Distribution Of Nicotinic Acetylcholine Receptors Research Articles

Recombinant human neuregulin-1 alleviates immobilization-induced neuromuscular dysfunction via neuregulin-1/ErbB signaling pathway in rat

Immobilization-induced Neuromuscular Dysfunction (NMD) increases morbidity and mortality of patients in Intensive Care Units. However, the underlying mechanism of NMD remain poorly elucidated which limited the development of therapeutic method for NMD. Here we developed an immobilization rat model and tested the hypothesis that decreased expression of NRG-1, abnormal expression and distribution of nicotinic acetylcholine receptors (nAChRs) in skeletal muscle caused by immobilization can lead to NMD. To investigate the role of NRG-1/ErbB pathway on immobilization-induced NMD, exogenous recombinant human neuregulin-1 (rhNRG-1) was used to increase the expression of NRG-1 in skeletal muscle during immobilization. It was observed rhNRG-1 significantly alleviated the muscle loss and enhanced the expression of ε-nAChR, while diminished the expression of γ- and α7-nAChR and NMD. Interestingly, ErbB inhibitor PD158780 blocked the protective effects of rhNRG-1. Collectively, the results of present study suggested that rhNRG-1 attenuated immobilization-induced muscle loss and NMD, suppressed γ- and α7-nAChR production, enhanced ε-nAChR synthesis via activating NRG-1/ErbB pathway. Taken together, our findings provide novel insights into NMD contribution, suggesting that the rhNRG-1 is a promising therapy to protect against immobilization-induced myopathy.

The Structural and Functional Characteristics of Rat Soleus Endplates under Short-Term Disruption of Motor Activity

Abstract—In this study we analyzed the distribution of nicotinic acetylcholine receptors, the degree of their fragmentation, endplate area, and membrane localization of the α2 isoform of the Na,K–ATPase in the rat soleus muscle after functional unloading (via the method of hindlimb suspension) for 1–3 days. After unloading increased endplate fragmentation accompanied by a decrease in the area of individual fragments was observed; the total area of the endplates did not change. The density of distribution of nicotinic acetylcholine receptors also remained unaltered; however, the density of the distribution of the α2 isoform of the Na,K–ATPase significantly decreased. Presumably, these changes resulted from adaptive skeletal muscle remodeling, which develops not only during chronic disorders, but even in the early stages of motor dysfunction.

Alleviating Sepsis-Induced Neuromuscular Dysfunction Linked With Acetylcholine Receptors by Agrin

BackgroundAbnormal expression and distribution of nicotinic acetylcholine receptors (nAChRs) in skeletal muscle caused by sepsis can lead to neuromuscular dysfunction. Here, we asked whether neural agrin regulates nAChRs to ameliorate muscle function, which could be associated with the agrin/muscle-specific kinase pathway. MethodsRats were subjected to cecal ligation and puncture (CLP) group, sham group, or control group to observe the alteration caused by sepsis. To verify the effect of improving function, rats were injected with agrin or normal saline intramuscularly after CLP. Electromyogram was used to measure neuromuscular function. Cytokines levels of serum and the expression of related proteins and mRNA were tested after treatment. ResultsCompared with the rats in control or sham group, CLP-treated rats showed an acute inflammatory status and a reduction of neuromuscular dysfunction in tibialis anterior muscle, which was associated with abnormal expression in agrin/muscle-specific kinase pathway and increased expression of γ- and α7-nAChR. Exogenous agrin alleviated neuromuscular dysfunction and decreased the expression of γ- and α7-nAChR through agrin-related signaling pathway. ConclusionsThe decreased expression of agrin may lead to skeletal muscle dysfunction. Early enhancement of intramuscular agrin levels after sepsis may be a potential strategy for the treatment of sepsis-induced muscle dysfunction.

Evaluation of the distribution of nicotine intravenous injection: an adult autopsy case report with a review of literature

We reported the first comprehensive autopsy case of death due to intravenous injection of nicotine. We examined the distribution of nicotine in the body tissues and fluid and exposed the pathophysiology of nicotine poisoning. A 19-year-old woman was rushed to the hospital in cardiorespiratory arrest and was confirmed dead upon arrival. Liquid nicotine, hydrogen peroxide water, and a syringe were found in the hotel room where she stayed. On autopsy, nicotine concentration was the highest (15,023 μg/mg) in the tissue around the injection mark on the right upper arm. Among the body fluids, the intraperitoneal fluid had the highest, whereas the pericardial fluid had the lowest (0.736 μg/mL) nicotine concentration. Among the organs, the brain had the highest (11.637 μg/mg), whereas the fat tissue had the lowest (1.307 μg/mg) nicotine concentration. The concentration of cotinine, which is the metabolite of nicotine, was the highest in the tissue around the injection mark on the right arm (5.495 μg/mg) and was almost the same among the other body fluids and organs. The respective concentrations of nicotine and cotinine were 1.529 μg/mL and 0.019 μg/mL in the left heart blood and 3.157 μg/mL and 0.002 μg/mL in right heart blood. In this case, the nicotine concentrations in blood reached the lethal level. The distributions of nicotine and cotinine, as indicated by the intravenous injection, were related to the distribution of organs that metabolize nicotine and the distribution of nicotinic acetylcholine receptors.

Abnormal Membrane Localization of α2 Isoform of Na,K-ATPase in m. soleus of Dysferlin-Deficient Mice.

Dysferlin protein plays a key role in the multimolecular complex responsible for the maintenance of sarcolemma integrity and skeletal muscle cell functioning. We studied the membrane distribution of nicotinic acetylcholine receptors and α2 isoform of Na,K-ATPase in motor endplates of m. soleus in dysferlin-deficient Bla/J mice (a dysferlinopathy model). Endplates of Bla/J mice were characterized by increased area (without changes in fragmentation degree) and reduced density of the membrane distribution of nicotinic acetylcholine receptors in comparison with the corresponding parameters in control С57Bl/6 mice. The density of the membrane distribution of α2 isoform of Na,K-ATPase was also reduced, but the level of the corresponding mRNA remained unchanged. It can be hypothesized that abnormal membrane localization of α2 isoform of Na,K-ATPase results from adaptive skeletal muscle remodeling under conditions of chronic motor dysfunction.

The Structural and Functional Characteristics of the Motor End Plates of Dysferlin-Deficient Mice

The molecular mechanisms that underlie neuromuscular junction plasticity are complex and remain to be fully elucidated. Experimental models of various forms of impaired motor activity may be promising for their study. The dysferlin protein plays a key role in the multimolecular complex, which maintains sarcolemma integrity and the functioning of skeletal muscle cells. We studied the structural and functional characteristics of the diaphragm muscle motor end plates of dysferlin-deficient Bla/J mice (a model of dysferlinopathy), dystrophin-deficient mdx mice (a model of Duchenne muscular dystrophy), and control C57Bl/6 mice. Increased end plate fragmentation and a decrease in the area of individual fragments were observed in mdx mice and absent in Bla/J mice, which indicates a difference in these models of myodystrophy from these characteristics. However, end plates of both mice lines were characterized by a decrease in the density of distribution of nicotinic acetylcholine receptors, as well as by membrane depolarization, presumably, due to altered functional interaction between the α2 isoform of Na,K-ATPase and the nicotinic acetylcholine receptors.

Antibody-Induced Acetylcholine Receptor Clusters Inhabit Liquid-Ordered and Liquid-Disordered Domains

The distribution of nicotinic acetylcholine receptor (AChR) clusters at the cell membrane was studied in CHO-K1/A5 cells using fluorescence microscopy. Di-4-ANEPPDHQ, a fluorescent probe that differentiates between liquid-ordered (Lo) and liquid-disordered (Ld) phases in model membranes, was used in combination with monoclonal anti-AChR antibody labeling of live cells, which induces AChR clustering. The so-called generalized polarization (GP) of di-4-ANEPPDHQ was measured in regions of the cell-surface membrane associated with or devoid of antibody-induced AChR clusters, respectively. AChR clusters were almost equally distributed between Lo and Ld domains, independently of receptor surface levels and agonist (carbamoylcholine and nicotine) or antagonist (α-bungarotoxin) binding. Cholesterol depletion diminished the cell membrane mean di-4-ANEPPDHQ GP and the number of AChR clusters associated with Ld membrane domains increased concomitantly. Depolymerization of the filamentous actin cytoskeleton by Latrunculin A had the opposite effect, with more AChR clusters associated with Lo domains. AChR internalized via small vesicles having lower GP and lower cholesterol content than the surface membrane. Upon cholesterol depletion, only 12% of the AChR-containing vesicles costained with the fluorescent cholesterol analog fPEG-cholesterol, i.e., AChR endocytosis was essentially dissociated from that of cholesterol. In conclusion, the distribution of AChR submicron-sized clusters at the cell membrane appears to be regulated by cholesterol content and cytoskeleton integrity.

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The BTB-MATH protein BATH-42 interacts with RIC-3 to regulate maturation of nicotinic acetylcholine receptors

RIC-3 is a member of a conserved family of proteins that affect nicotinic acetylcholine receptor maturation. In yeast and in vitro, BATH-42, a BTB- and MATH-domain-containing protein, interacts with RIC-3. BATH-42 is also known to interact with the CUL-3 ubiquitin ligase complex. Loss of BATH-42 function leads to increased RIC-3 expression and decreased activity of nicotinic acetylcholine receptors in Caenorhabditis elegans vulva muscles. Increased expression of RIC-3 is deleterious for activity and distribution of nicotinic acetylcholine receptors, and thus the effects of BATH-42 loss of function on RIC-3 expression explain the associated reduction in receptor activity. Overexpression of BATH-42 is also detrimental to nicotinic acetylcholine receptor function, leading to decreased pharyngeal pumping. This effect depends on the C-terminus of RIC-3 and on CUL-3. Thus, our work suggests that BATH-42 targets RIC-3 to degradation via CUL-3-mediated ubiquitylation. This demonstrates the importance of regulation of RIC-3 levels, and identifies a mechanism that protects cells from the deleterious effects of excess RIC-3.

Synaptic Organization of Lobula Plate Tangential Cells in Drosophila: Dα7 Cholinergic Receptors

: The nervous system of seeing animals derives information about optic flow in two subsequent steps. First, local motion vectors are calculated from moving retinal images, and second, the spatial distribution of these vectors is analyzed on the dendrites of large downstream neurons. In dipteran flies, this second step relies on a set of motion-sensitive lobula plate tangential cells (LPTCs), which have been studied in great detail in large fly species. Yet, studies on neurons that convey information to LPTCs and neuroanatomical investigations that enable a mechanistic understanding of the underlying dendritic computations in LPTCs are rare. We investigated the subcellular distribution of nicotinic acetylcholine receptors (nAChRs) on two sets of LPTCs: vertical system (VS) and horizontal system (HS) cells in Drosophila melanogaster. In this paper, we describe that both cell types express Dα7-type nAChR subunits specifically on higher order dendritic branches, similar to the expression of gamma aminobutyric acid (GABA) receptors. These findings support a model in which directional selectivity of LPTCs is achieved by the dendritic integration of excitatory, cholinergic, and inhibitory GABA-ergic input from local motion detectors with opposite preferred direction. Nonetheless, whole-cell recordings in mutant flies without Dα7 nAChRs revealed that direction selectivity of VS and HS cells is largely retained. In addition, mutant LPTCs were responsive to acetylcholine and remaining nAChR receptors were labeled by α-bungarotoxin. These results in LPTCs with genetically manipulated excitatory input synapses suggest a robust cellular implementation of dendritic processing that warrants direction selectivity. The underlying mechanism that ensures appropriate nAChR-mediated synaptic currents and the functional implications of separate sets or heteromultimeric nAChRs can now be addressed in this system.

Synaptic remodeling at the skeletal neuromuscular junction of acetylcholinesterase knockout mice and its physiological relevance

Acute inhibition of synaptic acetylcholinesterase (AChE) is fatal to normal animals, but AChE-knockout mice (AChE −/−) expressing normal levels of butyrylcholinesterase (BChE) could live to adulthood without AChE expression. The present study was undertaken to determine whether compensatory mechanisms occur in the mutant that allow an effective neuromuscular transmission in the chronic absence of AChE. For this we evaluated neuromuscular transmission and the distribution of nicotinic acetylcholine receptors (nAChRs) and motor nerve terminals on isolated nerve-muscle preparations from AChE −/− mice. AChE −/− hemidiaphragm muscles maintained at 32 °C can support muscle twitches, and tetanic contractions during intermittent nerve-stimulation over a wide range of physiological frequencies, even though they develop less force, than age-matched wild-type (AChE +/+) muscles. Tetanic fade in AChE −/− muscles was temperature-sensitive and more marked at 22 °C than at 32 °C. Inhibition of BChE by tetraisopropylpyrophosphoramide (Iso-OMPA) intensified tetanic fade in AChE −/− muscles, but had no effect on AChE +/+ muscles, suggesting that BChE plays a protective role in nerve terminals. Skeletal muscles from AChE −/− mice adapted to the lack of AChE enzymatic activity by triggering a synaptic remodeling that critically occurred between the second and third week of postnatal development, during synapse elimination. In AChE −/− muscles nAChRs distributed in a smaller and fragmented surface area, that mirrored the branching pattern of motor nerve terminals. These findings indicate that the neuromuscular system exhibits a remarkable plasticity and adaptive responses to the chronic absence of AChE activity that has important consequences for the functioning of the neuromuscular junction.

Nicotinic acetylcholine receptor distribution in relation to spinal neurotransmission pathways.

Neuronal nicotinic receptors (nAChR) are pentameric assemblies of subunits of a gene family where specified combinations of alpha and beta subunits form functional receptors. To extend our understanding of the role of spinal nAChR in the processing of sensory stimuli and regulation of autonomic and motor responses, we initiated investigations to localize nAChR subunit expression within discrete spinal regions and cell types. High-affinity epibatidine binding was present in the superficial dorsal and ventral horns, the mediolateral and central canal regions. RT-PCR identified transcripts for alpha3, alpha4, alpha5, beta2, and beta4 in both spinal cord parenchyma and dorsal root ganglia (DRG). Our affinity-purified antibodies against alpha3, alpha4, alpha5, beta2, and beta4 subunits identified specific protein bands of appropriate molecular mass (preadsorbed with the respective antigens) in specific tissues and cells that express nicotinic receptors, including the spinal cord and DRG neurons. Having established the absence of crossreactivity with related subunits, specific fluorescence labeling of nerve terminals and cell bodies was achieved and correlated with the distribution of defined marker proteins and nicotinic receptor binding sites determined autoradiographically. Our findings indicate that alpha3, alpha4, alpha5, beta2, and beta4 subunits are all expressed on primary afferents (IB4-positive terminals) in the spinal cord. The predominant presynaptic (synaptophysin colocalization) labeling is in the superficial layer of the dorsal horn. These receptor subunits, except for beta4, are also present in postsynaptic autonomic (anti-bNOS-positive) and somatic motor neurons (anti-VAChT-positive). The alpha3, alpha5, and beta2 subunits showed additional staining in glial (anti-GFAP-positive) cells. These studies reveal a dense and distinguishable distribution of nAChR subunits in the spinal cord and point toward future therapeutic targeting for specific spinal actions.

Nicotinic Acetylcholine Receptor Distribution in Alzheimer's Disease, Dementia with Lewy Bodies, Parkinson's Disease, and Vascular Dementia: In Vitro Binding Study Using 5-[125I]-A-85380

Nicotinic acetylcholine receptors (nAChRs) have been implicated in a number of neurological disorders. 5-Iodo-3-[2(S)-2-azetidinylmethoxy]pyridine (5-I-A-85380) is a novel nAChR marker, binding predominantly to the alpha4beta2 subtype. This in vitro autoradiography study describes the distribution of 5-[(125)I]-A-85380 binding in post-mortem brain tissue from normal elderly individuals and from cases with age-associated dementias of both neurodegenerative and vascular types. The binding distribution of 5-[(125)I]-A-85380 in normal brain tissue was found to be consistent with the reported distribution of other high-affinity nicotinic ligands. In addition to high thalamic and moderate striatal and temporal cortex density, moderate 5-[(125)I]-A-85380 binding was also seen in white matter tracts in cingulate, occipital, and temporal areas, indicating the presence of nAChRs along nerve fiber tracts, which has not been reported in other high-affinity nicotinic agonist distribution studies. In Parkinson's disease (PD), loss of striatal 5-[(125)I]-A-85380 binding closely parallels the loss of nigrostriatal dopaminergic markers previously observed. In dementia with Lewy bodies (DLB) reduced striatal 5-[(125)I]-A-85380 binding density, comparable to that in PD, may be a marker of early degeneration in nigrostriatal inputs, while in Alzheimer's disease (AD) reduced striatal 5-[(125)I]-A-85380 binding could be related to reduced cortical inputs. The reductions of nAChRs seen in AD, DLB, and PD were not apparent in vascular dementia (VaD). In conclusion, 5-I-A-85380 is clearly a useful ligand for both in vitro and in vivo single photon emission tomography human studies investigating disease symptoms and progression, response to acetylcholinesterase-inhibiting drugs and in differentiating primary degenerative dementia from VaD.

Functional maturation of nicotinic acetylcholine receptors as an indicator of murine muscular differentiation in a new nerve-muscle co-culture system.

Under normal conditions in situ, muscle fibers and motoneurons, the main partners of motor units, are strongly dependent on each other. This interdependence hinders ex vivo studies of neuromuscular disorders where nervous or muscular components are considered separately. To allow in vitro access to complex nerve-muscle relationships, we developed a novel nerve-muscle co-culture system where mouse muscle innervation is assured by rat spinal cord explants. The degree of muscular maturation during co-culture was evaluated using the distribution of nicotinic acetylcholine receptors (AChRs) and their electrophysiological characteristics before and after innervation. In myotubes from non-innervated cultures, AChRs were diffusely distributed over the entire myotube surface. Their single-channel conductance (33.5+/-0.6 pS) and mean open time (8.1+/-0.7 ms) are characteristic of AChRs described in embryonic or denervated skeletal muscles. In innervated muscle fibers from co-cultures, AChRs appear as discrete aggregates and co-localize with synaptotagmin. In addition to the embryonic type currents, in innervated fibers AChR currents having high conductance (53.3+/-5.9 pS) and short mean open time (2.6+/-0.1 ms), characteristic of AChRs at mature neuromuscular junctions, were observed. Our data support the use of this new nerve-muscle co-culture system as a reliable model for the study of murine muscular differentiation and function.

Topographic distribution of nicotinic acetylcholine receptors in the cristae of a turtle

The neurochemical basis of cholinergic efferent modulation of afferent function in the vestibular periphery remains incompletely understood; however, there is cellular, biochemical and molecular biological evidence for both muscarinic and nicotinic acetylcholine (ACh) receptors (nAChRs) in this system. This study examined the topographic distribution of α-bungarotoxin (α-BTX) nAChRs in the cristae of a turtle species. Cristae were perfusion-fixed, cut at 20 μm on a cryostat and incubated with α-BTX or polyclonal antibodies raised against Torpedo nAChR. Light microscopy showed abundant specific labeling of nAChR in the central zone of each hemicrista on the calyx-bearing afferents surrounding type I hair cells and on the base of the type II hair cells. Within the peripheral zone, dense labeling of type II hair cells near the torus and sparse or no label was observed on type II hair cells near the planum. The α-BTX binding showed a similar pattern within the cristae. The similarity between the topographic distribution of α-BTX binding nAChR and of efferent inhibition of afferents supports the notion that the inhibitory effect of afferents is mediated by nAChR.

A and ß Subunits of Acetylcholine Receptors in the Human Inner Ear

The localization and distribution of nicotinic acetylcholine receptors (n-ACh-r) was characterized by studying

Diversity and distribution of nicotinic acetylcholine receptors in the locus ceruleus neurons.

The neurons of the locus ceruleus are responsible for most of the noradrenergic innervation in the brain and nicotine potentiates noradrenaline release from their terminals. Here we investigated the diversity and subcellular distribution of nicotinic acetylcholine receptors (nAChRs) in the locus ceruleus both somatically, by combining single-cell reverse transcription-PCR with electrophysiological characterization, and at the level of nerve terminals, by conducting noradrenaline efflux experiments. The proportion of neurons in the locus ceruleus expressing the nicotinic subunit mRNAs varied from 100% (beta2) to 3% (alpha2). Yet, two populations of neurons could be distinguished on the basis of the pattern of expression of nAChR mRNAs and electrophysiological properties. One population (type A) of small cells systematically expressed alpha3 and beta4 mRNAs (and often alpha6, beta3, alpha5, alpha4), and nicotinic agonists elicited large currents with a potency order of cytisine > nicotine. Another population (type B) of cells with large soma did not contain alpha3 and beta4 mRNAs but, systematically, alpha6 and beta3 (and often alpha4) and responded to nicotinic agonists in the order of nicotine > cytisine. The nicotinic modulation of noradrenaline release in the hippocampus displayed an order of potency nicotine > cytisine, suggesting that noradrenergic terminals in the hippocampus originate largely from type B cells of the locus ceruleus. Accordingly, immunocytochemical labeling showed that beta3 is present in hippocampal terminals. The alpha6beta3beta2(alpha4) heterooligomer thus behaves as the main nicotinic regulator of the ceruleo-hippocampal pathway.

Distributions of nicotinic acetylcholine receptor α7 and β2 subunits on cultured hippocampal neurons

The hippocampus receives cholinergic afferents and expresses neuronal nicotinic acetylcholine receptors. In particular, the α7 and β2 nicotinic subunits are highly expressed in the hippocampus. There has been controversy about the location, distribution and roles of neuronal nicotinic acetylcholine receptors [Role L. W. and Berg D. K. (1996) Neuron 16, 1077–1085; Wonnacott S. (1997) Trends Neurosci. 20, 92–98]. Using immunocytochemistry and patch-clamp techniques, we examined the density and distribution of nicotinic receptors on rat hippocampal neurons in primary tissue culture. The density and distribution of α7 subunits change with days in culture. Before 10 days in culture, α7 expression, monitored immunocytochemically, is low and nicotinic currents are small or absent. In older cultures, about two-thirds of the neurons express nicotinic currents, and α7 appears in small patches on the soma and out along the neuronal processes. These patches of α7 subunits on the surface of the neuronal processes often co-localize with the presynaptic marker, synaptotagmin. The other most common nicotinic subunit, β2, stays confined mainly to the soma and proximal processes, and β2 is distributed more uniformly and is not specifically localized at presynaptic areas. The two subunits, α7 and β2, have different expression patterns on the surface of the cultured hippocampal neurons. Taken together with previous physiological studies, the results indicate that α7 subunits can be found at presynaptic terminals, and at these locations, these calcium-permeable channels may influence transmitter release.

Nicotinic acetylcholine receptor is involved in acetylcholine regulating stomatal movement

In animal cells, actions of acetylcholine depend on its binding to specific receptors. Activation of nicotinic acetylcholine receptor can affect the membrane permeability to ions directly. As concerned about acetylcholine regulating stomatal movement, nicotinic acetylcholine receptor may also be involved. Experiments with nicotinic acetylcholine receptor antagonist (D-tubocurarine) and agonist (nicotine) showed that nicotinic acetylcholine receptor was involved in acetylcholine inducing stomatal opening. In addition, these effects of D-tubocurarine and nicotine on stomatal movement can only be found in medium containing K(+) while no effects can be found in medium containing Ca(2+), The result by Western blotting showed that at least alpha-and beta-subunits of nicotinic receptor existed in microsomes of guard cell protoplasts. It was found that the distribution of nicotinic acetylcholine receptor was mainly on the surface of protoplasts as shown by FITC labelled alpha-bungarotoxin. The results above show that nicotinic acetylcholine receptor exists in guard cells and mediates acetylcholine to induce stomatal opening.

Nicotinic system involvement in Alzheimer's and Parkinson's diseases. Implications for therapeutics.

Advances in our understanding of the structure, function and distribution of nicotinic acetylcholine receptors in the CNS have provided the impetus for new studies examining the role(s) that these receptors and associated processes may play in CNS functions. Further motivation has come from the realisation that such receptors must be involved in the maintenance of cigarette smoking, and from clues provided by studies of degenerative neurological diseases such as Alzheimer's disease and Parkinson's disease, in which the loss of nicotinic receptors has been described. Ongoing investigations of the molecular substructure of central nicotinic receptors and their pharmacology have begun to open up new possibilities for novel CNS therapeutics with nicotinic agents. Exploiting these possibilities will require understanding of the role(s) that these receptor systems play in human cognitive, behavioural, motor and sensory functioning. Clues from careful studies of human cognition are beginning to emerge and will provide direction for studies of potentially therapeutic novel nicotinic agents. Despite the promising results of acute studies, few long term studies with nicotine or nicotinic drugs have been performed in dementing disorders. Thus there is uncertainty as to whether long term nicotinic treatment will provide sustained cognitive benefit. It is even more uncertain whether such cognitive benefit will have a significant clinical impact on patients and their families. To maximise the potential benefit of long term treatment with nicotinic agonists (or other cholinergic drugs), we suggest that drug treatment should be combined with cognitive rehabilitation strategies. This will enable patients and/or their families to focus on the particular cognitive domains that may be improved.