Endogenous cholinergic inputs and local circuit mechanisms govern the phasic mesolimbic dopamine response to nicotine

Nicotine exerts its reinforcing action by stimulating nicotinic acetylcholine receptors (nAChRs) and boosting dopamine (DA) output from the ventral tegmental area (VTA). Recent data have led to a debate about the principal pathway of nicotine action: direct stimulation of the DAergic cells through nAChR activation, or disinhibition mediated through desensitization of nAChRs on GABAergic interneurons. We use a computational model of the VTA circuitry and nAChR function to shed light on this issue. Our model illustrates that the α4β2-containing nAChRs either on DA or GABA cells can mediate the acute effects of nicotine. We account for in vitro as well as in vivo data, and predict the conditions necessary for either direct stimulation or disinhibition to be at the origin of DA activity increases. We propose key experiments to disentangle the contribution of both mechanisms. We show that the rate of endogenous acetylcholine input crucially determines the evoked DA response for both mechanisms. Together our results delineate the mechanisms by which the VTA mediates the acute rewarding properties of nicotine and suggest an acetylcholine dependence hypothesis for nicotine reinforcement.Peer reviewe

Improving Pediatric Readiness in General Emergency Departments: A Prospective Interventional Study

OBJECTIVE: To describe the impact of a national interventional collaborative on pediatric readiness within general emergency departments (EDs). STUDY DESIGN: A prospective, multicenter, interventional study measured pediatric readiness in general EDs before and after participation in a pediatric readiness improvement intervention. Pediatric readiness was assessed using the weighted pediatric readiness score (WPRS) on a 100-point scale. The study protocol extended over 6 months and involved 3 phases: (1) a baseline on-site assessment of pediatric readiness and simulated quality of care; (2) pediatric readiness interventions; and (3) a follow-up on-site assessment of WPRS. The intervention phase included a benchmarking performance report, resources toolkits, and ongoing interactions between general EDs and academic medical centers. RESULTS: Thirty-six general EDs were enrolled, and 34 (94%) completed the study. Four EDs (11%) were located in Canada, and the rest were in the US. The mean improvement in WPRS was 16.3 (P < .001) from a baseline of 62.4 (SEM = 2.2) to 78.7 (SEM = 2.1), with significant improvement in the domains of administration/coordination of care; policies, protocol, and procedures; and quality improvement. Six EDs (17%) were fully adherent to the protocol timeline. CONCLUSIONS: Implementing a collaborative intervention model including simulation and quality improvement initiatives is associated with improvement in WPRS when disseminated to a diverse group of general EDs partnering with their regional pediatric academic medical centers. This work provides evidence that innovative collaboration facilitated by academic medical centers can serve as an effective strategy to improve pediatric readiness and processes of care