DISTRIBUTION OF NICOTINIC SUBTYPES IN HUMAN BRAIN

The distribution of high-affinity nicotine and alpha-bungarotoxin rece ptors has been compared in a number of human brain areas and related t o the available data on receptor subtype mRNA expression. Nicotine bin ding is high in the thalamus, striatum, and substantia nigra pars comp acta, 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 i n the cerebral cortex, but it demonstrates varied patterns of distribu tion in different areas. Nicotine binding is also present in the cereb ellar cortex and dentate nucleus, Nicotine binding in the thalamus cor responds to a, expression, but at variance to data from rodents, there is little evidence of beta(2) mRNA in this brain area. By contrast, t here is beta(2) mRNA but not alpha(3) mRNA in the striatum. In the hip pocampal formation both alpha(3) and beta(2) mRNAs are expressed, bur the pattern of distribution does not resemble nicotine binding, only r eaching moderate levels in the dentate granule cell layer and in the C A(3) region. In the neocortex, alpha(4) expression is more widely dist ributed than alpha(3), but both are associated with pyramidal neurons. The distribution of nicotine binding, concentrated in brain areas gat ing multimodal inputs and often uncorrelated with cholinergic innervat ion, suggests a neuromodulatory role, possibly facilitating glutamater gic transmission. The distribution of alpha-bungarotoxin binding is di fferent from that of nicotine in the hippocampal formation, being high est in the CA(1) region and the dentate granule cell layer, but simila r to nicotine binding in the substantia nigra pars compacta. Alpha-7 m RNA expression is concentrated in the CA(3) region and the dentate gra nule cell layer of the hippocampal formation, and it is low in the tha lamus. The highest brain levels of nicotine binding are observed in th e preterm infant (22-27 weeks' gestation). This is particularly striki ng in the brainstem and cerebellar dentate nucleus. This indicates a r ole for nicotine receptors during brain development and a possible cau se 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 bet ween nicotinic acetylcholine receptor loss and the initiation of patho logy.