channel receptors, which are widely distributed throughout the mammalian central nervous system. Most nicotine receptors are pentomers, made up of two alpha and three non-alpha subunits per receptor. However, a subgroup of nicotinic receptors is made up of purely alpha 7, alpha 8, or alpha 9 subunits, forming so called homomeric receptors. Eleven neuronally-expressed nicotinic receptor subunits have been identified,
Muscarinic receptors in schizophrenia
The impetus to investigate the muscarinic receptor system in schizophrenia is derived in part from an association of muscarinic activity with modulation of a number of central nervous system functions. Such functions include cognition, memory, motor activity, and sleep, which are altered in schizophrenia (Jin-Long and Shuang-Ning, 1993, Neeper et al., 1991, Tandon et al., 1991, Grimm et al., 1994, Zorn et al., 1994). Moreover, there are high affinity anti-muscarinic actions of the atypical
Nicotinic receptors in schizophrenia
The study of nicotine receptors in schizophrenic subjects has been stimulated in part by the association between cigarette smoking and schizophrenia. Schizophrenic patients have an extremely high rate of cigarette smoking, estimated to be about 80–90% of the adult schizophrenic population (Hughes et al., 1986, Lohr and Flynn, 1992). Possibly, alterations in nicotinic cholinergic neurotransmission are part of the primary pathology of schizophrenia; more likely, nicotine helps ameliorate some of
Cholinergic cell groups and projection pathways in schizophrenia
Alterations in cholinergic neurotransmission could result from pathological changes in cholinergic cell groups and/or projection pathways. While studies of postsynaptic receptors provide an indirect measure of such changes, a more direct measure is the study of cholinergic cell groups, fibers, and pre-synaptic receptors. In a limited study, El-Mallakh et al. (1991) found no change in the density of neurons in the Ch4 cell group. However, this study is yet to be replicated and extended using
Theoretical considerations regarding cholinergic systems in schizophrenia
Alterations in cholinergic parameters may be a primary component of the pathophysiology of schizophrenia, or a down-stream effect from pathology in other neurotransmitter systems or structures. While post mortem human brain studies suggest a role for abnormal cholinergic neurotransmission in schizophrenia, none are definitive. The confounding nature of ante mortem medication administration and cigarette smoking make it difficult to ascribe changes in cholinergic parameters to the illness
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