Partial agonists of the [alpha]3[beta]4[ast] neuronal nicotinic acetylcholine receptor reduce ethanol consumption and seeking in rats

Alcohol use disorders (AUDs) impact millions of individuals and there remain few effective treatment strategies. Despite evidence that neuronal nicotinic acetylcholine receptors (nAChRs) have a role in AUDs, it has not been established which subtypes of the nAChR are involved. Recent human genetic association studies have implicated the gene cluster CHRNA3-CHRNA5-CHRNB4 encoding the α3, α5, and β4 subunits of the nAChR in susceptibility to develop nicotine and alcohol dependence; however, their role in ethanol-mediated behaviors is unknown due to the lack of suitable and selective research tools. To determine the role of the α3, and β4 subunits of the nAChR in ethanol self-administration, we developed and characterized high-affinity partial agonists at α3β4 nAChRs, CP-601932, and PF-4575180. Both CP-601932 and PF-4575180 selectively decrease ethanol but not sucrose consumption and operant self-administration following long-term exposure. We show that the functional potencies of CP-601932 and PF-4575180 at α3β4 nAChRs correlate with their unbound rat brain concentrations, suggesting that the effects on ethanol self-administration are mediated via interaction with α3β4 nAChRs. Also varenicline, an approved smoking cessation aid previously shown to decrease ethanol consumption and seeking in rats and mice, reduces ethanol intake at unbound brain concentrations that allow functional interactions with α3β4 nAChRs. Furthermore, the selective α4β2(*) nAChR antagonist, DHβE, did not reduce ethanol intake. Together, these data provide further support for the human genetic association studies, implicating CHRNA3 and CHRNB4 genes in ethanol-mediated behaviors. CP-601932 has been shown to be safe in humans and may represent a potential novel treatment for AUDs.

Mutations in exon 3 of the beta-catenin gene are rare in melanoma cell lines

Mutations in exon 3 of the CTNNB1 gene encoding beta-catenin have been reported in colorectal cancer cell lines and tumours. Although one study reported mutations or deletions affecting beta-catenin in 20% of melanoma cell lines, subsequent reports detected a much lower frequency of aberrations in uncultured melanomas. To determine whether this difference in mutation frequency reflected an in vitro culturing artefact, exon 3 of CTNNB1 was screened in a panel of 62 melanoma cell lines. In addition, reverse transcription-polymerase chain reaction (RT-PCR) was performed to detect intragenic deletions affecting exon 3. One out of 62 (1.6%) cell lines was found to carry a mutation, indicating that aberration of the Wnt-1/wingless pathway through activation of beta-catenin is a rare event, even in melanoma cell lines.

The asthmatic athlete, inhaled beta agonists, and performance

INTRODUCTION: The large increase in the number of athletes who apply to use inhaled beta agonists (IBAs) at the Olympic Games is a concern to the medical community. This review will examine the use of IBAs in the asthmatic athlete, the variability that exists between countries and sport, and outline a plan to justify the use of these medications. DATA SOURCES: Much of this article is a result of an International Olympic Committee (IOC) Medical Commission-sponsored meeting that took place in May 2001. Records of the use of IBAs at previous Olympics were reviewed. MEDLINE Searches (PubMed interface) were performed using key words to locate published work relating to asthma, elite athletes, performance, treatment, and ergogenic aids. MAIN RESULTS: Since 1984 there have been significant increases in the use of IBAs at the Olympic Games as well as marked geographical differences in the percentage of athletes requesting the use of IBAs. There are large differences in the incidence of IBA use between sports with a trend towards increased use in endurance sports. There are no ergogenic effects of any IOC-approved IBA given in a therapeutic dose. CONCLUSIONS: In many cases, the prescription of IBAs to this population has been made on empirical grounds. Beginning with the 2002 Winter Games, athletes will be required to submit to the IOC Medical Commission clinical and laboratory evidence that justifies the use of this medication. The eucapnic voluntary hyperpnea test will be used to assess individuals who have not satisfied an independent medical panel of the need to use an IBA.

Cytokine synthesis by intestinal intraepithelial lymphocytes. Both gamma/delta T cell receptor-positive and alpha/beta T cell receptor-positive T cells in the G1 phase of cell cycle produce IFN-gamma and IL-5

Murine intestinal intraepithelial lymphocytes (IEL) have been shown to contain subsets of alpha/beta TCR+ and gamma/delta TCR+ T cells that spontaneously produce cytokines such as IFN-gamma and IL-5. We have now determined the nature and cell cycle stage of these cytokine-producing T lymphocytes in EIL by using IFN-gamma- and IL-5-specific ELISPOT assay, cytokine-specific mRNA-cDNA dot-blot hybridization and polymerase chain reaction, and flow cytometry (FACS) for DNA analysis. When CD3+ T cells from IEL of normal C3H/HeN mice were separated into low and high density fractions by discontinuous Percoll gradients, IFN-gamma and IL-5 spot-forming cells were only found in the former population. Analysis of mRNA for these cytokines by both IFN-gamma- and IL-5-specific dot-blot hybridization and polymerase chain reaction revealed that higher levels of message for IFN-gamma and IL-5 were also seen in the low density fraction. However, cell cycle analysis of these two fractions by FACS using propidium iodide showed a similar pattern of cell cycle stages in both low and high density populations (G0 + G1 approximately 96 to 98% and S/G2 + M approximately 2 to 4%). Finally, mRNA from gamma/delta TCR+ and alpha/beta TCR+ T cells in both low and high density fractions of IEL were analyzed for IFN-gamma and IL-5 message by polymerase chain reaction. After 35 cycles of amplification, both gamma/delta TCR+ and alpha/beta TCR+ T cells in the low density fraction expressed higher levels of message for these two cytokines when compared with the high density population. These results have now shown that both gamma/delta and alpha/beta TCR+ IEL can be separated into low and high density subsets and both fractions possess a similar stage of cell cycle. However, only the low density cells (in G1 phase) of both gamma/delta and alpha/beta TCR types possess increased cytokine-specific mRNA and produce the cytokines IFN-gamma and IL-5. Our results suggest that alpha/beta TCR+ and gamma/delta TCR+ IEL can produce cytokines without cell proliferation.

Molecular and structural requirements of the ß1L-adrenoceptor

Noradrenaline which occurs naturally in the body binds to beta-adrenoceptors on the heart, causing the heart to beat faster and with greater force in response to increased demand. This enables the heart to provide oxygenated blood to vital organs. Prolonged overstimulation by noradrenaline can be harmful to the heart and lead to the progression of heart disease. In these circumstances beta-adrenoceptors are blocked with drugs called beta-blockers. Beta-blockers block the effects of noradrenaline by binding to the same site on the beta-adrenoceptor. Some beta-blockers such as CGP12177 can also cause increases in heart rate. Therefore it was proposed that CGP12177 could bind in a different place to noradrenaline. The aim of this study was to determine where CGP12177 binds to on the beta-adrenoceptor. The results have revealed a separate binding site named beta-1-low. These results may lead to the development of improved -blockers for the management of heart conditions.

What drives the commodity price beta of oil industry stocks

We test theoretical drivers of the oil price beta of oil industry stocks. The strongest statistical and economic support comes for market conditions-type variables as the prime drivers: namely, oil price (+), bond rate (+), volatility of oil returns (−) and cost of carry (+). Though statistically significant, exogenous firm characteristics and oil firms' financing decisions have less compelling economic significance. There is weaker support for the prediction that financial risk management reduces the exposure of oil stocks to crude oil price variation. Finally, extended modelling shows that mean reversion in oil prices also helps explain cross-sectional variation in the oil beta.