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.

Drug law enforcement : a review of the evaluation literature

This article describes the results of a systematic review of drug law enforcement evaluations. The authors describe the search procedures and document the results in five main categories: international/national interventions (e.g., interdiction and drug seizure), reactive/ directed interventions (e.g., crackdowns, raids, buy-busts, saturation patrol, etc.), proactive/ partnership interventions (e.g., third-party policing, problem-oriented policing, community policing, drug nuisance abatement, etc.), individualized interventions (e.g., arrest referral and diversion), or interventions that used a combination of reactive/directed and proactive/ partnership strategies. Results indicate that proactive interventions involving partnerships between the police and third parties and/or community entities appear to be more effective at reducing both drug and nondrug problems in drug problem places than are reactive/ directed approaches. But the general quality of research in drug law enforcement is poor, the range of interventions that have been evaluated is limited, and more high-quality research is needed across a greater variety of drug interventions.

Street-level drug law enforcement : a meta-analytical review

Our paper presents the results of a meta-analytical review of street level drug law enforcement. We conducted a series of meta-analyses to compare and contrast the effectiveness of four types of drug law enforcement approaches, including community-wide policing, problem-oriented/ partnership approaches that were geographically focused, hotspots policing and standard, unfocused law enforcement efforts. We examined the relative impact of these different crime control tactics on streetlevel drug problems as well as associated problems such as property crime, disorder and violent crime. The results of the meta-analyses, together with examination of forest plots, reveal that problem-oriented policing and geographically-focused interventions involving cooperative partnerships between police and third parties tend to be more effective at controlling drug problems than community-wide policing efforts that are unfocused and spread out across a community. But geographically focused and community-wide drug law enforcement interventions that leverage partnerships are more effective at dealing with drug problems than traditional, law enforcement-only interventions. Our results suggest that the key to successful drug law enforcement lies in the capacity of the police to forge productive partnerships with third parties rather than simply increasing police presence or intervention (e.g., arrests) at drug hotspots.