Selective changes in nicotinic acetylcholine receptor subtypes related to tobacco smoking: an immunohistochemical study.

Increases in neuronal nicotinic receptors (nAChRs) in response to nicotine exposure have been reported in cell cultures, rodent brains, and in the brains of human smokers. The present study examines alterations in alpha4 and alpha7 nAChR subunit cellular expression in human hippocampus and entorhinal cortex from normal elderly individuals with known smoking history. There were significant increases in the intensity of alpha4 immunoreactive neuropil, but not the number of cell bodies, in many regions of hippocampus and entorhinal cortex in smokers compared to age-matched non-smokers and ex-smokers. There was also an increase in alpha7 immunoreactive perikarya in the granular cell layer of dentate gyrus in smokers but not other regions examined. There was, in contrast, a significant reduction in alpha7 immunoreactive astrocytes in smokers and ex-smokers compared to non-smokers. These findings suggest exposure to tobacco smoke acutely up-regulates alpha4 receptors in axon terminals and dendrites but not perikarya, whereas tobacco smoking induced down-regulation of alpha7 expression on astrocytes is a long-term effect. As the alpha4 subunit decreases with ageing and degenerative diseases such as Alzheimer's disease, whereas alpha7 increases in astrocytes in Alzheimer's disease, the findings further indicate the therapeutic relevance of nicotinic agonists such as nicotine.

Human brain nicotinic receptors, their distribution and participation in neuropsychiatric disorders.

Mapping of nicotinic acetylcholine receptor (nAChR) subtypes and subunits in human brain is far from complete, however it is clear that multiple subunits are present (including alpha3, alpha4, alpha5, alpha6 and alpha7, beta2, alpha3 and beta4) and that these receptors are not solely distributed on neurones, but also on cerebral vasculature and astrocytes. It is important to elucidate subunit composition of receptors associated with different cell types and pathways within the human CNS in terms of potential nicotinic therapy for a range of both developmental and age-related disorders in which nAChR attenuation occurs. Reductions in nAChRs are reported in Alzheimer's and Parkinson's diseases, dementia with Lewy bodies, schizophrenia and autism, but may not be associated with reduced cortical cholinergic innervation observed in vascular dementia or occur at an early stage in Down's syndrome. Changes in nAChR expression in neuropsychiatric disorders appear to be brain region and subtype specific and have been shown in some instances to be associated with pathology and symptomatology. It is likely that deficits in alpha4-containing receptors predominate in cortical areas in Alzheimer's disease and autism, whereas reduction of alpha7 receptors may be more important in schizophrenia. Changes in astrocytic and vascular nAChR expression in neurodegenerative diseases should also be considered. Studies using both animal models and human autopsy tissue suggest that nAChRs can play a role in neuroprotection against age-related pathology. It is possible that the development of nAChR subtype specific drugs may lead to advances in therapy for both age-related and psychiatric disorders.