Analysis of human, mouse, and other animal genomes revealed that nicotinic acetylcholine receptors have been conserved throughout evolution, and that ancestor genes appeared early, in the simplest forms of life. Indeed, more nicotinic receptor genes have been identified in mollusks than in vertebrates, indicating that these receptors may play an even larger role Inhibitors,research,lifescience,medical in invertebrates. The observation of this high degree of conservation called for further reflections about the role of these receptors in brain activity, and forced the design of new experiments to examine their function and dysfunction

in the central nervous system. Labeling experiments carried out with different probes revealed that nicotinic receptors are widely expressed both in the cortex, white Inhibitors,research,lifescience,medical matter, and in groups of neurons in brain nuclei.5 For example, intense labeling was observed in the fasciculus retroflexus, which connects the habenula to the interpeduncular nuclei.6 The development of novel molecules, such as A-85380, which label with high affinity Inhibitors,research,lifescience,medical the major brain a432 nicotinic receptors, opened up the possibility of measuring receptor distribution

using positron emission tomography.7-9 Confirming the high degree of receptor expression in the thalamus, these studies were rapidly extended to medical pathological conditions.5,10,11 Inhibitors,research,lifescience,medical Importantly, significant labeling was also observed in the white matter.5 While providing further evidence about the importance of the nicotinic receptors they also highlight the need for more precise mapping of the receptor distribution with ligands of the receptor subtypes in normal or pathological conditions. Obtaining precise mapping of receptor distribution becomes indispensable for understanding the role of nAChRs in brain function. Inhibitors,research,lifescience,medical Progress toward this goal has, however, been hampered by the absence of selective antibodies, as shown by studies carried out in knockout animals.12 The isolation of the genes encoding for the nicotinic receptors allowed their reconstitution in

host systems and, consequently, their functional characterization. Experiments carried out in Xenopus oocytes or in cell lines expressing the human receptors confirmed that these ligand gated channels are permeable to cations, causing a depolarization of the cell when they are activated.2,13,14 The ionic selectivity Annual Review of Medicine of nAChRs differs markedly in function of the receptor subtype. For example, while the muscle receptors display a very low permeability to the divalent calcium ions, the homomeric α7 nAChRs present a higher permeability to calcium than sodium.15 Activation of α7 nAChRs was shown to increase the intracellular calcium concentration and, for receptors expressed presynaptically, indirectly causing neurotransmitter release.