Development of the olfactory epithelia of the African clawed frog, Xenopus laevis, was studied by scanning and transmission electron microscopy. Stages examined ranged from hatching through the end of metamorphosis. The larval olfactory organ consists of two chambers, the principal cavity and the vomeronasal organ (VNO). A third sensory chamber, the middle cavity, arises during metamorphosis. In larvae, the principal cavity is exposed to water-borne odorants, but after metamorphosis it is exposed to airborne odorants. The middle cavity and the VNO are always exposed to waterborne odorants. Electron microscopy reveals that in larvae, principal cavity receptor cells are of two types, ciliated and microvillar. Principal cavity supporting cells are also of two types, ciliated and secretory (with small, electron-lucent granules). After metamorphosis, the principal cavity contains only ciliated receptor cells and secretory supporting cells, and the cilia on the receptor cells are longer than in larvae. Supporting cell secretory granules are now large and electron-dense. In contrast, the middle cavity epithelium contains the same cell types seen in the larval principal cavity. The VNO has microvillar receptor cells and ciliated supporting cells throughout life. The cellular process by which the principal cavity epithelium changes during metamorphosis is not entirely clear. Morphological evidence from this study suggests that both microvillar and ciliated receptor cells die, to be replaced by newly generated cells. In addition, ciliated supporting cells also appear to die, whereas there is evidence that secretory supporting cells transdifferentiate into the adult type. In summary, significant developmental additions and neural plasticity are involved in remodeling the olfactory epithelium in Xenopus at metamorphosis.

Recent advances concerning effects of chronic nicotine exposure on nicotinic acetylcholine receptor (nAChR) expression are reviewed. Implications are assessed of these findings for roles of nAChR in health and disease and for design of drugs for treatment of neurological and psychiatric disorders. Most studies continue to show that chronic nicotine exposure induces increases in numbers of nAChR-like binding or antigenic sites ("upregulation") across all nAChR subtypes investigated, but with time- and dose-dependencies and magnitudes for these effects that are unique to subsets of nAChR subtypes. These effects appear to be post-transcriptionally based, but mechanisms involved remain obscure. With notable exceptions, most studies also show that chronic nicotine exposure induces several phases of nAChR functional loss ("desensitization" and longer-lasting "persistent inactivation") assessed in response to acute nicotinic agonist challenges. Times for onset and recovery and dose-dependencies for nicotine-induced functional loss also are nAChR subtype-specific. Some findings suggest that upregulation and functional loss are not causally- or mechanistically-related. It is suggested that upregulation is not as physiologically significant in vivo as functional effects of chronic nicotine exposure. By contrast, brain levels of nicotine in tobacco users, and perhaps levels of acetylcholine in the extracellular space, clearly are in the range that would alter the balance between nAChR in functionally ready or inactivated states. Further work is warranted to illuminate how effects of chronic nicotinic ligand exposure are integrated across nAChR subtypes and the neuronal circuits and chemical signaling pathways that they service to produce nicotine dependence and/or therapeutic benefit.

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Effects of prolonged nicotinic ligand exposure on the function of human ␣4␤2-and ␣4␤4-nicotinic acetylcholine receptor (nAChR) subtypes were studied using receptors heterologously expressed in SH-EP1 human epithelial cells. Magnitudes of acute, nAChR-mediated, specific 86 Rb ϩ efflux responses to 1 mM carbamylcholine were reduced after pretreatment with specific nAChR ligands in effects that depended on pretreatment drug dose, duration of drug pretreatment, and duration of drug-free recovery. Fifty percent inhibition of ␣4␤2-nAChR function following 5 min of recovery occurred after 1 min of pretreatment with 1 mM nicotine but also after 1-h pretreatment at 10 nM nicotine. Seventy-five percent loss in function persisted 1 h after drug removal following 15 min or more of exposure to 1 mM nicotine. However, functional recovery was nearly complete after 1 h in drug-free medium following 1 min to 24 h pretreatment with 0.1 to 1 M nicotine, i.e., in the range of smoker plasma nicotine levels. ␣4␤4-nAChR was similarly sensitive to persistent inactivation by prolonged nicotine exposure. Carbamylcholine exhibited slightly lower persistent inactivation potency than nicotine at both ␣4␤2-and ␣4␤4-nAChR. The nAChR antagonist, mecamylamine, exhibited persistent inactivation potency and efficacy similar to nicotine at ␣4␤2-nAChR but had a reduced effect on ␣4␤4-nAChR. These studies illustrate persistent inactivation of human ␣4␤2-or ␣4␤4-nAChR induced by prolonged exposure to nicotine and show that other ligands induce nAChR persistent inactivation in a subtype-specific manner.

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