Persistent Effects of Self-Administered Cocaine on Cognitive Function and Brain Dopamine Receptors: The Consequences of Differential Drug Access.

Drug addicts exhibit a number of cognitive deficits including deficits in frontocortical function and memory that persist long after the discontinuation of drug use. It is not clear, however, whether the cognitive deficits are a consequence of drug use, or are present prior to drug use, and thus are a potential predisposing factor for addiction. Characterizing the ability of drugs of abuse to lead to alterations in cognition and elucidating the molecular mechanisms that underlie these deficits may allow us to develop better treatment regimens for addicts. Animal models provide us with a means to examine the effects of drugs of abuse on cognitive function and underlying dopamine systems however, the usefulness of these models is only as good as they accurately model the human condition. For decades, researchers have utilized relatively limited access self-administration procedures (1-3 hours of daily access) to study addiction. However, more recently, researchers have started utilizing more extended access drug self-administration procedures that provide animals with either months of shorter daily self-administration sessions or longer daily access for 3-4 weeks. These extended access models have allowed experimenters to model the transition to compulsive drug use in animals and provide us with an excellent model with which to study the ability of cocaine to lead to deficits in cognitive function and alterations in ascending dopamine systems. We report that extended access self-administration leads to deficits in both cognitive flexibility and recognition memory performance and these deficits persist during prolonged abstinence. In addition, we report that extended access cocaine self-administration leads to a persistent decrease in dopamine D2 mRNA and protein levels in the prefrontal cortex. In the striatum, we found that cocaine self-administration, both extended and limited access, leads to a persistent increase in the proportion of dopamine D2 high-affinity receptors, while having no effect on total D2 levels. Finally, we determined that extended access cocaine self-administration leads to a biphasic striatal rCBF response, with increases seen during early withdrawal and decreases seen following prolonged withdrawal. This work has important implications for the development of cocaine addiction treatment options, both for pharmacological and cognitive therapies.Ph.D.NeuroscienceUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/57659/2/lbriand_1.pd

Impact of repeated four-monthly anthelmintic treatment on Plasmodium infection in preschool children: a double-blind placebo-controlled randomized trial

<p>Abstract</p> <p>Background</p> <p>Helminth infections can alter susceptibility to malaria. Studies need to determine whether or not deworming programs can impact on <it>Plasmodium </it>infections in preschool children.</p> <p>Methods</p> <p>A double-blind placebo-controlled randomised trial was conducted to investigate the impact of anthelmintic treatment on <it>Plasmodium </it>infection in children aged 12-59 months. Children were randomly assigned to receive either albendazole or placebo every four months for 12 months with a follow-up at 14 months.</p> <p>Results</p> <p>320 children (out of 1228, 26.1%) complied with all the follow-up assessments. <it>Plasmodium </it>prevalence and mean <it>Plasmodium </it>parasite density was significantly higher in the treatment group (44.9% and 2319 ± SE 511) compared to the placebo group (33.3% and 1471 ± 341) at baseline. The odds of having <it>Plasmodium </it>infection increased over time for children in both the placebo and treatment groups, however this increase was significantly slower for children in the treatment group (P = 0.002). By month 14, mean <it>Plasmodium </it>density had increased by 156% in the placebo group and 98% in the treatment group but the rate of change in <it>Plasmodium </it>density was not significantly different between the groups. The change from baseline in haemoglobin had a steeper increase among children in the treatment group when compared to the placebo group but this was not statistically significant.</p> <p>Conclusions</p> <p>Repeated four-monthly anthelminthic treatments for 14 months resulted in a significantly lower increase in the prevalence of <it>Plasmodium </it>infection in preschool children which coincided with a reduction in both the prevalence and intensity of <it>A. lumbricoides </it>infections.</p> <p>Trial Registration</p> <p>Current controlled trials ISRCTN44215995</p

Impact of malaria during pregnancy on pregnancy outcomes in a Ugandan prospective cohort with intensive malaria screening and prompt treatment

Malaria in pregnancy (MiP) is a major public health problem in endemic areas of sub-Saharan Africa and has important consequences on birth outcome. Because MiP is a complex phenomenon and malaria epidemiology is rapidly changing, additional evidence is still required to understand how best to control malaria. This study followed a prospective cohort of pregnant women who had access to intensive malaria screening and prompt treatment to identify factors associated with increased risk of MiP and to analyse how various characteristics of MiP affect delivery outcomes

Robust estimation of bacterial cell count from optical density

Optical density (OD) is widely used to estimate the density of cells in liquid culture, but cannot be compared between instruments without a standardized calibration protocol and is challenging to relate to actual cell count. We address this with an interlaboratory study comparing three simple, low-cost, and highly accessible OD calibration protocols across 244 laboratories, applied to eight strains of constitutive GFP-expressing E. coli. Based on our results, we recommend calibrating OD to estimated cell count using serial dilution of silica microspheres, which produces highly precise calibration (95.5% of residuals &lt;1.2-fold), is easily assessed for quality control, also assesses instrument effective linear range, and can be combined with fluorescence calibration to obtain units of Molecules of Equivalent Fluorescein (MEFL) per cell, allowing direct comparison and data fusion with flow cytometry measurements: in our study, fluorescence per cell measurements showed only a 1.07-fold mean difference between plate reader and flow cytometry data

Neuropsychosocial profiles of current and future adolescent alcohol misusers

A comprehensive account of the causes of alcohol misuse must accommodate individual differences in biology, psychology and environment, and must disentangle cause and effect. Animal models1 can demonstrate the effects of neurotoxic substances; however, they provide limited insight into the psycho-social and higher cognitive factors involved in the initiation of substance use and progression to misuse. One can search for pre-existing risk factors by testing for endophenotypic biomarkers2 in non-using relatives; however, these relatives may have personality or neural resilience factors that protect them from developing dependence3. A longitudinal study has potential to identify predictors of adolescent substance misuse, particularly if it can incorporate a wide range of potential causal factors, both proximal and distal, and their influence on numerous social, psychological and biological mechanisms4. Here we apply machine learning to a wide range of data from a large sample of adolescents (n = 692) to generate models of current and future adolescent alcohol misuse that incorporate brain structure and function, individual personality and cognitive differences, environmental factors (including gestational cigarette and alcohol exposure), life experiences, and candidate genes. These models were accurate and generalized to novel data, and point to life experiences, neurobiological differences and personality as important antecedents of binge drinking. By identifying the vulnerability factors underlying individual differences in alcohol misuse, these models shed light on the aetiology of alcohol misuse and suggest targets for prevention

Differential predictors for alcohol use in adolescents as a function of familial risk

Abstract: Traditional models of future alcohol use in adolescents have used variable-centered approaches, predicting alcohol use from a set of variables across entire samples or populations. Following the proposition that predictive factors may vary in adolescents as a function of family history, we used a two-pronged approach by first defining clusters of familial risk, followed by prediction analyses within each cluster. Thus, for the first time in adolescents, we tested whether adolescents with a family history of drug abuse exhibit a set of predictors different from adolescents without a family history. We apply this approach to a genetic risk score and individual differences in personality, cognition, behavior (risk-taking and discounting) substance use behavior at age 14, life events, and functional brain imaging, to predict scores on the alcohol use disorders identification test (AUDIT) at age 14 and 16 in a sample of adolescents (N = 1659 at baseline, N = 1327 at follow-up) from the IMAGEN cohort, a longitudinal community-based cohort of adolescents. In the absence of familial risk (n = 616), individual differences in baseline drinking, personality measures (extraversion, negative thinking), discounting behaviors, life events, and ventral striatal activation during reward anticipation were significantly associated with future AUDIT scores, while the overall model explained 22% of the variance in future AUDIT. In the presence of familial risk (n = 711), drinking behavior at age 14, personality measures (extraversion, impulsivity), behavioral risk-taking, and life events were significantly associated with future AUDIT scores, explaining 20.1% of the overall variance. Results suggest that individual differences in personality, cognition, life events, brain function, and drinking behavior contribute differentially to the prediction of future alcohol misuse. This approach may inform more individualized preventive interventions

Sharing and community curation of mass spectrometry data with Global Natural Products Social Molecular Networking

The potential of the diverse chemistries present in natural products (NP) for biotechnology and medicine remains untapped because NP databases are not searchable with raw data and the NP community has no way to share data other than in published papers. Although mass spectrometry techniques are well-suited to high-throughput characterization of natural products, there is a pressing need for an infrastructure to enable sharing and curation of data. We present Global Natural Products Social molecular networking (GNPS, http://gnps.ucsd.edu), an open-access knowledge base for community wide organization and sharing of raw, processed or identified tandem mass (MS/MS) spectrometry data. In GNPS crowdsourced curation of freely available community-wide reference MS libraries will underpin improved annotations. Data-driven social-networking should facilitate identification of spectra and foster collaborations. We also introduce the concept of ‘living data’ through continuous reanalysis of deposited data

Differential predictors for alcohol use in adolescents as a function of familial risk

Abstract: Traditional models of future alcohol use in adolescents have used variable-centered approaches, predicting alcohol use from a set of variables across entire samples or populations. Following the proposition that predictive factors may vary in adolescents as a function of family history, we used a two-pronged approach by first defining clusters of familial risk, followed by prediction analyses within each cluster. Thus, for the first time in adolescents, we tested whether adolescents with a family history of drug abuse exhibit a set of predictors different from adolescents without a family history. We apply this approach to a genetic risk score and individual differences in personality, cognition, behavior (risk-taking and discounting) substance use behavior at age 14, life events, and functional brain imaging, to predict scores on the alcohol use disorders identification test (AUDIT) at age 14 and 16 in a sample of adolescents (N = 1659 at baseline, N = 1327 at follow-up) from the IMAGEN cohort, a longitudinal community-based cohort of adolescents. In the absence of familial risk (n = 616), individual differences in baseline drinking, personality measures (extraversion, negative thinking), discounting behaviors, life events, and ventral striatal activation during reward anticipation were significantly associated with future AUDIT scores, while the overall model explained 22% of the variance in future AUDIT. In the presence of familial risk (n = 711), drinking behavior at age 14, personality measures (extraversion, impulsivity), behavioral risk-taking, and life events were significantly associated with future AUDIT scores, explaining 20.1% of the overall variance. Results suggest that individual differences in personality, cognition, life events, brain function, and drinking behavior contribute differentially to the prediction of future alcohol misuse. This approach may inform more individualized preventive interventions

Sex Differences in Psychiatric Disease: A Focus on the Glutamate System

Alterations in glutamate, the primary excitatory neurotransmitter in the brain, are implicated in several psychiatric diseases. Many of these psychiatric diseases display epidemiological sex differences, with either males or females exhibiting different symptoms or disease prevalence. However, little work has considered the interaction of disrupted glutamatergic transmission and sex on disease states. This review describes the clinical and preclinical evidence for these sex differences with a focus on two conditions that are more prevalent in women: Alzheimer's disease and major depressive disorder, and three conditions that are more prevalent in men: schizophrenia, autism spectrum disorder, and attention deficit hyperactivity disorder. These studies reveal sex differences at multiple levels in the glutamate system including metabolic markers, receptor levels, genetic interactions, and therapeutic responses to glutamatergic drugs. Our survey of the current literature revealed a considerable need for more evaluations of sex differences in future studies examining the role of the glutamate system in psychiatric disease. Gaining a more thorough understanding of how sex differences in the glutamate system contribute to psychiatric disease could provide novel avenues for the development of sex-specific pharmacotherapies