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.

An experimental research investigation into disused flat rail wagons as bridges with applications for low volume rural roads in Australia

An experimental laboratory investigation was carried out to assess the structural adequacy of a disused PHO Class Flat Bottom Rail Wagon (FRW) for a single lane low volume road bridge application as per the design provisions of the Australian Bridge Design Standard AS 5100(2004). The investigation also encompassed a review into the risk associated with the pre-existing damage in wagons incurred during their service life on rail. The main objective of the laboratory testing of the FRW was to physically measure its performance under the same applied traffic loading it would be required to resist as a road bridge deck. In order to achieve this a full width (5.2m) single lane, single span (approximately 10m), simply supported bridge would be required to be constructed and tested in a structural laboratory. However, the available clear spacing between the columns of the loading portal frame encountered within the laboratory was insufficient to accommodate the 5.2m wide bridge deck excluding clearance normally considered necessary in structural testing. Therefore, only half of the full scale bridge deck (single FRW of width 2.6m) was able to be accommodated and tested; with the continuity of the bridge deck in the lateral direction applied as boundary constraints along the full length of the FRW at six selected locations. This represents a novel approach not yet reported in the literature for bridge deck testing to the best of the knowledge of the author. The test was carried out under two loadings provided in AS 5100 (2004) – one stationary W80 wheel load and the second a moving axle load M1600. As the bridge investigated in the study is a single lane single span low volume road bridge, the risk of pre-existing damage and the expected high cycle fatigue failure potential was assessed as being minimal and hence the bridge deck was not tested structurally for fatigue/ fracture. The high axle load requirements have instead been focussed upon the investigation into the serviceability and ultimate limit state requirements. The testing regime adopted however involved extensive recording of strains and deflections at several critical locations of the FRW. Three locations of W80 point load and two locations of the M1600 Axle load were considered for the serviceability testing; the FRW was also tested under the ultimate load dictated by the M1600. The outcomes of the experimental investigation have demonstrated that the FRW is structurally adequate to resist the prescribed traffic loadings outlaid in AS 5100 (2004). As the loading was directly applied on to the FRW, the laboratory testing is assessed as being significantly conservative. The FRW bridge deck in the field would only resist the load transferred by the running platform, where, depending on the design, composite action might exist – thereby the share of the loading which needs to be resisted by the FRW would be smaller than the system tested in the lab. On this basis, a demonstration bridge is under construction at the time of writing this thesis and future research will involve field testing in order to assess its performance.