Neuronal nicotinic receptors in the human brain David Paterson, Agneta Nordberg* Department of Clinical Neuroscience, Occupational Therapy and Elderly Care Research, Division of Molecular Neuropharmacology, Karolinska Institute, Huddinge University Hospital, S-14186 Huddinge, Sweden Received 20 July 1999 Abstract Neuronal nicotinic acetylcholine receptors (nAChRs) are a family of ligand gated ion channels which are widely distributed in the human brain. Multiple subtypes of these receptors exist, each with individual pharmacological and functional pro®les. They mediate the eects of nicotine, a widely used drug of abuse, are involved in a number of physiological and behavioural processes and are additionally implicated in a number of pathological conditions such as Alzheimer's disease, Parkinson's disease and schizophrenia. The nAChRs have a pentameric structure composed of ®ve membrane spanning subunits, of which nine dierent types have thus far been identi®ed and cloned. The multiple subunits identi®ed provide the basis for the heterogeneity of structure and function observed in the nAChR subtypes and are responsible for the individual characteristics of each. A substantial amount of information on human nAChR structure and function has come from studies on neuroblastoma cell lines which naturally express nAChRs and from recombinant nAChRs expressed in Xenopus oocytes. In vitro brain nAChR distribution can be mapped with a number of appropriate agonist and antagonist radioligands and subunit distribution may be mapped by in situ hybridization using subunit speci®c mRNA probes. Receptor distribution in the living human brain can be studied with non- invasive imaging techniques such as PET and SPECT, with a signi®cant reduction in nAChRs in the brains of Alzheimer's patients having been identi®ed with  11 C nicotine in PET studies. Despite the signi®cant body of knowledge now accumulated about nAChRs, much remains to be elucidated. This review will attempt to describe the current knowledge on the nAChR subtypes in the human brain, their functional roles and neuropathological involvement. # 2000 Elsevier Science Ltd. All rights reserved. Contents 1. Introduction ........................................................... 76 1.1. Nicotinic receptor structure ........................................... 77 1.2. Ligand binding sites ................................................ 77 1.2.1. ACh binding site ............................................. 78 1.2.2. Allosteric binding sites ......................................... 78 1.3. Transition states of nicotinic receptors ................................... 80 1.4. Nicotinic receptor upregulation ........................................ 80 Progress in Neurobiology 61 (2000) 75±111 0301-0082/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved. PII: S0301-0082(99)00045-3 www.elsevier.com/locate/pneurobio * Corresponding author. Tel: +46-8-58585467; fax: +46-8-6899210. E-mail address: agneta.nordberg@neurotec.ki.se (A. Nordberg). Abbreviations: aBTX, Alpha bungarotoxin; Ach, Acetylcholine; nAChRs, nicotinic acetylcholine receptors; AChRs, nicotinic receptor sites that bind nicotinic agonists with high anity; ACTH, Adrenocorticotropic hormone; AD, Alzheimer's disease; ADNFLE, Autosomal dominant frontal lobe epilepsy; APP, Amyloid precursor protein; bA4, b amyloid; BTXRs, nicotinic receptor sites that bind bungarotoxin with high a- nity; CGRP, calcitonin gene related peptide; ChAT, Choline acetyltransferase; CNS, Central nervous system; DA, Dopamine; DHbE, Dihydro- b-erythroidine; DMEA, Dimethylethanolamine; DMPP, 1,1-dimethyl-4-phenylpiperazanium; EEG, Electro encephalograph; GABA, gamma amino butyric acid; 5-HT, 5 hydroxy tryptamine (serotonin); kBTX, kappa bungarotoxin; Kd, Dissociation constant; MLA, Methylcaconitine; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropine; MRI, Magnetic resonance imaging; NA, Noradrenaline; NBM, Nucleus basalis of Meynert; NMDA, N-methyl-D-aspartame; PCP, phencyclidine; PD, Parkinson's disease; PET, Positron emission tomography; PKA, Protein kinase A; PKC, Protein kinase C; SPECT, Single photon emission computed tomography; TS, Gilles de Tourette syndrome.