DISTRIBUTION OF NICOTINIC SUBTYPES IN HUMAN BRAIN

The distribution of high-affinity nicotine and alpha-bungarotoxin receptors has been compared in a number of human brain areas and related to the available data on receptor subtype mRNA expression. Nicotine binding is high in the thalamus, striatum, and substantia nigra pars compacta, and although not generally high in the hippocampal formation, it is concentrated in the entorhinal cortex, the subicular complex, and the stratum lacunosum moleculare. Nicotine binding is relatively low in the cerebral cortex, but it demonstrates varied patterns of distribution in different areas. Nicotine binding is also present in the cerebellar cortex and dentate nucleus, Nicotine binding in the thalamus corresponds to a, expression, but at variance to data from rodents, there is little evidence of beta(2) mRNA in this brain area. By contrast, there is beta(2) mRNA but not alpha(3) mRNA in the striatum. In the hippocampal formation both alpha(3) and beta(2) mRNAs are expressed, bur the pattern of distribution does not resemble nicotine binding, only reaching moderate levels in the dentate granule cell layer and in the CA(3) region. In the neocortex, alpha(4) expression is more widely distributed than alpha(3), but both are associated with pyramidal neurons. The distribution of nicotine binding, concentrated in brain areas gating multimodal inputs and often uncorrelated with cholinergic innervation, suggests a neuromodulatory role, possibly facilitating glutamatergic transmission. The distribution of alpha-bungarotoxin binding is different from that of nicotine in the hippocampal formation, being highest in the CA(1) region and the dentate granule cell layer, but similar to nicotine binding in the substantia nigra pars compacta. Alpha-7 mRNA expression is concentrated in the CA(3) region and the dentate granule cell layer of the hippocampal formation, and it is low in the thalamus. The highest brain levels of nicotine binding are observed in the preterm infant (22-27 weeks' gestation). This is particularly striking in the brainstem and cerebellar dentate nucleus. This indicates a role for nicotine receptors during brain development and a possible cause of foetal susceptibility to maternal smoking and nicotine exposure. The relationship of nicotine receptor loss with the neuropathology of aging and dementia suggests that changes in receptors occur early in disease processes and before cell loss, possibly indicating a link between nicotinic acetylcholine receptor loss and the initiation of pathology.