Altered Social Reward and Attention in Anorexia Nervosa

Dysfunctional social reward and social attention are present in a variety of neuropsychiatric disorders including autism, schizophrenia, and social anxiety. Here we show that similar social reward and attention dysfunction are present in anorexia nervosa (AN), a disorder defined by avoidance of food and extreme weight loss. We measured the implicit reward value of social stimuli for female participants with (n = 11) and without (n = 11) AN using an econometric choice task and also tracked gaze patterns during free viewing of images of female faces and bodies. As predicted, the reward value of viewing bodies varied inversely with observed body weight for women with anorexia but not control women, in contrast with their explicit ratings of attractiveness. Surprisingly, women with AN, unlike control women, did not find female faces rewarding and avoided looking at both the face and eyes – independent of observed body weight. These findings suggest comorbid dysfunction in the neural circuits mediating gustatory and social reward in anorexia nervosa

Antagonism of triazolam self-administration in rhesus monkeys responding under a progressive-ratio schedule: In vivo apparent pA2 analysis.

BACKGROUND: Conventional benzodiazepines bind non-selectively to GABAA receptors containing α1, α2, α3, and α5 subunits (α1GABAA, α2GABAA, α3GABAA, and α5GABAA receptors, respectively), and the role of these different GABAA receptor subtypes in the reinforcing effects of benzodiazepines has not been characterized fully. We used a pharmacological antagonist approach with available subtype-selective ligands to evaluate the role of GABAA receptor subtypes in the reinforcing effects of the non-selective conventional benzodiazepine, triazolam. METHODS: Rhesus monkeys (n=4) were trained under a progressive-ratio schedule of intravenous midazolam delivery and dose-response functions were determined for triazolam, in the absence and presence of flumazenil (non-selective antagonist), βCCT and 3-PBC (α1GABAA-preferring antagonists), and XLi-093 (α5GABAA-selective antagonist). RESULTS: Flumazenil, βCCT and 3-PBC shifted the dose-response functions for triazolam to the right in a surmountable fashion, whereas XLi-093 was ineffective. Schild analyses revealed rank orders of potencies of flumazenil=βCCT\u3e3-PBC. Comparison of potencies between self-administration and previous binding studies with human cloned GABAA receptor subtypes suggested that the potencies for βCCT and 3-PBC were most consistent with binding at α2GABAA and α3GABAA receptors, but not α1GABAA or α5GABAA receptor subtypes. CONCLUSIONS: Our findings were not entirely consistent with blockade of α1GABAA receptors and are consistent with the possibility of α2GABAA and/or α3GABAA subtype involvement in antagonism of the reinforcing effects of triazolam. The α5GABAA receptor subtype likely does not play a substantial role in self-administration under these conditions

Using complex behavior to understand brain mechanisms in health and disease

At this point in the history of the science of behavior, a focus on neuroscience-based outcomes has become dominant in neuropsychiatric fields at the preclinical and clinical levels of analysis. The notion that behavior is caused by brain function, and that changing brain function can alter behavior, has fueled this push to understand these neurobiological mechanisms. Within this conceptual framework and the funding to incentivize its adoption, the neuroscience field grew rapidly with the goal to understand the relation between the brain and behavior. As such, a reductionist perspective emerged whereby neural manipulations of increasing sophistication became required for assessing the necessity and sufficiency of a particular brain mechanism’s role in behavior (Krakauer et al., 2017). Yet, despite the amazing advances in neuroscience, some, such as the former director of the National Institute of Mental Health, Dr. Thomas Insel, have noted the lack of progress in treatment outcomes for mental illness following the shift in funding from behavioral research to genetics and neuroscience research (Barry, 2022)

Aβ Vaccination in Combination with Behavioral Enrichment in Aged Beagles: Effects on Cognition, Aβ, and Microhemorrhages

Beta-amyloid (Aβ) immunotherapy is a promising intervention to slow Alzheimer’s disease (AD). Aging dogs naturally accumulate Aβ and show cognitive decline. An active vaccine against fibrillar Aβ 1–42 (VAC) in aged beagles resulted in maintenance but not improvement of cognition along with reduced brain Aβ. Behavioral enrichment (ENR) led to cognitive benefits but no reduction in Aβ. We hypothesized cognitive outcomes could be improved by combining VAC with ENR in aged dogs. Aged dogs (11–12 years) were placed into 4 groups: (1) control/control (C/C); (2) control/VAC (C/V); (3) ENR/control (E/C); (4) ENR and VAC (E/V) and treated for 20 months. VAC decreased brain Aβ, pyroglutamate Aβ, increased CSF Aβ42 and BDNF RNA levels but also increased microhemorrhages. ENR reduced brain Aβ and prevented microhemorrhages. The combination treatment resulted in a significant maintenance of learning over time, reduced Aβ and increased BDNF mRNA despite increased microhemorrhages, however there were no benefits to memory. These results suggest that the combination of immunotherapy with behavioral enrichment leads to cognitive maintenance associated with reduced neuropathology that may benefit people with AD

Obesity and Diabetes Cause Cognitive Dysfunction in the Absence of Accelerated β-Amyloid Deposition in a Novel Murine Model of Mixed or Vascular Dementia

Mid-life obesity and type 2 diabetes mellitus (T2DM) confer a modest, increased risk for Alzheimer\u27s disease (AD), though the underlying mechanisms are unknown. We have created a novel mouse model that recapitulates features of T2DM and AD by crossing morbidly obese and diabetic db/db mice with APPΔNL/ΔNLx PS1P264L/P264L knock-in mice. These mice (db/AD) retain many features of the parental lines (e.g. extreme obesity, diabetes, and parenchymal deposition of β-amyloid (Aβ)). The combination of the two diseases led to additional pathologies-perhaps most striking of which was the presence of severe cerebrovascular pathology, including aneurysms and small strokes. Cortical Aβ deposition was not significantly increased in the diabetic mice, though overall expression of presenilin was elevated. Surprisingly, Aβ was not deposited in the vasculature or removed to the plasma, and there was no stimulation of activity or expression of major Aβ-clearing enzymes (neprilysin, insulin degrading enzyme, or endothelin-converting enzyme). The db/AD mice displayed marked cognitive impairment in the Morris Water Maze, compared to either db/db or APPΔNLx PS1P264L mice. We conclude that the diabetes and/or obesity in these mice leads to a destabilization of the vasculature, leading to strokes and that this, in turn, leads to a profound cognitive impairment and that this is unlikely to be directly dependent on Aβ deposition. This model of mixed or vascular dementia provides an exciting new avenue of research into the mechanisms underlying the obesity-related risk for age-related dementia, and will provide a useful tool for the future development of therapeutics

Design, synthesis, and subtype selectivity of 3,6-disubstituted β-carbolines at Bz/GABA(A)ergic receptors. SAR and studies directed toward agents for treatment of alcohol abuse

A series of 3,6-disubstituted β-carbolines was synthesized and evaluated for their in vitro affinities at αxβ3γ2 GABAA/benzodiazepine receptor subtypes by radioligand binding assays in search of α1 subtype selective ligands to treat alcohol abuse. Analogues of β-carboline-3-carboxylate-t-butyl ester (βCCt, 1) were synthesized via a CDI-mediated process and the related 6-substituted β-carboline-3-carboxylates 6 including WYS8 (7) were synthesized via a Sonogashira or Stille coupling processes from 6-iodo βCCt (5). The bivalent ligands of βCCt (32 and 33) were also designed and prepared via a palladium-catalyzed homocoupling process to expand the structure-activity relationships (SAR) to larger ligands. Based on the pharmacophore/receptor model, a preliminary SAR study on 34 analogues illustrated that large substituents at position -6 of the β-carbolines were well tolerated. As expected, these groups are proposed to project into the extracellular domain (LDi region) of GABAA/Bz receptors (see 32 and 33). Moreover, substituents located at position -3 of the β-carboline nucleus exhibited a conserved stereo interaction in lipophilic pocket L1, while N(2) presumably underwent a hydrogen bonding interaction with H1. Three novel β-carboline ligands (βCCt, 3PBC and WYS8), which preferentially bound to α1 BzR subtypes permitted a comparison of the pharmacological efficacies with a range of classical BzR antagonists (flumazenil, ZK93426) from several different structural groups and indicated these β-carbolines were “near GABA neutral antagonists”. Based on the SAR, the most potent (in vitro) α1 selective ligand was the 6-substituted acetylenyl βCCt (WYS8, 7). Earlier both βCCt and 3PBC had been shown to reduce alcohol self-administration in alcohol preferring (P) and high alcohol drinking (HAD) rats but had little or no effect on sucrose self-administration.1–3 These data prompted the synthesis of the β-carbolines presented here

Testing for sexually transmitted infections and blood borne viruses on admission to Western Australian prisons

<p>Abstract</p> <p>Background</p> <p>Prison populations are known to be at high risk of sexually transmitted infections (STIs) and blood borne viruses (BBVs). In accordance with State health guidelines, the Western Australian Department of Correctional Services' policy is to offer testing for STIs and BBVs to all new prison entrants. This audit was undertaken to assess the completeness and timeliness of STI and BBV testing among recent prison entrants in Western Australia, and estimate the prevalence of STIs and BBVs on admission to prison.</p> <p>Methods</p> <p>A retrospective audit of prison medical records was conducted among 946 individuals admitted to prison in Western Australia after the 1^stJanuary 2005, and discharged between the 1^stJanuary and 31^stDecember 2007 inclusive. Quota sampling was used to ensure adequate sampling of females, juveniles, and individuals from regional prisons. Main outcomes of interest were the proportion of prisoners undergoing STI and BBV testing, and the prevalence of STIs and BBVs.</p> <p>Results</p> <p>Approximately half the sample underwent testing for the STIs chlamydia and gonorrhoea, and almost 40% underwent testing for at least one BBV. Completeness of chlamydia and gonorrhoea testing was significantly higher among juveniles (84.1%) compared with adults (39.8%; p < 0.001), and Aboriginal prisoners (58.3%) compared with non-Aboriginal prisoners (40.4%; p < 0.001). Completeness of BBV testing was significantly higher among adults (46.5%) compared with juveniles (15.8%; p < 0.001) and males (43.3%) compared with females (33.1%; p = 0.001). Among prisoners who underwent testing, 7.3% had a positive chlamydia test result and 24.8% had a positive hepatitis C test result.</p> <p>Conclusion</p> <p>The documented coverage of STI and BBV testing among prisoners in Western Australia is not comprehensive, and varies significantly by age, gender and Aboriginality. Given the high prevalence of STIs and BBVs among prisoners, increased test coverage is required to ensure optimal use of the opportunity that prison admission presents for the treatment and control of STIs and BBVs among this high risk group.</p

Use of Non-Steroidal Anti-Inflammatory Drugs and Prostate Cancer Risk: A Population-Based Nested Case-Control Study

BACKGROUND: Despite strong laboratory evidence that non-steroidal anti-inflammatory drugs (NSAIDs) could prevent prostate cancer, epidemiological studies have so far reported conflicting results. Most studies were limited by lack of information on dosage and duration of use of the different classes of NSAIDs. METHODS: We conducted a nested case-control study using data from Saskatchewan Prescription Drug Plan (SPDP) and Cancer Registry to examine the effects of dose and duration of use of five classes of NSAIDs on prostate cancer risk. Cases (N = 9,007) were men aged ≥40 years diagnosed with prostatic carcinoma between 1985 and 2000, and were matched to four controls on age and duration of SPDP membership. Detailed histories of exposure to prescription NSAIDs and other drugs were obtained from the SPDP. RESULTS: Any use of propionates (e.g., ibuprofen, naproxen) was associated with a modest reduction in prostate cancer risk (Odds ratio = 0.90; 95%CI 0.84-0.95), whereas use of other NSAIDs was not. In particular, we did not observe the hypothesized inverse association with aspirin use (1.01; 0.95-1.07). There was no clear evidence of dose-response or duration-response relationships for any of the examined NSAID classes. CONCLUSIONS: Our findings suggest modest benefits of at least some NSAIDs in reducing prostate cancer risk