Multidisciplinary Management and Pulp Vitality Preservation of a Tooth With Extensive Iatrogenic Furcal Root Perforation and Biologic Width Violation.

This article describes the case of a vital molar tooth with a vast furcal iatrogenic root perforation and biologic width violation, which was successfully managed by a multidisciplinary approach aimed at preserving pulp vitality. The root perforation was cleaned and then sealed with mineral trioxide aggregate, which was positioned onto the pulp at the canal orifices. After one month, the patient was not reporting symptoms, and the tooth was positively responding to the thermal test. The tooth was orthodontically extruded, subjected to minimally invasive crown lengthening, and prepared to receive a full-crown restoration. Radiotransparent composite resin was chosen as a permanent restorative material to better monitor possible endodontic complications at the coronal level. The patient's tooth was followed up for eight years uneventfully. The present case is an example of the possibility to subject a root-repaired tooth with fully formed apices to conservative yet complex multidisciplinary treatment while maintaining pulp vitality.

Longitudinal cognitive decline in mild cognitive impairment subjects with early amyloid-ß neocortical deposition.

PURPOSE: The rate of clinical progression of cognitive impairment in subjects with early amyloid deposition is unknown. The primary aim of the study was to follow the rate of cognitive decline over 1 year in patients with amnestic mild cognitive impairment (aMCI) by determining amyloid retention levels in terms of standardized uptake value ratios (SUVr) that ranged from 0.85 to 1.57. The secondary objective was to compare the rate of cognitive decline between subjects with and without early amyloid positivity. METHODS: Of 66 aMCI subjects evaluated with [18F]florbetaben PET imaging and neuropsychological tests at baseline, 41 completed the 1-year follow-up. Amyloid status was determined with SUVr cut-off values generated from baseline images by visual assessment by three independent certified readers. Repeated-measures ANOVA with amyloid load and neuropsychological scores as the main effects was use to test group, time and group-by-time interactions. The Tukey post-hoc test was used to analyse all significant interactions. RESULTS: Of the 41 aMCI subjects, 38 completed the assessment according to the study protocol. Amyloid-positive (Aß+ ) subjects (N = 18, age 75.6 ± 5.8 years, six men, 12 women) showed greater clinical deterioration according to the Mattis Dementia Rating Scale (MDRS) score (p = 0.006). Amyloid-negative (Aß-) subjects (N = 20, age 72.4 ± 5.8 years, 11 men, 6 women) showed no significant changes in MDRS score over 1 year. MDRS score significantly decreased (MDRS+) in 37% of the aMCI subjects, and remained stable (MDRS-) in the remaining 63%. Among subjects with cognitive deterioration, 86% were Aß+ and 14% were Aß-, while 25% of the MDRS- subjects were Aß+ and 75% were Aß- (χ2 = 13, P = 0.0003). SUVr above 1.21 identified individuals who would show significant progression over 1 year, with a sensitivity of 67% and a specificity of 90%, as compared to Aß- subjects. The positive predictive value, negative predictive value, and likelihood ratio were 86% (95% CI 70-94%), 75% (95% CI 58-87%), 7 (95% CI 5-10). CONCLUSION: This study demonstrated that early amyloid deposition predicts cognitive decline in subjects with aMCI, with a higher rate of decline in those with SUVr above a threshold of 1.21. Detection of early amyloid positivity may help in selecting the target population for preventive therapeutic interventions and in designing treatment trials (Trial number, EudraCT 2015-001184-39).

Do Nanofilled/Nanohybrid Composites Allow for Better Clinical Performance of Direct Restorations Than Traditional Microhybrid Composites? A Systematic Review.

This systematic review was carried out to assess the clinical effectiveness of nanofilled and nanohybrid composites used for direct restorations in comparison with microhybrid composites. The guidelines for the preferred reporting items for systematic reviews and meta-analyses were followed. A search of articles published from July 1996 to February 2017 was performed in PubMed, SciVerse Scopus, Latin American and Caribbean Health Sciences, the Scientific Electronic Library Online, and the Cochrane Library. The present review selected only randomized controlled trials comparing the clinical performance of a nanofilled or nanohybrid composite for direct restorations with that of a microhybrid composite. The research found 201 studies. Twenty-one articles fulfilled the criteria of the present review. However, the included studies were characterized by great methodological diversities. As a general trend, nanofilled and nanohybrid composites were found to be capable of clinical performance, marginal quality, and resistance to wear similar to that of traditional composites without showing improved surface characteristics. The risk of bias of included studies was judged unclear or high. The clinical performance of nanofilled/nanohybrid composites was found to be comparable to that of traditional composites in the posterior area. The data concerning anterior and cervical restorations were insufficient. With regard to the esthetic properties, there is a compelling need for studies on anterior teeth in which the operators are kept unaware of the restorative material. Nanofilled/nanohybrid composites seem to be a valid alternative to traditional microhybrid composites, and at the moment, there is low-level evidence attesting a lack of their superiority.

Influence of finish line on the marginal seal of nanohybrid composite crowns after periodontal scaling: a microleakage study.

AIM: The aim of the present microleakage study was to assess the sealing ability of nanohybrid composite crowns with different finish lines exposed to simulated mechanical periodontal treatment (SMPT). METHODS: After sample size calculation (α=0.05; ß=0.20; δ=1.0; σ=0.8), sixty extracted mandibular molars were divided into four groups (N.=15): G1, 90° shoulder; G2, beveled 90° shoulder; G3, 90° shoulder and SMPT; G4, beveled 90° shoulder and SMPT. Tooth preparations were carried out by means of diamond burs and Arkansas stones. The buildup of crowns was performed with a nanohybrid composite on master casts obtained after polyether impressions and crowns were cemented with self-adhesive cement. Groups G3 and G4 were subjected to the equivalent of five years of semestral mechanical periodontal scaling with Gracey curettes (2-mm long strokes, 5 N). Samples were immersed into a methylene blue supersaturated solution for 10 minutes. Microleakage was measured by stereomicroscopic observation of multiple sections of the samples and leakage data underwent statistical analysis with non-parametric tests. RESULTS: Marginal microleakage was 1.53±1.27% and 17.60±12.72% of the length of the adhesive interface in G1 and G2, respectively. SMPT reduced dye penetration (P<0.001) with G3 not leaking at all and G4 leaking along the 5.58±1.84% of the adhesive interface. The bevel preparation significantly worsened the marginal seal both in control and treated crowns (P<0.001). CONCLUSION: Microleakage of nanohybrid composite crowns increased by adding a bevel to a 90° shoulder preparation and diminished after SMPT.

Assessment of affective and somatic signs of ethanol withdrawal in C57BL/6J mice using a short-term ethanol treatment.

Alcohol is one of the most prevalent addictive substances in the world. Withdrawal symptoms result from abrupt cessation of alcohol consumption in habitual drinkers. The emergence of both affective and physical symptoms produces a state that promotes relapse. Mice provide a preclinical model that could be used to study alcohol dependence and withdrawal while controlling for both genetic and environmental variables. The use of a liquid ethanol diet offers a reliable method for the induction of alcohol dependence in mice, but this approach is impractical when conducting high-throughput pharmacological screens or when comparing multiple strains of genetically engineered mice. The goal of this study was to compare withdrawal-associated behaviors in mice chronically treated with a liquid ethanol diet vs. mice treated with a short-term ethanol treatment that consisted of daily ethanol injections containing the alcohol dehydrogenase inhibitor, 4-methylpyrazole. Twenty-four hours after ethanol treatment, mice were tested in the open field arena, the elevated plus maze, the marble burying test, or for changes in somatic signs during spontaneous ethanol withdrawal. Anxiety-like and compulsive-like behaviors, as well as physical signs, were all significantly elevated in mice undergoing withdrawal, regardless of the route of ethanol administration. Therefore, a short-term ethanol treatment can be utilized as a screening tool for testing genetic and pharmacological agents before investing in a more time-consuming ethanol treatment.

New mechanisms and perspectives in nicotine withdrawal.

Diseases associated with tobacco use constitute a major health problem worldwide. Upon cessation of tobacco use, an unpleasant withdrawal syndrome occurs in dependent individuals. Avoidance of the negative state produced by nicotine withdrawal represents a motivational component that promotes continued tobacco use and relapse after smoking cessation. With the modest success rate of currently available smoking cessation therapies, understanding mechanisms involved in the nicotine withdrawal syndrome are crucial for developing successful treatments. Animal models provide a useful tool for examining neuroadaptative mechanisms and factors influencing nicotine withdrawal, including sex, age, and genetic factors. Such research has also identified an important role for nicotinic receptor subtypes in different aspects of the nicotine withdrawal syndrome (e.g., physical vs. affective signs). In addition to nicotinic receptors, the opioid and endocannabinoid systems, various signal transduction pathways, neurotransmitters, and neuropeptides have been implicated in the nicotine withdrawal syndrome. Animal studies have informed human studies of genetic variants and potential targets for smoking cessation therapies. Overall, the available literature indicates that the nicotine withdrawal syndrome is complex, and involves a range of neurobiological mechanisms. As research in nicotine withdrawal progresses, new pharmacological options for smokers attempting to quit can be identified, and treatments with fewer side effects that are better tailored to the unique characteristics of patients may become available. This article is part of the Special Issue entitled 'The Nicotinic Acetylcholine Receptor: From Molecular Biology to Cognition'.

Influence of simulated apical resorption following orthodontic treatment on working length determination: an in vitro study.

AIM: External apical root resorption (EARR) is a common complication that may occur during and after orthodontic treatment. In case of need of endodontic therapy for a tooth with EARR, it has not been clarified yet which benefits can be derived by the use of electronic apex locators (EALs). The present study aimed to assess the accuracy of EALs on extracted teeth before and after simulation of EARR subsequent to orthodontic treatment. MATERIALS AND METHODS: Standard access cavities were prepared on 64 single-rooted teeth. After working length (CWL) determination, specimens were embedded in an alginate mass, connected to two EALs (Apit, Osada, Tokyo, Japan; Root ZX, Morita Corp., Tokyo, Japan) and the electronic working length (EWL) was measured. The apical portion of the specimens was then modified to simulate EARR, and the EWL was determined again. The discrepancy between CWL and EWL was regarded as statistical unit. Collected data underwent statistical analysis by means of non-parametric tests (p < 0.05). RESULTS: Within a range of ± 0.5 and ± 1.0 mm from CWL, the accuracies were 79.7% and 98.4% (Apit/intact tooth); 82.8% and 96.9% (Apit/simulated EARR); 81.3% and 98.4% (Root ZX/intact tooth); 76.6% and 96.9% (Root ZX/simulated EARR). No statistically significant differences in relation to device or apical condition emerged (p > 0.05). CONCLUSION: The two considered EALs showed similar accuracy, which was not affected by the EARR simulation. The use of EALs in the treatment of teeth with EARR following orthodontic treatment may be useful.

Scientific overview: 2013 BBC plenary symposium on tobacco addiction.

Nicotine dependence plays a critical role in addiction to tobacco products, and thus contributes to a variety of devastating tobacco-related diseases (SGR 2014). Annual costs associated with smoking in the US are estimated to be between $289 and $333 billion. Effective interventions for nicotine dependence, especially in smokers, are a critical barrier to the eradication of tobacco-related diseases. This overview highlights research presented at the Plenary Symposium of Behavior, Biology and Chemistry: Translational Research in Addiction Conference (BBC), hosted by the UT Health Science Center San Antonio, on March 9-10, 2013. The Plenary Symposium focused on tobacco addiction, and covered topics ranging from basic science to national policy. As in previous years, the meeting brought together globally-renowned scientists, graduate student recruits, and young scientists from underrepresented populations in Texas and other states with the goal of fostering interest in drug addiction research in young generations.

The α3ß4* nicotinic ACh receptor subtype mediates physical dependence to morphine: mouse and human studies.

BACKGROUND AND PURPOSE: Recent data have indicated that α3ß4* neuronal nicotinic (n) ACh receptors may play a role in morphine dependence. Here we investigated if nACh receptors modulate morphine physical withdrawal. EXPERIMENTAL APPROACHES: To assess the role of α3ß4* nACh receptors in morphine withdrawal, we used a genetic correlation approach using publically available datasets within the GeneNetwork web resource, genetic knockout and pharmacological tools. Male and female European-American (n = 2772) and African-American (n = 1309) subjects from the Study of Addiction: Genetics and Environment dataset were assessed for possible associations of polymorphisms in the 15q25 gene cluster and opioid dependence. KEY RESULTS: BXD recombinant mouse lines demonstrated an increased expression of α3, ß4 and α5 nACh receptor mRNA in the forebrain and midbrain, which significantly correlated with increased defecation in mice undergoing morphine withdrawal. Mice overexpressing the gene cluster CHRNA5/A3/B4 exhibited increased somatic signs of withdrawal. Furthermore, α5 and ß4 nACh receptor knockout mice expressed decreased somatic withdrawal signs compared with their wild-type counterparts. Moreover, selective α3ß4* nACh receptor antagonists, α-conotoxin AuIB and AT-1001, attenuated somatic signs of morphine withdrawal in a dose-related manner. In addition, two human datasets revealed a protective role for variants in the CHRNA3 gene, which codes for the α3 nACh receptor subunit, in opioid dependence and withdrawal. In contrast, we found that the α4ß2* nACh receptor subtype is not involved in morphine somatic withdrawal signs. CONCLUSION AND IMPLICATIONS: Overall, our findings suggest an important role for the α3ß4* nACh receptor subtype in morphine physical dependence.

Genetic variation within the Chrna7 gene modulates nicotine reward-like phenotypes in mice.

Mortality from tobacco smoking remains the leading cause of preventable death in the world, yet current cessation therapies are only modestly successful, suggesting new molecular targets are needed. Genetic analysis of gene expression and behavior identified Chrna7 as potentially modulating nicotine place conditioning in the BXD panel of inbred mice. We used gene targeting and pharmacological tools to confirm the role of Chrna7 in nicotine conditioned place preference (CPP). To identify molecular events downstream of Chrna7 that may modulate nicotine preference, we performed microarray analysis of α7 knock-out (KO) and wild-type (WT) nucleus accumbens (NAc) tissue, followed by confirmation with quantitative polymerase chain reaction (PCR) and immunoblotting. In the BXD panel, we found a putative cis expression quantitative trait loci (eQTL) for Chrna7 in NAc that correlated inversely to nicotine CPP. We observed that gain-of-function α7 mice did not display nicotine preference at any dose tested, whereas conversely, α7 KO mice demonstrated nicotine place preference at a dose below that routinely required to produce preference. In B6 mice, the α7 nicotinic acetylcholine receptor (nAChR)-selective agonist, PHA-543613, dose-dependently blocked nicotine CPP, which was restored using the α7 nAChR-selective antagonist, methyllycaconitine citrate (MLA). Our genomic studies implicated a messenger RNA (mRNA) co-expression network regulated by Chrna7 in NAc. Mice lacking Chrna7 demonstrate increased insulin signaling in the NAc, which may modulate nicotine place preference. Our studies provide novel targets for future work on development of more effective therapeutic approaches to counteract the rewarding properties of nicotine for smoking cessation.

Nicotine consumption is regulated by a human polymorphism in dopamine neurons.

Smoking is the most important preventable cause of morbidity and mortality worldwide. Recent genome-wide association studies highlighted a human haplotype on chromosome 15 underlying the risk for tobacco dependence and lung cancer. Several polymorphisms in the CHRNA3-CHRNA5-CHRNB4 cluster coding for the nicotinic acetylcholine receptor (nAChR) α3, α5 and ß4 subunits were implicated. In mouse models, we define a key role in the control of sensitivity to nicotine for the α5 subunit in dopaminergic (DAergic) neurons of the ventral tegmental area (VTA). We first investigated the reinforcing effects of nicotine in drug-naive α5(-/-) mice using an acute intravenous nicotine self-administration task and ex vivo and in vivo electrophysiological recordings of nicotine-elicited DA cell activation. We designed lentiviral re-expression vectors to achieve targeted re-expression of wild-type or mutant α5 in the VTA, in general, or in DA neurons exclusively. Our results establish a crucial role for α5*-nAChRs in DAergic neurons. These receptors are key regulators that determine the minimum nicotine dose necessary for DA cell activation and thus nicotine reinforcement. Finally, we demonstrate that a single-nucleotide polymorphism, the non-synonymous α5 variant rs16969968, frequent in many human populations, exhibits a partial loss of function of the protein in vivo. This leads to increased nicotine consumption in the self-administration paradigm. We thus define a critical link between a human predisposition marker, its expression in DA neurons and nicotine intake.

[Time trends of incidence rates of work accident with blood contamination in a North Italian teaching hospital]. / Ana+lisi dei trend temporali (2004-11) dei tassi di infortunio biologico in un ospedale universitario del nord Italia. Quali evidenze di efficacia dei sistemi di prelievo a vuoto?

Unbiased estimates of incidence rates of accidents with blood contaminations (ABC) and time trends is the milieu for assessing the effectiveness of preventive interventions. A standardised procedure for registration and follow-up of ABC was et up in a North Italian hospital since 2002. Accurate estimates of rate denominator, as full-time equivalent (FTE) person-years, was calculated, for exposed workers only and excluding periods of prolonged absence. In the observation period (2004-2011), training courses for head nurses on security procedures were repeatedly carried out as well as the progressive introduction of vacuum blood collection systems (since 2009). 1287 ABC have been reported, corresponding to an overall annual crude incidence rate of 4.73 per 100 FTE. Temporal trends, calculated on the biennial incidence, resulted in a reductions over the time period considered, in particular for needlestick injuries. Our results support the notions on the efficacy of the adopted prevention measures.

Quality of thermoplasticized and single point root fillings assessed by micro-computed tomography.

AIM: To evaluate ex vivo the quality of root fillings completed by two thermoplasticized gutta-percha techniques (Thermafil and System B) and a cold gutta-percha technique (single point) by µCT analysis. METHODOLOGY: A total of 30 freshly extracted human single-rooted permanent teeth were selected. Root canals were prepared with ProTaper Universal instruments and then randomly divided into three groups (n = 10) depending on the filling technique. In group 1, canals were filled with a single-point technique; group 2 was filled with Thermafil; in group 3 System B was used. In group 1 and group 3, the root filling was performed using ProTaper Universal gutta-percha points, in group 2 Thermafil obturators were used; AH-Plus sealer was used in all groups. Assessment of the root filling was carried out by µCT, using a desktop X-ray micro focus CT scanner. Percentage of root canal filling materials and voids was calculated for each specimen. Data were statistically analysed using Kruskal-Wallis test (P < 0.05). RESULTS: Mean percentages of filling materials were 98.379 ± 1.204 in the single-point group, 99.023 ± 1.457 in Thermafil group, and 98.167 ± 3.432 in System B group. No statistically significant difference was found amongst the groups. CONCLUSION: All techniques produced comparable results in terms of percentage of filling and void distribution.

Progesterone modulation of alpha5 nAChR subunits influences anxiety-related behavior during estrus cycle.

Smokers often report an anxiolytic effect of cigarettes. In addition, stress-related disorders such as anxiety, post-traumatic stress syndrome and depression are often associated with chronic nicotine use. To study the role of the alpha5 nicotinic acetylcholine receptor subunit in anxiety-related responses, control and alpha5 subunit null mice (alpha5(-/-)) were subjected to the open field activity (OFA), light-dark box (LDB) and elevated plus maze (EPM) tests. In the OFA and LDB, alpha5(-/-) behaved like wild-type controls. In the EPM, female alpha5(-/-) mice displayed an anxiolytic-like phenotype, while male alpha5(-/-) mice were undistinguishable from littermate controls. We studied the hypothalamus-pituitary-adrenal axis by measuring plasma corticosterone and hypothalamic corticotropin-releasing factor. Consistent with an anxiolytic-like phenotype, female alpha5(-/-) mice displayed lower basal corticosterone levels. To test whether gonadal steroids regulate the expression of alpha5, we treated cultured NTera 2 cells with progesterone and found that alpha5 protein levels were upregulated. In addition, brain levels of alpha5 mRNA increased upon progesterone injection into ovariectomized wild-type females. Finally, we tested anxiety levels in the EPM during the estrous cycle. The estrus phase (when progesterone levels are low) is anxiolytic-like in wild-type mice, but no cycle-dependent fluctuations in anxiety levels were found in alpha5(-/-) females. Thus, alpha5-containing neuronal nicotinic acetylcholine receptors may be mediators of anxiogenic responses, and progesterone-dependent modulation of alpha5 expression may contribute to fluctuations in anxiety levels during the ovarian cycle.

Nicotine relieves anxiogenic-like behavior in mice that overexpress the read-through variant of acetylcholinesterase but not in wild-type mice.

Stress increases vulnerability and causes relapse to drugs of abuse. The usually rare read-through variant of acetylcholinesterase (AChE-R) is causally involved in stress-related behaviors, and transgenic mice constitutively overexpressing AChE-R (TgR) show behaviors characteristic of chronic stress. We measured anxiety-like behavior on TgR and control mice under normal conditions and under long-term nicotine treatment. In addition, we measured epibatidine binding in the brain and transcription status in the striatum, using microarrays, in wild-type and TgR mice. TgR mice behaved as more anxious than controls, an effect normalized by long-term nicotine intake. In control mice, long-term nicotine augmented epibatidine binding in several areas of the brain, including the hippocampus and striatum. In TgR transgenics, long-term nicotine increased epibatidine binding in some areas but not in the hippocampus or the striatum. Because the striatum is involved in the mechanisms of drug addiction, we studied how the transgene affected striatal gene expression. Whole-genome DNA microarray showed that 23 transcripts were differentially expressed in TgR mouse striata, including 15 known genes, 7 of which are anxiety-related. Subsequent reverse-transcriptase polymerase chain reaction validated changes in 7 of those 15 genes, confirmed the increase trend in 5 more transcripts, and further revealed changes in 5 genes involved in cholinergic signaling. In summary, we found that nicotine acts as an anxiolytic in TgR mice but not in control mice and that continuously overexpressed AChE-R regulates striatal gene expression, modulating cholinergic signaling and stress-related pathways.

Evaluating the suitability of nicotinic acetylcholine receptor antibodies for standard immunodetection procedures.

Nicotinic acetylcholine receptors play important roles in numerous cognitive processes as well as in several debilitating central nervous system (CNS) disorders. In order to fully elucidate the diverse roles of nicotinic acetylcholine receptors in CNS function and dysfunction, a detailed knowledge of their cellular and subcellular localizations is essential. To date, methods to precisely localize nicotinic acetylcholine receptors in the CNS have predominantly relied on the use of anti-receptor subunit antibodies. Although data obtained by immunohistology and immunoblotting are generally in accordance with ligand binding studies, some discrepancies remain, in particular with electrophysiological findings. In this context, nicotinic acetylcholine receptor subunit-deficient mice should be ideal tools for testing the specificity of subunit-directed antibodies. Here, we used standard protocols for immunohistochemistry and western blotting to examine the antibodies raised against the alpha3-, alpha4-, alpha7-, beta2-, and beta4-nicotinic acetylcholine receptor subunits on brain tissues of the respective knock-out mice. Unexpectedly, for each of the antibodies tested, immunoreactivity was the same in wild-type and knock-out mice. These data imply that, under commonly used conditions, these antibodies are not suited for immunolocalization. Thus, particular caution should be exerted with regards to the experimental approach used to visualize nicotinic acetylcholine receptors in the brain.

Potential applications of nicotinic ligands in the laboratory and clinic.

The nicotinic acetylcholine receptor (nAChR) is a receptor, ion channel complex composed of five polypeptide subunits. There are many different nAChR subtypes constructed from a variety of different subunit combinations. This structural diversity contributes to the varied roles of nAChRs in the peripheral and central nervous system, and this diversity offers an excellent opportunity for chemists who are producing ligands. Subunit specific ligands could have wide and varied effects in the laboratory as experimental tools and in the clinic as therapeutic agents. Because presynaptic nAChRs have been shown to enhance the release of many neurotransmitters, new nicotinic ligands that potentiate nAChR activity would be very useful. Such ligands could enhance the release of various neurotransmitters during degenerative diseases that cause neurotransmitter systems to decrease their output. For example, boosting the release from cholinergic neurons would help patients with Alzheimer's disease, and boosting the release from dopaminergic neurons would help patients with Parkinson's disease.

The elderly cancer patient: a nursing perspective.

Since cancer incidence tends to increase with age, health professionals will encounter ever-greater numbers of older people with cancer. Elderly cancer patients present complex problems that need comprehensive physical and psychosocial support. In order to give specialised care to this segment of the population, a multidisciplinary approach must be used; only in this way can an individualised treatment program be provided. Oncology nurses are an important component of this team and can contribute significantly to the panorama of needs of this segment of the population, which include the prevention and early detection of cancer, the use of state-of-the-art treatments, patient education, care during and after hospitalisation and quality of life (QOL) issues. In this way, the older person with cancer can be treated in an optimal manner and survival can hopefully be improved in a meaningful way.

Cellular mechanisms of nicotine addiction.

In developed countries, tobacco use is estimated to be the largest single cause of premature death [Lancet 339 (1992) 1268]. Nicotine is the main addictive component of tobacco that motivates continued use despite the harmful effects. Nicotinic acetylcholine receptors (nAChRs) are widely distributed throughout the mammalian central nervous system (CNS), where they normally respond to acetylcholine (ACh) and modulate neuronal excitability and synaptic communication. Nicotinic receptors are structurally diverse and have varied roles. Presynaptic and preterminal nAChRs enhance neurotransmitter release. Postsynaptic and somal nAChRs mediate a small proportion of fast excitatory transmission and modulate cytoplasmic second messenger systems. Although the impact of nicotine obtained from tobacco is not completely understood, a portion of nicotine's addictive power is attributable to actions upon the dopaminergic systems, which normally help to reinforce rewarding behaviors. As obtained from tobacco, nicotine activates and desensitizes nAChRs, and both processes contribute to the cellular events that underlie nicotine addiction.

Altered baroreflex responses in alpha7 deficient mice.

The autonomic nervous system controls and coordinates several cardiovascular functions, including heart rate, arterial pressure, blood flow and vasomotor tone. Neuronal nicotinic acetylcholine receptors (nAChRs) are the interface between the nervous system and the cardiovascular system, but it is not known which nAChR subtypes regulate autonomic function in vivo. Nicotinic AChRs containing the alpha7 subunit are a candidate subtype in autonomic ganglia. Stimulation of these nAChRs can increase neurotransmitter release via presynaptic mechanisms, as well as mediate fast synaptic transmission via postsynaptic mechanisms. To investigate the role of the alpha7 nAChR subunit in cardiac autonomic function, we measured baroreflex-mediated responses in alpha7 null mice. Here we show that the alpha7 null mice have impaired sympathetic responses to vasodilatation, as sodium nitroprusside infusion triggered a 48% heart rate increase in wild type mice but only a 21% increase in the alpha7 nulls (P < 0.001). The mutant mice developed supersensitivity to adrenergic agonists, although norepinephrine release from sympathetic nerve terminals could be elicited through mechanisms alternative to nAChR stimulation. Baroreflex-mediated parasympathetic responses were normal in alpha7 null mice. The decreased baroreflex-mediated tachycardia in alpha7 mutant mice indicates that alpha7-containing nAChRs participate in the autonomic reflex that maintains blood pressure homeostasis. The alpha7 mutant mice may serve as a model of baroreflex impairment arising from autonomic dysfunction.