The Anatomical Society core anatomy syllabus for pharmacists: outcomes to create a foundation for practice.

The Anatomical Society has developed a series of learning outcomes that 'experts' within the field would recommend as core knowledge outputs for a Master's Degree Programme in Pharmacy (MPharm) within the UK. Using the Anatomical Society core gross anatomy syllabus for medical anatomy as a foundation, a modified Delphi technique was used to develop outcomes specific to pharmacy graduates. A Delphi panel consisting of medical practitioners, pharmacists and anatomists (n = 39) was created and involved 'experts' representing 20 UK Higher Education Institutions. The output from this study was 49 pharmacy-specific learning outcomes that are applicable to all pharmacy programmes. The new MPharm anatomy syllabus offers a basic anatomical framework upon which pharmacy educators can build the necessary clinical practice and knowledge. These learning outcomes could be used to develop anatomy teaching within an integrated curriculum as per requirements of the General Pharmaceutical Council (GPhC).

Sexually dimorphic effects of prenatal alcohol exposure on the murine skeleton.

BACKGROUND: Prenatal alcohol exposure (PAE) can result in lifelong disabilities known as foetal alcohol spectrum disorder (FASD) and is associated with childhood growth deficiencies and increased bone fracture risk. However, the effects of PAE on the adult skeleton remain unclear and any potential sexual dimorphism is undetermined. Therefore, we utilised a murine model to examine sex differences with PAE on in vitro bone formation, and in the juvenile and adult skeleton. METHODS: Pregnant C57BL/6J female mice received 5% ethanol in their drinking water during gestation. Primary calvarial osteoblasts were isolated from neonatal offspring and mineralised bone nodule formation and gene expression assessed. Skeletal phenotyping of 4- and 12-week-old male and female offspring was conducted by micro-computed tomography (µCT), 3-point bending, growth plate analyses, and histology. RESULTS: Osteoblasts from male and female PAE mice displayed reduced bone formation, compared to control (≤ 30%). Vegfa, Vegfb, Bmp6, Tgfbr1, Flt1 and Ahsg were downregulated in PAE male osteoblasts only, whilst Ahsg was upregulated in PAE females. In 12-week-old mice, µCT analysis revealed a sex and exposure interaction across several trabecular bone parameters. PAE was detrimental to the trabecular compartment in male mice compared to control, yet PAE females were unaffected. Both male and female mice had significant reductions in cortical parameters with PAE. Whilst male mice were negatively affected along the tibial length, females were only distally affected. Posterior cortical porosity was increased in PAE females only. Mechanical testing revealed PAE males had significantly reduced bone stiffness compared to controls; maximum load and yield were reduced in both sexes. PAE had no effect on total body weight or tibial bone length in either sex. However, total growth plate width in male PAE mice compared to control was reduced, whilst female PAE mice were unaffected. 4-week-old mice did not display the altered skeletal phenotype with PAE observed in 12-week-old animals. CONCLUSIONS: Evidence herein suggests, for the first time, that PAE exerts divergent sex effects on the skeleton, possibly influenced by underlying sex-specific transcriptional mechanisms of osteoblasts. Establishing these sex differences will support future policies and clinical management of FASD.

Prenatal alcohol exposure (PAE) can lead to a set of lifelong cognitive, behavioural, and physical disabilities known as foetal alcohol spectrum disorder (FASD). FASD is a significant burden on healthcare, justice and education systems, which is set to worsen with rising alcohol consumption rates. FASD children have an increased risk of long bone fracture and adolescents are smaller in stature. However, sex differences and the long-term effects of PAE on the skeleton have not been investigated and was the aim of this study. Using a mouse model of PAE, we examined the function and gene expression of bone-forming cells (osteoblasts). We then analysed the skeletons of male and female mice at 12-weeks-old (adult) and 4-weeks-old (juvenile). PAE reduced osteoblast bone formation in both sexes, compared to control. Differential gene expression was predominantly observed in PAE males and largely involved genes related to blood vessel formation. High resolution x-ray imaging (micro-CT) revealed PAE had a detrimental effect on the inner trabecular bone component in 12-week-old male mice only. Analysis of the outer cortical bone revealed that whilst both male and female PAE mice were negatively affected, anatomical variations were observed. Mechanical testing also revealed differences in bone strength in PAE mice, compared to control. Interestingly, 4-week-old mice did not possess these sex differences observed in our PAE model at 12 weeks of age. Our data suggest PAE has detrimental and yet sex-dependent effects on the skeleton. Establishing these sex differences will support future policies and clinical management of FASD.

Antidepressant-like effects of oxytocin in mice are dependent on the presence of insulin-regulated aminopeptidase.

Oxytocin is a neuromodulator with antidepressant-like effects. In vitro, oxytocin is rapidly cleaved by insulin-regulated aminopeptidase (IRAP). Oxytocin metabolites are known to exert strong central activities that are different from the effects of the parent molecule. Our goal is to investigate in vivo whether IRAP deletion modifies the antidepressant-like effects of oxytocin. Male and female C57Bl/6 mice, IRAP wild-type (IRAP(+/+)) and knock-out (IRAP(-/-)) mice were injected subcutaneously with saline, oxytocin or oxytocin combined with angiotensin IV. One hour after injection, immobility was timed during a 5 min forced swim that was preceded by an open field to study locomotor behaviour. Oxytocin induced antidepressant-like effects in male (0.25 mg/kg oxytocin) and female (0.15 mg/kg oxytocin) C57Bl/6 mice subjected to the forced swim test. Oxytocin did not influence locomotor behaviour in mice, as shown with the open field. These findings were reproduced in transgenic male (aged 3-6 months) and female (aged 12-18 months) IRAP(+/+) mice. However, the major findings of our study were that the antidepressant-like effect was reversed in angiotensin IV treated IRAP(+/+) mice and was completely absent in age- and gender-matched IRAP(-/-) mice. The lack of an antidepressant-like effect of oxytocin in young male and middle-aged female IRAP(-/-) mice attributes an important role to IRAP in mediating this effect.

Blood pro-inflammatory cytokines in Alzheimer's disease in relation to the use of acetylcholinesterase inhibitors.

OBJECTIVE: A potential anti-inflammatory role for acetylcholinesterase inhibitors (AChEIs) has been supported by animal studies. As very limited data exist from individuals with Alzheimer's disease (AD), the aim of this study was to assess the potential influence of AChEIs on blood pro-inflammatory cytokines. We hypothesized that pro-inflammatory cytokine concentrations were lower in individuals with AD stabilized on AChEIs. METHODS: Blood interleukin-1 beta, interleukin-6, and tumor necrosis factor-alpha concentrations were assessed using specific enzyme-linked immunosorbent assays in three groups of participants: patients with AD stabilized on a therapeutic dose of an AChEI (n = 42); AChEIs drug naïve patients (n = 24); and a cognitively unimpaired control group (n = 35). Patients in the AChEIs group had received medication for an average of one year. RESULTS: Patients stabilized on an AChEI did not differ significantly from drug naïve patients in relation to the concentrations of interleukin-1 beta, interleukin-6, and tumor necrosis factor-alpha (p = 0.874, 0.225, and 0.978, respectively). Within the group taking AChEIs, the levels of cytokines did not differ between those taking donepezil, rivastigmine, or galantamine (p = 0.368, 0.851, and 0.299, respectively). CONCLUSIONS: Results from animal studies suggesting a modulatory anti-inflammatory role for AChEIs was not advanced in this study. In individuals with AD, very limited evidence currently exists to support the hypothesis that AChEIs may influence inflammatory blood markers and function beyond the enhancement of neuronal transmission. However, further studies assessing a wider range of inflammatory markers and processes are still needed before this hypothesis can be ruled out.

Fetal alcohol spectrum disorders: an overview of current evidence and activities in the UK.

Estimates for the UK suggest that alcohol consumption during pregnancy and prevalence of fetal alcohol spectrum disorder (FASD)-the most common neurodevelopmental condition-are high. Considering the significant health and social impacts of FASD, there is a public health imperative to prioritise prevention, interventions and support. In this article, we outline the current state of play regarding FASD knowledge and research in the UK, which is characterised by a lack of evidence, a lack of dedicated funding and services, and consequently little policy formulation and strategic direction. We highlight progress made to date, as well as current knowledge and service gaps to propose a way forward for UK research.

Non-adherence to antihypertensive medication and impaired cognition: which comes first?

OBJECTIVE: Antihypertensive medications are important in the prevention of serious consequences of hypertension, such as stroke and heart failure. Up to one-third of elderly hypertensive patients, however, do not adhere to their medication. Adherence to medication decreases with increasing age, and with decreasing cognitive ability, thus elderly, cognitively-impaired patients have poorer control of blood pressure. Good control of blood pressure is associated with decreased prevalence of dementia and Alzheimer's disease. This study assessed the evidence that antihypertensive medications have effects on the prevalence or severity of mild cognitive impairment, dementia or Alzheimer's disease. METHODS: The ISI Web of Knowledge database was searched; including replicates, the nine searches identified 14400 publications since 1952, of which 9.9% had been published in 2009. This review considers the 18 studies meeting the set criteria published in 2009 or later. KEY FINDINGS: Not all antihypertensive medications are equivalent in their positive cognitive effects, with brain-penetrating angiotensin-converting-enzyme inhibitors and possibly angiotensin receptor antagonists being the most effective. CONCLUSIONS: Based on evidence of blood-pressure control and cost, UK National Institute for Health and Clinical Excellence guidelines recommend calcium-channel blockers or thiazide-type diuretics for the treatment of hypertension in patients over 55 years. These guidelines take no account of the potential cognitive effects of the antihypertensive therapies, consideration of which might lead to a review. There may be benefit in stressing that adherence to antihypertensive medication not only decreases the risk of cardiovascular disease and death, but may also decrease the risk or severity of mild cognitive impairment, dementia and Alzheimer's disease.

Metabolism of captopril carboxyl ester derivatives for percutaneous absorption.

OBJECTIVES: To determine the metabolism of captopril n-carboxyl derivatives and how this may impact on their use as transdermal prodrugs. The pharmacological activity of the ester derivatives was also characterised in order to compare the angiotensin converting enzyme inhibitory potency of the derivatives compared with the parent drug, captopril. METHODS: The metabolism rates of the ester derivatives were determined in vitro (using porcine liver esterase and porcine ear skin) and in silico (using molecular modelling to investigate the potential to predict metabolism). KEY FINDINGS: Relatively slow pseudo first-order metabolism of the prodrugs was observed, with the ethyl ester displaying the highest rate of metabolism. A strong relationship was established between in-vitro methods, while in-silico methods support the use of in-vitro methods and highlight the potential of in-silico techniques to predict metabolism. All the prodrugs behaved as angiotensin converting enzyme inhibitors, with the methyl ester displaying optimum inhibition. CONCLUSIONS: In-vitro porcine liver esterase metabolism rates inform in-vitro skin rates well, and in-silico interaction energies relate well to both. Thus, in-silico methods may be developed that include interaction energies to predict metabolism rates.

Hip subluxation and dislocation in cerebral palsy - a prospective study on the effectiveness of postural management programmes.

BACKGROUND AND PURPOSE: Hip subluxation and dislocation are common sequelae in children with bilateral cerebral palsy and are currently managed by surgical interventions. This study aimed to investigate the effectiveness of early postural management programmes on hip subluxation and dislocation at five years, and the need for treatment in children with bilateral cerebral palsy, and to compare these findings with a historical control group. METHODS: A prospective cohort study followed 39 children who commenced using postural management equipment under 18 months of age. Levels of ability, type and amount of equipment use and treatments were recorded every three months. At 30 and 60 months, the hips were X-rayed and the hip migration percentage was measured. The results were compared with the historical control group. RESULTS: Children who used equipment at recommended and moderate levels had significantly less chance of both hips being subluxed than those using equipment at minimal levels (two-tailed Fisher's exact chi(2) p = 0.024). The frequency of children with hip problems was significantly less in the intervention group in comparison to the historical control group at five years (chi(2) = 11.53, df = 2, p = 0.006). The frequency of children receiving bilateral or unilateral treatments, i.e. surgery, use of a hip and spinal orthosis and/or botulinum toxin injections, in the intervention group was significantly less compared to the historical control group (two-tailed Fisher's exact p = 0.001). CONCLUSION: The early provision of postural management equipment has a role to play in reducing the number of hip problems and therefore the need for treatment of hip subluxation/dislocation in cerebral palsy at five years of age.

Changing status in health care: community and hospital pharmacists' perceptions of pharmacy practice.

OBJECTIVES: This study aimed to explore experienced community and hospital pharmacists' perceptions of how their pharmacy practice and status in health care are affected by others' views of them. METHODS: A qualitative collective case study was conducted. The primary data were 20 in-depth semistructured interviews of community and hospital pharmacists in England that were audio-recorded, transcribed and analysed thematically. KEY FINDINGS: Thematic analysis of the data identified four themes: (1) ambiguities about being professionals, (2) internal divisions, (3) medicines experts and (4) shopkeepers as healthcare providers. CONCLUSIONS: Pharmacists want to be recognised as medicines experts in health care. They are aware that their status is assessed by the public based on their practice, which is dispensing of medicines, and that the public's image of all pharmacists is that of 'a typical community pharmacist' working in a retail shop while having little experience of pharmacists in other healthcare settings. Pharmacists consider that the public does not view them as registered healthcare professionals. They mainly associate being registered professionals with being controlled from afar by their professional regulator, instead of utilising this as an enabling strategy to support their reprofessionalisation efforts. Pharmacists remain the hidden healthcare profession and need to act in practice as healthcare professionals, so the public is aware of their place and contributions in health care to maintain or enhance their status. Internal divisions between community and hospital pharmacists appear to be due to differences in practice, knowledge and aspirations having the potential to adversely affect the pharmacy profession's status.

Decreased behavioural and neurochemical effects of angiotensin IV following prenatal alcohol exposure in the mouse.

Angiotensin IV (ang IV) is known to improve learning and memory in animal models but the mechanism is unclear. We have previously demonstrated sex differences in the pro-cognitive effects of ang IV, and that prenatal alcohol exposure (PAE) abolishes these effects. This study aimed to explore a possible mechanism underlying the sex differences and the effects of PAE in male mice. Mouse breeding harems received 5% ethanol in drinking water throughout pregnancy and lactation in a two-bottle schedule. The effects of ang IV were assessed in offspring at 4 months of age using the open field test, novel object recognition test and elevated plus maze. Aminopeptidase activity of brain insulin-regulated aminopeptidase (IRAP), a putative target of ang IV, was determined. As seen in a previous similar study, ang IV administered immediately after the second training trial significantly improved novel object recognition 24 h later in male mice but not female. PAE abolished this pro-cognitive effect in males. PAE also increased anxiety-like behaviour in male but not female offspring. Ang IV decreased the aminopeptidase activity of brain IRAP in control male, but not female, mice; PAE abolished this inhibitory effect. Ang IV improved memory consolidation in male but not female mice and PAE abolished this effect in the males. While the effects of PAE may be related to increased anxiety; ang IV decreased the aminopeptidase activity in male but not female mice and PAE abolished this inhibitory effect. The results therefore suggest that improvements in learning and memory induced by peripheral administration of ang IV correlate with a reduction of the enzyme activity of IRAP. This is the first demonstration that ang IV administered peripherally can induce long-term (24 h) changes in IRAP function which are probably not simple competitive inhibition and the first demonstration that PAE alters IRAP activity.

Reduction of paraquat-induced renal cytotoxicity by manganese and copper complexes of EGTA and EHPG.

Superoxide anion generation plays an important role in the development of paraquat toxicity. Although superoxide dismutase mimetics (SODm) have provided protection against organ injury involving generation of superoxide anions, they often suffer problems, e.g., regarding their bioavailability or potential pro-oxidant activity. The aim here was to investigate and compare the therapeutic potential of two novel SODm, manganese(II) and copper(II) complexes of the calcium chelator ethylenebis(oxyethylenenitrilo)tetraacetic acid (EGTA) and of the contrast agent ethylenebis(hydroxyphenylglycine) (EHPG), against paraquat-induced renal toxicity in vitro. Incubation of renal NRK-52E cells with paraquat (1 mM) for 24 h produced submaximal, yet significant, reduction in cellular viability and cell death and produced significant increases in superoxide anion and hydroxyl radical generation. Manganese and copper complexes of EGTA (10-100 microM) and EHPG (30-100 microM) reduced paraquat-induced renal cell toxicity and reduced superoxide anion and hydroxyl radical generation significantly. Manganese complexes displayed greater efficacy than copper complexes and, at equivalent concentrations, manganese complexed with EHPG provided the greatest protection. Furthermore, these metal complexes did not interfere with the uptake of [methyl-(14)C]paraquat into NRK-52E cells, suggesting that they provided protection against paraquat cytotoxicity via intracellular mechanisms. These complexes did not display cytotoxicity at the concentrations examined. Together, these results suggest that manganese and copper complexes of EGTA and EHPG, and especially the manganese-EHPG complex, could provide benefit against paraquat nephrotoxicity.

Cognitive-enhancing effects of angiotensin IV.

Angiotensin IV is a derivative of the potent vasoconstrictor angiotensin II and it has been shown to enhance acquisition, consolidation and recall in animal models of learning and memory when administered centrally or peripherally. Whether changes in angiotensin IV activity underlie the cognitive effects of those cardiovascular drugs designed to disrupt the peripheral renin-angiotensin system in humans remains undetermined, but angiotensin IV appears to be a worthy candidate for consideration in drug development programmes. The mechanism of action of angiotensin IV is still debated, although its AT4 receptor has been convincingly identified as being insulin-regulated amino peptidase, which is also known as oxytocinase and placental leucine aminopeptidase. It is speculated that angiotensin IV may interact with insulin-regulated amino peptidase to enhance neuronal glucose uptake, prevent metabolism of other neuroactive peptides, induce changes in extracellular matrix molecules, or induce release of acetylcholine and/or dopamine. All of these things may be responsible for the beneficial effects on cognition, but none of them are yet proven. Importantly, strain differences in murine responses to angiotensin IV suggest that some individuals may benefit from drugs targeted to the AT4 receptor whilst others may be refractory. At present it thus appears that those individuals with the poorest baseline cognition may receive greatest benefit, but possible genetic differences in responses to angiotensin IV cannot be ruled-out.

Pharmacist awareness and views towards counterfeit medicine in Lebanon.

BACKGROUND: Pharmacists, as healthcare professionals, have patients' well-being and safety as their primary concern. However, the safety and efficacy of treatments may be compromised by the availability of counterfeit medicine (CFM) which could have serious consequences for public health. OBJECTIVES: To assess pharmacist awareness and views towards CFM in Lebanon. METHODS: The study used convenience sampling and selected pharmacists based on their willingness to participate and used a questionnaire as a tool to determine their experiences and views towards CFM. The questionnaires were completed in different regions in Lebanon. KEY FINDINGS: A total of 223 pharmacists participated in the study, and all were able to define CFM, however were inconsistent in their definitions. The majority reported identifying CFM by the medicine's effect (67.7%), followed by cost (66.8%). Almost 43% reported knowing of pharmacists who dispensed CFM. Additionally, participants reported that they believed that pharmacists who dealt with CFM were unprofessional (89.2%) and unethical (86.5%), and that they did it for the 'easy money' (87.9%) and large profit (86.5%). CONCLUSION: The study highlighted the need for additional CFM awareness campaigns with an emphasis on the role that pharmacists have in protecting patients from using CFM. In addition, there is a need for an official CFM definition that distinguishes between the different types of counterfeiting. Furthermore, the Lebanese Ministry of Public Health and regulatory authorities should control and secure the supply chain of medicine in the country and enforce the law.

Prenatal alcohol exposure reduces 5-HT concentration in mouse intestinal muscle and mucosa.

The influence of prenatal alcohol exposure on the serotoninergic system in the brain has been well studied, however its influence on the serotoninergic system in the gastrointestinal system remains unknown. The objective of the study was to use a mouse model of prenatal alcohol exposure to investigate the effects on serotonin and its metabolites and precursors in colonic tissue. This study used treatment of mouse breeding harems with 5% ethanol with saccharin via drinking water throughout pregnancy and compared the results with a saccharin control group. Tryptophan, serotonin (5-HT) and 5- hydroxyindoleacetic acid (5-HIAA) concentrations were measured in the longitudinal muscle myenteric plexus (LMMP) and mucosa of intestinal tissue by high-performance liquid chromatography (HPLC). Decreased 5-HT concentrations in mucosa and LMMP (females only) were observed in prenatally exposed mice compared to controls. Increases in mucosal and LMMP tryptophan concentration were only observed in prenatally exposed female mice. In conclusion, prenatal alcohol exposure causes a decrease in conversion of tryptophan to 5-HT in both muscle and mucosa although the effect is more pronounced in females. The observed sex difference may be related to changes associated with the estrous cycle.

Comparison of the effects of the superoxide dismutase mimetics EUK-134 and tempol on paraquat-induced nephrotoxicity.

Paraquat-induced nephrotoxicity involves severe renal cell damage caused by reactive oxygen species (ROS), specifically via increasing concentrations of superoxide anions in the kidney. Recently, superoxide dismutase (SOD) mimetics (SODm) have been developed that display safe SOD activities but which also possess additional antioxidant enzyme (e.g., catalase) or ROS-scavenging activities. The aim of this study was to compare the effects of two such SODm, specifically, EUK-134, a SODm with catalase activity, and tempol, a SODm with ROS-scavenging properties, on paraquat-induced nephrotoxicity of renal NRK-52E cells. Incubation with paraquat (1 mM) for 24 h reduced cell viability and increased necrosis significantly. Paraquat also generated significant quantities of superoxide anions and hydroxyl radicals. Both EUK-134 (10-300 microM) and tempol (0.3-1.0 mM) were able to improve cell viability and reduced paraquat-induced cell death significantly via dismutation or scavenging of superoxide anions and reduced hydroxyl radical generation. The data presented here suggest that SODm such as EUK-134 and tempol, which possess additional catalase and/or ROS-scavenging activities, can significantly reduce renal cell damage caused by paraquat. These effects were evident at concentrations which avoid the pro-oxidant activities associated with higher concentrations of SOD. Such SODm could therefore prove to be beneficial as therapies for paraquat nephrotoxicity.

Renin-angiotensin-system gene polymorphisms and depression.

Given the abundance of the renin-angiotensin system (RAS) components in the brain, their importance in behavior and cognition, and the data that implicates them in the etiology and treatment of depression, it is possible that those RAS gene polymorphisms associated with increased RAS activity may also be associated with depression. The frequencies of common polymorphisms of genes encoding for components of the RAS, namely angiotensinogen (M235T), angiotensin converting enzyme (ACE) (insertion, I; deletion, D), angiotensin receptor type I (A1166C), and angiotensin receptor type II (C3123A) were determined in DNA extracted from buccal cells from a Lebanese population of 132 depressed patients and their first-degree relative case-controls. The angiotensin receptor type 1 (A1166C) CC genotype was significantly associated with depression (p=0.036). None of the other common RAS-associated polymorphisms were significantly associated. The results support the hypothesis that increased RAS activity may increase relative risk of depression in that the angiotensin receptor type 1 (A1166C) CC genotype is associated with increased responsiveness to angiotensin II.

Buccal cell DNA extraction: yield, purity, and cost: a comparison of two methods.

Simple and cost-effective methods are needed to extract DNA in order to use it in large-scale studies. Blood is an excellent DNA source; however, it is costly and invasive thus an alternative is needed. Several kits and chemical protocols using buccal cells have been proposed for DNA extraction. The objective of the study is to evaluate buccal NaOH chemical protocol and Nucleospin Tissue Kit (BD Biosciences, Macery-Nagel, Germany) for DNA extraction. DNA swab samples were collected from 300 voluntary participants. DNA yields and purity were measured by NaOH and Nucleospin Tissue Kit techniques; the cost and time consumption for DNA extraction per sample were assessed as well. Results have shown that DNA amount and purity extracted by NaOH procedure was compared to that of the kit (p = 0.164; p = 0.249, respectively). NaOH method was considered cheaper and less time consuming (0.06 versus 3.80 USD, and 1.33 versus 3.59 minutes per sample, p < 0.001). Buccal cell derived DNA extracted by NaOH protocol can be considered a feasible substitute for more expensive and time-consuming kits.

Interactions of angiotensin IV and oxytocin on behaviour in mice.

INTRODUCTION: Angiotensin (Ang) IV enhances learning and memory in rats but there are strain differences in its effects in mice. Oxytocin (OT) also influences learning and memory in rats and mice and, in the light of the proposed effects of Ang IV on oxytocinase, the hypothesis that the effects of Ang IV on cognition in mice involve OT was tested. MATERIALS AND METHODS: The effects of Ang IV and OT, alone and combined, were determined in rat isolated uterine smooth muscle and in object recognition and forced swim tests in BKW mice. RESULTS: Ang potentiated the contractile effects of OT in the uterus. Neither peptide had any effect on object recognition nor locomotor activity. Ang IV had no effect in the forced swim test but abolished the effects of OT. CONCLUSIONS: Ang IV influences the actions of OT in vitro and in vivo, possibly by inhibition of oxytocinase, but the lack of effect of Ang IV on object recognition in BKW mice is unlikely to be a consequence of a deficiency endogenous OT. Unlike OT, Ang IV alone has no effect on learned helplessness in the forced swim test, an effect often used to predict potential antidepressant efficacy in humans.

Performance monitoring in nicotine dependence: Considering integration of recent reinforcement history.

INTRODUCTION: Impaired monitoring of errors and conflict (performance monitoring; PM) is well documented in substance dependence (SD) including nicotine dependence and may contribute to continued drug use. Contemporary models of PM and complementary behavioural evidence suggest that PM works by integrating recent reinforcement history rather than evaluating individual behaviours. Despite this, studies of PM in SD have typically used indices derived from reaction to task error or conflict on individual trials. Consequently impaired integration of reinforcement history during action selection tasks requiring behavioural control in SD populations has been underexplored. METHODS: A reinforcement learning task assessed the ability of abstinent, satiated, former and never smokers (N=60) to integrate recent reinforcement history alongside a more typical behavioural index of PM reflecting the degree of reaction time slowing following an error (post-punishment slowing; PPS). RESULTS: On both indices there was a consistent pattern in PM data: Former smokers had the greatest and satiated smokers the poorest PM. Specifically satiated smokers had poorer reinforcement integration than former (p=0.005) and never smokers (p=0.041) and had less post-punishment slowing than former (p<0.001), never (p=0.003) and abstinent smokers (p=0.026). CONCLUSIONS: These are the first data examining the effects of smoking status on PM that use an integration of reinforcement history metric. The concordance of the reinforcement integration and PPS data suggest that this could be a promising method to interrogate PM in future studies. PM is influenced by smoking status. As PM is associated with adapting behaviour, poor PM in satiated smokers may contribute towards continued smoking despite negative consequences. Former smokers show elevated PM suggesting this may be a good relapse prevention target for individuals struggling to remain abstinent however prospective and intervention studies are needed. A better understanding of PM deficits in terms of reinforcement integration failure may stimulate development of novel treatment approaches.

Low-dose chronic prenatal alcohol exposure abolishes the pro-cognitive effects of angiotensin IV.

Prenatal ethanol exposure (PAE) in humans results in a spectrum of disorders including deficits in learning and memory. Animal models to date have typically used high ethanol doses but have not identified the biochemical changes underlying the cognitive deficit. This study used treatment of mouse breeding harems with 5% ethanol via drinking water throughout pregnancy and lactation and explored the behavioural consequences in the progeny at 3-6 months of age using the open field test, novel object recognition test and elevated plus maze to measure anxiety and memory consolidation. The effects of angiotensin IV on behaviour of the progeny were also determined. The results indicated that PAE increased anxiety-like behaviour as determined in the open field test in male but not female progeny. In control animals, angiotensin IV enhanced memory consolidation in males, but this effect was abolished by PAE. The abolition of the pro-cognitive effect of angiotensin IV was not a consequence of increased anxiety, and there was some evidence of a long-lasting anxiolytic effect of angiotensin IV in the male PAE progeny. These results suggest that PAE may act via alteration of the actions of the brain renin-angiotensin system to impair memory consolidation, but these effects may be partially sex-dependent.