The Discriminative Stimulus Properties of the Atypical Antipsychotic Clozapine in C57BL/6 Mice

Serotonin and α1 adrenergic receptor antagonism may contribute to atypical antipsychotic drug effects. Clozapine (2.5 mg/kg) drug discrimination in C57BL/6 mice may selectively screen atypical antipsychotic drugs. Previous data show that the atypical antipsychotics olanzapine, risperidone, ziprasidone but not the typical antipsychotic haloperidol fully substitutes for clozapine. The present study demonstrated that the atypical antipsychotics quetiapine, sertindole, zotepine, iloperidone, melperone fully substituted for clozapine but aripiprazole did not. The typical antipsychotics fluphenazine and perphenazine failed to fully substitute for clozapine but chlorpromazine and thioridazine fully substituted for clozapine. This model does not differentiate between atypical and typical antipsychotic drugs but it may be useful in the detection of antipsychotics with potent serotonin and α1 adrenergic receptor antagonist actions

National survey of commissioners' and service planners' views of public health nursing in the UK

Improving public health is a key policy area both in the United Kingdom (UK) and internationally. The governments across the four UK countries each have specific strategies to guide improvements in public health services, promote greater emphasis on how people can best be helped to live healthier lives and to help address the unprecedented challenges of both an increasing population and financial austerity. Nurses are often ideally suited and uniquely placed to respond to public health challenges as they understand the particular risks of individuals but also know the population and the communities they work in. Traditionally in the UK public health nurses have been seen as those in specialist community roles such as health visitors, school nurses and occupational health nurses and in some cases specialist practitioners. However, there is an increasing need for all nurses to embrace the contribution they can have to make every contact count. During 2015 the Royal College of Nursing in the UK (RCN) undertook a programme of work building on a previous project2 to showcase public health nursing (see www.nurses4PH.org.uk). As part of this wider RCN programme, a survey was conducted to explore the views of commissioners and others involved in designing and planning public health services about the nursing and midwifery contribution to public health. The aims were to explore the perceived value of nursing in public health, to better understand the roles of nurses and midwives in public health, how these roles were valued, and what and where the gaps were in public health nursing knowledge and education

Discriminative stimulus properties of 1.25 mg/kg clozapine in rats: Mediation by serotonin 5-HT2 and dopamine D4 receptors

The atypical antipsychotic drug clozapine remains one of most effective treatments for schizophrenia, given a lack of extrapyramidal side effects, improvements in negative symptoms, cognitive impairment, and in symptoms in treatment-resistant schizophrenia. The adverse effects of clozapine, including agranulocytosis, make finding a safe clozapine-like a drug a goal for drug developers. The drug dis- crimination paradigm is a model of interoceptive stimulus that has been used in an effort to screen experimental drugs for clozapine-like atypical antipsychotic effects. The present study was conducted to elucidate the receptor-mediated stimulus properties that form this clozapine discriminative cue by testing selective receptor ligands in rats trained to discriminate a 1.25 mg/kg dose of clozapine from vehicle in a two choice drug discrimination task. Full substitution occurred with the 5-HT2A inverse agonist M100907 and the two preferential D4/5-HT2/α1 receptor antagonists Lu 37-114 ((S)-1-(3-(2-(4- (1H-indol-5-yl)piperazin-1-yl)ethyl)indolin-1-yl)ethan-1-one) and Lu 37-254 (1-(3-(4-(1H-indol-5-yl) piperazin-1-yl)propyl)-3,4-dihydroquinolin-2(1H)-one). Partial substitution occurred with the D4 re- ceptor antagonist Lu 38-012 and the α1 adrenoceptor antagonist prazosin. Drugs selective for 5-HT2C, 5-HT6 muscarinic, histamine H1, and benzodiazepine receptors did not substitute for clozapine. The present findings suggest that 5-HT2A inverse agonism and D4 receptor antagonism mediate the dis- criminative stimulus properties of 1.25 mg/kg clozapine in rats, and further confirm that clozapine produces a complex compound discriminative stimulus

Subcellular Location of PKA Controls Striatal Plasticity: Stochastic Simulations in Spiny Dendrites

Dopamine release in the striatum has been implicated in various forms of reward dependent learning. Dopamine leads to production of cAMP and activation of protein kinase A (PKA), which are involved in striatal synaptic plasticity and learning. PKA and its protein targets are not diffusely located throughout the neuron, but are confined to various subcellular compartments by anchoring molecules such as A-Kinase Anchoring Proteins (AKAPs). Experiments have shown that blocking the interaction of PKA with AKAPs disrupts its subcellular location and prevents LTP in the hippocampus and striatum; however, these experiments have not revealed whether the critical function of anchoring is to locate PKA near the cAMP that activates it or near its targets, such as AMPA receptors located in the post-synaptic density. We have developed a large scale stochastic reaction-diffusion model of signaling pathways in a medium spiny projection neuron dendrite with spines, based on published biochemical measurements, to investigate this question and to evaluate whether dopamine signaling exhibits spatial specificity post-synaptically. The model was stimulated with dopamine pulses mimicking those recorded in response to reward. Simulations show that PKA colocalization with adenylate cyclase, either in the spine head or in the dendrite, leads to greater phosphorylation of DARPP-32 Thr34 and AMPA receptor GluA1 Ser845 than when PKA is anchored away from adenylate cyclase. Simulations further demonstrate that though cAMP exhibits a strong spatial gradient, diffusible DARPP-32 facilitates the spread of PKA activity, suggesting that additional inactivation mechanisms are required to produce spatial specificity of PKA activity

Efficacy of Aircraft Mounted Lighting to Reduce Bird Strikes

A question has lingered over the Aviation Industry for over 30 years. Can we improve the visibility of aircraft to birds so as to reduce the probability of bird aircraft collisions? At the outset, I want to make clear that reducing bird hazards to aircraft is a comprehensive and systemic problem which can be mitigated in part by active control of causative factors in and around airports. However, aircraft rapidly transition out of the airport boundary in a matter of seconds and are still transitioning miles away from the airport at altitudes where birds may still be commonly found. It will only be an onboard system that can significantly reduce the bird hazard in this airspace. Our work both in application and research has been utilizing variations in aircraft mounted lighting to reduce this hazard. Collisions between wildlife and aircraft worldwide are increasing in number and severity. The United Kingdom’s Central Science Laboratory estimates that wildlife strikes to aircraft cost the aviation industry worldwide as much as one billion dollars each year. In the United States alone the annual loss is estimated at $300-$400 million. 1 National Transportation Safety Board Chairman Jim Hall has stated that birdstrikes are on his list of most wanted concerns. Assistant Secretary of Agriculture, Jim Dunn, has stated that “...There has never been a greater potential for catastrophe than in the current conflict between wildlife and aviation.” During a four month period in late 1999, at Detroit Metropolitan Airport alone, Northwest Airlines suffered over $24 million in damage due to bird ingestion

Generalization to Atypical Antipsychotic Drugs Depends On Training Dose in Rats Trained to Discriminate 1.25 Mg/Kg Clozapine Versus 5.0 Mg/Kg Clozapine Versus Vehicle in a Three-Choice Drug Discrimination Task

The prototypical atypical antipsychotic drug (APD) clozapine (CLZ) elicits a discriminative cue that appears to be similar to the stimulus properties elicited by atypical, but not typical, antipsychotic drugs in two-choice drug discrimination procedures. However, the ability of CLZ to generalize to atypical APDs depends on the training dose, since several atypical APDs (e.g. sertindole, risperidone) do not substitute for a 5.0 mg/kg CLZ training dose in rats, but do so for a 1.25 mg/kg CLZ training dose. Yet, a 1.25 mg/kg CLZ discriminative stimulus has not generalized to all atypical APDs either (e.g. quetiapine); thus, both 1.25 mg/kg and 5.0 mg/kg CLZ discriminative stimuli may be necessary to provide a better screen for atypical APDs. The present study sought to determine whether a three-choice 1.25 mg/kg CLZ versus 5.0 mg/kg CLZ versus vehicle drug discrimination task in rats might better distinguish atypical from typical APDs. Adult male Sprague-Dawley rats were trained in this three-choice drug discrimination task with a fixed ratio 30 reinforcement schedule for food. Clozapine produced full substitution (≥ 80% condition-appropriate responding) for both the 1.25 mg/kg CLZ dose (ED 50 = 0.09 mg/kg) and the 5.0 mg/kg CLZ dose (ED50 = 2.71 mg/kg). The atypical APD olanzapine produced full substitution for the 5.0 mg/kg CLZ dose, but not for the 1.25 mg/kg CLZ dose (ED50 = 1.55 mg/kg). In contrast, the atypical APD quetiapine produced full substitution for the 1.25 mg/kg CLZ dose (ED50 = 0.13 mg/kg), but not for the 5.0 mg/kg CLZ dose. Similarly, the atypical APD sertindole produced full substitution for only the 1.25 mg/kg CLZ dose (ED50 = 0.94 mg/kg). Risperidone, another atypical APD, produced partial substitution (≥ 60% and ≤, 80% condition-appropriate responding) for the 1.25 mg/kg CLZ dose, and failed to substitute for the 5.0 mg/kg CLZ dose. The atypical APD ziprasidone and the typical APDs haloperidol and chlorpromazine failed to substitute for either CLZ training dose. These results demonstrated that the 1.25 mg/kg CLZ training dose provides partial or full stimulus generalization to more atypical APDs than does the 5.0 mg/kg CLZ training dose. Full substitution by olanzapine for only the 5.0 mg/kg CLZ dose suggests that this higher training dose is also important for screening atypical APDs