Deep learning of cell spatial organizations identifies clinically relevant insights in tissue images.

Recent advancements in tissue imaging techniques have facilitated the visualization and identification of various cell types within physiological and pathological contexts. Despite the emergence of cell-cell interaction studies, there is a lack of methods for evaluating individual spatial interactions. In this study, we introduce Ceograph, a cell spatial organization-based graph convolutional network designed to analyze cell spatial organization (for example,. the cell spatial distribution, morphology, proximity, and interactions) derived from pathology images. Ceograph identifies key cell spatial organization features by accurately predicting their influence on patient clinical outcomes. In patients with oral potentially malignant disorders, our model highlights reduced structural concordance and increased closeness in epithelial substrata as driving features for an elevated risk of malignant transformation. In lung cancer patients, Ceograph detects elongated tumor nuclei and diminished stroma-stroma closeness as biomarkers for insensitivity to EGFR tyrosine kinase inhibitors. With its potential to predict various clinical outcomes, Ceograph offers a deeper understanding of biological processes and supports the development of personalized therapeutic strategies.

Deep Learning of Cell Spatial Organizations Identifies Clinically Relevant Insights in Tissue Images.

Recent advancements in tissue imaging techniques have facilitated the visualization and identification of various cell types within physiological and pathological contexts. Despite the emergence of cell-cell interaction studies, there is a lack of methods for evaluating individual spatial interactions. In this study, we introduce Ceograph, a novel cell spatial organization-based graph convolutional network designed to analyze cell spatial organization (i.e. the cell spatial distribution, morphology, proximity, and interactions) derived from pathology images. Ceograph identifies key cell spatial organization features by accurately predicting their influence on patient clinical outcomes. In patients with oral potentially malignant disorders, our model highlights reduced structural concordance and increased closeness in epithelial substrata as driving features for an elevated risk of malignant transformation. In lung cancer patients, Ceograph detects elongated tumor nuclei and diminished stroma-stroma closeness as biomarkers for insensitivity to EGFR tyrosine kinase inhibitors. With its potential to predict various clinical outcomes, Ceograph offers a deeper understanding of biological processes and supports the development of personalized therapeutic strategies.

Plasminogen activator system homeostasis and its dysregulation by ethanol in astrocyte cultures and the developing brain.

In utero alcohol exposure can cause fetal alcohol spectrum disorders (FASD), characterized by structural brain abnormalities and long-lasting behavioral and cognitive dysfunction. Neuronal plasticity is affected by in utero alcohol exposure and can be modulated by extracellular proteolysis. Plasmin is a major extracellular serine-protease whose activation is tightly regulated by the plasminogen activator (PA) system. In the present study we explored the effect of ethanol on the expression of the main components of the brain PA system in sex-specific cortical astrocyte primary cultures in vitro and in the cortex and hippocampus of post-natal day (PD) 9 male and female rats. We find that ethanol alters the PA system in astrocytes and in the developing brain. In particular, the expression of tissue-type PA (tPA), encoded by the gene Plat, is consistently upregulated by ethanol in astrocytes in vitro and in the cortex and hippocampus in vivo. Astrocytes exhibit endogenous plasmin activity that is increased by ethanol and recombinant tPA and inhibited by tPA silencing. We also find that tPA is expressed by astrocytes of the developing cortex and hippocampus in vivo. All components of the PA system investigated, with the exception of Neuroserpin/Serpini1, are expressed at higher levels in astrocyte cultures than in the developing brain, suggesting that astrocytes are major producers of these proteins in the brain. In conclusion, astrocyte PA system may play a major role in the modulation of neuronal plasticity; ethanol-induced upregulation of tPA levels and plasmin activity may be responsible for altered neuronal plasticity in FASD.

Sex differences in the association of alcohol with cognitive decline and brain pathology in a cohort of octogenarians.

RATIONALE: The beneficial effects of moderate alcohol may differ in aging men versus women. OBJECTIVES: Cognitive and functional decline and neuropathology were investigated in a cohort of aging men and women with diverse alcohol histories. METHODS: Non-demented (Clinical Dementia Rating (CDR) of ≤ 0.5 and a Mini-Mental State Examination (MMSE) score of > 24), autonomously living participants were tracked in longitudinal aging studies to examine self-report and objective tests of rates of decline in a cohort (n = 486) of octogenarians. Neurofibrillary tangles (NFTs; Braak stage) and neuritic plaques (NPs) were staged at autopsy in a subset of participants (n = 149) using current standard neuropathologic diagnostic criteria. RESULTS: Moderate drinking men had an attenuated rate of decline compared to rare/never drinkers and women on the MMSE and CDR sum of boxes. In contrast, moderate drinking women had a reduced rate of decline only in the Logical Memory Delayed Recall Test (LMDR) compared to rare/never drinkers and men. Moderate alcohol consumption was associated with a reduction in the incidence of advanced (stages 5-6) Braak NFT stage in men (p < 0.05), with no effect in women. CONCLUSIONS: In this cohort, men experienced a broader range of beneficial effects associated with alcohol. Alcohol's effects may differ in men and women in important ways that suggest a narrower beneficial window.

Peripheral immune factors are elevated in women with current or recent alcohol dependence and associated with altered mood and memory.

BACKGROUND: The adverse effects of alcohol on brain function result, in part, from inflammatory processes. The sex-specific neuropsychiatric consequences and inflammatory status of active alcohol dependence and early remission from dependence have not been investigated. METHODS: Neuropsychiatric symptoms, inflammatory factors, and liver enzymes were compared in a prospective cohort study of adults with (n=51) or without (n=31) a current or recent history of alcohol dependence. RESULTS: Neuropsychiatric profiles were similar in adults with current or recent alcohol dependence regardless of sex. In male and female participants measures of depression (female p<0.05, male p<0.001), anxiety (female p<0.001, male p<0.001), and memory complaints (female p<0.001, male p<0.05) were elevated, relative to non-dependent controls. Significant sex×alcohol dependence history interactions were observed for plasma levels of tissue inhibitor of metalloproteinase 1 (TIMP-1) and brain derived neurotrophic factor (BDNF), with women in the alcohol dependent group exhibiting increased levels of both analytes (p<0.05) relative to controls. Positive correlations between TIMP-1 levels and measures of depression (r2=0.35, p<0.01), anxiety (r2=0.24, p<0.05) and memory complaints (r2=0.44, p<0.01) were found in female, but not male, participants. CONCLUSIONS: Though neuropsychiatric profiles were similar for men and women with current or recent alcohol dependence, plasma factors associated with increases in depression, anxiety, and memory impairment differed and support the need to tailor treatments based on sex.

Parallel Effects of Methamphetamine on Anxiety and CCL3 in Humans and a Genetic Mouse Model of High Methamphetamine Intake.

BACKGROUND: Methamphetamine (MA) abuse causes immune dysfunction and neuropsychiatric impairment. The mechanisms underlying these deficits remain unidentified. METHODS: The effects of MA on anxiety-like behavior and immune function were investigated in mice selectively bred to voluntarily consume high amounts of MA [i.e., MA high drinking (MAHDR) mice]. MA (or saline) was administered to mice using a chronic (14-day), binge-like model. Performance in the elevated zero maze (EZM) was determined 5 days after the last MA dose to examine anxiety-like behavior. Cytokine and chemokine expressions were measured in the hippocampus using quantitative polymerase chain reaction (qPCR). Human studies were also conducted to evaluate symptoms of anxiety using the General Anxiety Disorder-7 Scale in adults with and without a history of MA dependence. Plasma samples collected from human research participants were used for confirmatory analysis of murine qPCR results using an enzyme-linked immunosorbent assay. RESULTS: During early remission from MA, MAHDR mice exhibited increased anxiety-like behavior on the EZM and reduced expression of chemokine (C-C motif) ligand 3 (ccl3) in the hippocampus relative to saline-treated mice. Human adults actively dependent on MA and those in early remission had elevated symptoms of anxiety as well as reductions in plasma levels of CCL3, relative to adults with no history of MA abuse. CONCLUSIONS: The results highlight the complex effects of MA on immune and behavioral function and suggest that alterations in CCL3 signaling may contribute to the mood impairments observed during remission from MA addiction.

A neurotoxic alcohol exposure paradigm does not induce hepatic encephalopathy.

Alcohol abuse is associated with neurological dysfunction, brain morphological deficits and frank neurotoxicity. Although these disruptions may be a secondary effect due to hepatic encephalopathy, no clear evidence of causality is available. This study examined whether a 72h period of alcohol intoxication known to induce physical dependence, followed by a single withdrawal, was sufficient to induce signs of hepatic encephalopathy in male and female mice. Animals were continuously intoxicated via alcohol vapor inhalation, a procedure previously shown to induce significant neurotoxicity in female mice. At peak synchronized withdrawal (8h following the end of alcohol exposure), blood samples were taken and levels of several liver-regulated markers and brain swelling were characterized. Glutathione levels were also determined in the medial frontal cortex (mFC) and hippocampus. Results revealed elevated levels of cholesterol, albumin, alkaline phosphatase (ALP), alanine aminotransferase (ALT) and decreased levels of blood urea nitrogen and total bilirubin in alcohol-exposed male and female groups compared to controls. Brain water weight was not affected by alcohol exposure, though males tended to have slightly more water weight overall. Alcohol exposure led to reductions in tissue levels of glutathione in both the hippocampus and mFC which may indicate increased oxidative stress. Combined, these results suggest that hepatic encephalopathy does not appear to play a significant role in the neurotoxicity observed following alcohol exposure in this model.

Astrocyte Dysfunction Induced by Alcohol in Females but Not Males.

Chronic alcohol abuse is associated with brain damage in a sex-specific fashion, but the mechanisms involved are poorly described and remain controversial. Previous results have suggested that astrocyte gene expression is influenced by ethanol intoxication and during abstinence in vivo. Here, bioinformatic analysis of astrocyte-enriched ethanol-regulated genes in vivo revealed ubiquitin pathways as an ethanol target, but with sexually dimorphic cytokine signaling and changes associated with brain aging in females and not males. Consistent with this result, astrocyte activation was observed after exposure in female but not male animals, with reduced S100ß levels in the anterior cingulate cortex and increased GFAP(+) cells in the hippocampus. In primary culture, the direct effects of chronic ethanol exposure followed by recovery on sex-specific astrocyte function were examined. Male astrocyte responses were consistent with astrocyte deactivation with reduced GFAP expression during ethanol exposure. In contrast, female astrocytes exhibited increased expression of Tnf, reduced expression of the neuroprotective cytokine Tgfb1, disrupted bioenergetics and reduced excitatory amino acid uptake following exposure or recovery. These results indicate widespread astrocyte dysfunction in ethanol-exposed females and suggest a mechanism that may underlie increased vulnerability to ethanol-induced neurotoxicity in females.

Females uniquely vulnerable to alcohol-induced neurotoxicity show altered glucocorticoid signaling.

Women are more sensitive to the harmful effects of alcohol (EtOH) abuse than men, yet the underlying mechanisms remain poorly understood. Previous gene expression analysis of the medial prefrontal cortex (mPFC) following a chronic intoxication paradigm using continuous 72 h vapor inhalation found that females, but not males, exhibit an inflammatory response at peak withdrawal that is associated with cell damage. Given that glucocorticoids can function as anti-inflammatories, are known to increase with EtOH exposure, and influence neurotoxicity, we hypothesized that males and females may exhibit an altered corticosterone (CORT) response following chronic intoxication. Analysis of serum CORT levels revealed the expected increase during withdrawal with no difference between males and females, while control males but not females exhibited higher CORT concentrations than naive animals. Glucocorticoid signaling characterized using focused qPCR arrays identified a sexually dimorphic response in the mPFC during withdrawal, particularly among astrocyte-enriched genes. These genes include aquaporin-1 (Aqp1), sphingosine kinase 1 (Sphk1) and connective tissue growth factor (Ctgf); genes associated with inflammatory signaling, and tissue damage and repair. Bioinformatic analysis also revealed activation of inflammatory signaling and cell death pathways in females. Confirmation studies showed that female mice exhibited significant neuronal degeneration within the anterior cingulate cortex (ACC). By contrast, EtOH exposure lead to a significant reduction in cell death in males. Thus, distinct glucocorticoid signaling pathways are associated with sexually dimorphic neurotoxicity, suggesting one mechanism by which EtOH-exposed females are particularly vulnerable to the damaging effects of alcohol in the CNS.

Fetal Alcohol Spectrum Disorders: An Overview from the Glia Perspective.

Alcohol consumption during pregnancy can produce a variety of central nervous system (CNS) abnormalities in the offspring resulting in a broad spectrum of cognitive and behavioral impairments that constitute the most severe and long-lasting effects observed in fetal alcohol spectrum disorders (FASD). Alcohol-induced abnormalities in glial cells have been suspected of contributing to the adverse effects of alcohol on the developing brain for several years, although much research still needs to be done to causally link the effects of alcohol on specific brain structures and behavior to alterations in glial cell development and function. Damage to radial glia due to prenatal alcohol exposure may underlie observations of abnormal neuronal and glial migration in humans with Fetal Alcohol Syndrome (FAS), as well as primate and rodent models of FAS. A reduction in cell number and altered development has been reported for several glial cell types in animal models of FAS. In utero alcohol exposure can cause microencephaly when alcohol exposure occurs during the brain growth spurt a period characterized by rapid astrocyte proliferation and maturation; since astrocytes are the most abundant cells in the brain, microenchephaly may be caused by reduced astrocyte proliferation or survival, as observed in in vitro and in vivo studies. Delayed oligodendrocyte development and increased oligodendrocyte precursor apoptosis has also been reported in experimental models of FASD, which may be linked to altered myelination/white matter integrity found in FASD children. Children with FAS exhibit hypoplasia of the corpus callosum and anterior commissure, two areas requiring guidance from glial cells and proper maturation of oligodendrocytes. Finally, developmental alcohol exposure disrupts microglial function and induces microglial apoptosis; given the role of microglia in synaptic pruning during brain development, the effects of alcohol on microglia may be involved in the abnormal brain plasticity reported in FASD. The consequences of prenatal alcohol exposure on glial cells, including radial glia and other transient glial structures present in the developing brain, astrocytes, oligodendrocytes and their precursors, and microglia contributes to abnormal neuronal development, reduced neuron survival and disrupted brain architecture and connectivity. This review highlights the CNS structural abnormalities caused by in utero alcohol exposure and outlines which abnormalities are likely mediated by alcohol effects on glial cell development and function.

Effect of epigallocatechin gallate supplementation in schizophrenia and bipolar disorder: an 8-week, randomized, double-blind, placebo-controlled study.

OBJECTIVES: Strategies that focus on the reduction of oxidative stress and inflammation may have therapeutic benefit for the treatment of schizophrenia. This clinical trial sought to determine, in a double-blind study, whether epigallocatechin gallate (EGCG), a green tea extract, is a useful adjunct to maintenance antipsychotic medication. METHODS: Adults with schizophrenia, schizoaffective disorder or bipolar disorder who were maintained on antipsychotic and other psychotropic medications were randomized to supplemental EGCG or placebo. Study participants completed clinical assessments and blood draws to evaluate supplemental treatment effects on psychiatric symptoms and plasma inflammatory markers. RESULTS: A total of 34 participants (17 EGCG, 17 placebo) were randomized and 25 participants (14 EGCG, 11 placebo) completed the study. Both treatment groups showed significant reductions in psychotic, depressive and anxiety symptoms from baseline to end of treatment. However, EGCG did not significantly affect psychiatric symptoms or inflammatory markers, as compared with placebo. Adverse effects were mild and comparable between groups. CONCLUSION: There was no signal for a therapeutic effect of the green tea extract EGCG on psychiatric symptoms in this placebo-controlled pilot study.

Partial MHC/neuroantigen peptide constructs: a potential neuroimmune-based treatment for methamphetamine addiction.

Relapse rates following current methamphetamine abuse treatments are very high (∼40-60%), and the neuropsychiatric impairments (e.g., cognitive deficits, mood disorders) that arise and persist during remission from methamphetamine addiction likely contribute to these high relapse rates. Pharmacotherapeutic development of medications to treat addiction has focused on neurotransmitter systems with only limited success, and there are no Food and Drug Administration approved pharmacotherapies for methamphetamine addiction. A growing literature shows that methamphetamine alters peripheral and central immune functions and that immune factors such as cytokines, chemokines, and adhesion molecules play a role in the development and persistence of methamphetamine induced neuronal injury and neuropsychiatric impairments. The objective of this study was to evaluate the efficacy of a new immunotherapy, partial MHC/neuroantigen peptide construct (RTL551; pI-A(b)/mMOG-35-55), in treating learning and memory impairments induced by repeated methamphetamine exposure. C57BL/6J mice were exposed to two different methamphetamine treatment regimens (using repeated doses of 4 mg/kg or 10 mg/kg, s.c.). Cognitive performance was assessed using the Morris water maze and CNS cytokine levels were measured by multiplex assay. Immunotherapy with RTL551 improved the memory impairments induced by repeated methamphetamine exposure in both mouse models of chronic methamphetamine addiction. Treatment with RTL551 also attenuated the methamphetamine induced increases in hypothalamic interleukin-2 (IL-2) levels. Collectively, these initial results indicate that neuroimmune targeted therapies, and specifically RTL551, may have potential as treatments for methamphetamine-induced neuropsychiatric impairments.

Vulnerability to somatic symptoms of depression during interferon-alpha therapy for hepatitis C: a 16-week prospective study.

OBJECTIVE: This study evaluated the distinctive clinical and biological manifestations of depressive symptom subtypes (i.e., cognitive-affective and somatic) in Veterans with hepatitis C viral infection (HCV) before and during interferon-alpha (IFN) based antiviral therapy. METHODS: Thirty-two Veterans with HCV and no prior history of IFN therapy were followed prospectively during the first 16weeks of therapy to evaluate depressive symptoms and to determine if baseline cytokine and serotonin levels predicted subsequent changes in depressive scores. RESULTS: IFN therapy resulted in a significant increase in total depressive symptoms from baseline (week 0) to week 16, with neurovegetative and somatic symptoms of depression including loss of appetite, fatigue and irritability increasing within the first two weeks of therapy and continuing to increase throughout IFN therapy. When depressive symptoms were evaluated using a two-factor (i.e., Cognitive-Affective and Somatic) model, the Cognitive-Affective factor score did not change significantly following IFN therapy initiation, while the Somatic factor score showed a significant increase from week 0 to week 16. Veterans with the largest increases in somatic symptoms from week 0 to week 2 had significantly higher levels of tumor necrosis factor-alpha (TNF-α) and lower levels of serotonin at baseline, as compared to Veterans with minimal or no increase in somatic symptoms. CONCLUSION: Somatic symptoms of depression can be significantly exacerbated during IFN therapy and may be predicted by higher TNF-α levels and lower serotonin levels at baseline.

Adipocytokine signaling is altered in Flinders sensitive line rats, and adiponectin correlates in humans with some symptoms of depression.

Major depression is a complex multi-factorial disorder with a lifetime diagnosis of nearly 1 out of 6. We used the Flinders Sensitive Line (FSL) of rats, a model of depression, and the parent Sprague-Dawley (SD) rats to identify genes, gene ontology categories and pathways associated with depression. Depression-like behavior was verified in the FSL line by forced swim testing, with FSL animals exhibiting greater immobility compared to SD rats. RNA samples from the hippocampus were isolated from a group of experimentally naïve FSL and SD rats for microarray analysis. Microarray analysis yielded a total of 361 genes that were differentially regulated between FSL and SD rats, with catechol-O-methyltransferase (COMT) being the most up-regulated. The genes that were differentially regulated between FSL and SD rats were subjected to bioinformatic analysis using the Database for Annotation, Visualization and Integrated Discovery (DAVID), which yielded several gene ontology categories that were overrepresented. Subsequent pathway analysis indicated dysregulation of the adipocytokine signaling pathway. To test the translational impact of this pathway, metabolic factors and psychiatric symptoms were evaluated in a sample of human research participants. Results from our human subjects indicated that anxiety and a subset of depressive symptoms were correlated with adiponectin levels (but not leptin levels). Our results and those of others suggest that disruption of the adipocytokine signaling pathway may be a critical component of the depressive-like behaviors observed in the FSL rats and may also be an important indicator of depressive and anxiety symptoms in humans.

Acute ethanol does not always affect delay discounting in rats selected to prefer or avoid ethanol.

AIMS: The purpose of this study was to determine whether animals predisposed to prefer alcohol possess an altered acute response to alcohol on a delay discounting task relative to animals predisposed to avoid alcohol. METHODS: We used rats selected to prefer or avoid alcohol to assess whether genotype moderates changes in delay discounting induced by acute ethanol exposure. Selectively bred rat lines of Sardinian alcohol-preferring (sP; n = 8) and non-preferring (sNP; n = 8) rats, and alko alcohol (AA, n = 8) and alko non-alcohol (ANA, n = 8) rats were trained in an adjusting amount task to assess delay discounting. RESULTS: There were no significant effects of line on baseline discounting; however, both lines of alcohol-preferring rats exhibit slowed reaction times. Acute ethanol (0, 0.25, 0.5 g/kg) treatment also had no effect on delay discounting in any of the selectively bred rat lines. CONCLUSION: Our data indicate that in these lines of animals, alcohol preference or avoidance has no impact on delay discounting following acute ethanol exposure. It is possible that other genetic models or lines may be differentially affected by alcohol and exhibit qualitatively and quantitatively different responses in delay discounting tasks.

Corticotropin releasing factor-1 receptor antagonism alters the biochemical, but not behavioral effects of repeated interleukin-1ß administration.

Activation of the immune system via administration of cytokines is used for the treatment of chronic viral infections such as hepatitis C and for cancers resistant to radiotherapy. Cytokine-based treatments induce a range of "sickness" behaviors (e.g. depression, anxiety, pain, anorexia, and fatigue). Activation of the hypothalamic pituitary-adrenal axis via the induction of corticotropin releasing factor (CRF) may underlie these unwanted side effects. This study used repeated systemic injections of the pro-inflammatory cytokine interleukin-1ß (IL-1ß) to model the sickness behaviors and biochemical effects of immune system activation. We assessed the ability of CRF type I receptor (CRF(1)) antagonism to reduce biochemical and behavioral signs of sickness induced by IL-1ß treatment. Forty Wistar rats were assigned to one of four groups: 1) saline+vehicle; 2) saline+DMP904 (CRF(1) antagonist); 3) IL-1ß+vehicle; 4) IL-1ß+DMP904. Rats received intraperitoneal injections of either DMP904 or vehicle and of IL-1ß or saline for six days. Sickness behavior was evaluated using body weight assessments and forced swim testing (FST). Blood and brain samples were collected to measure cytokine, p38 mitogen-activated protein kinase (MAPK), and phospho-p38 MAPK levels using multiplex techniques. There were significant reductions in body weights and FST immobility times associated with IL-1ß administration. Rats administered IL-1ß had significantly higher serum levels of IL-10, but not interferon-γ. Within the hippocampus, IL-1ß reduced levels of p38 MAPK, but had no impact on levels of phospho-p38 MAPK except in the presence of DMP904. When administered alone, DMP904 had no significant effect on p38 MAPK or phospho-p38 MAPK in the hippocampus, but when given with IL-1ß led to increased phosphorylation of p38 MAPK. IL-1ß and DMP904 reduced levels of p38 MAPK within the hypothalamus, while co-administration of IL-1ß and DMP904 abolished the effects of either drug alone. IL-1ß decreased immobility time in the FST, and led to reductions in body weight, changes in serum cytokine levels and p38 MAPK regulation within the hippocampus and hypothalamus. DMP904 blocked some of the neurochemical effects of IL-1ß, but did not impact the behavioral measures, or serum cytokines. Thus, additional studies will be needed to determine whether CRF(1) antagonism is an effective treatment for cytokine-induced sickness. This article is part of a Special Issue entitled 'Anxiety and Depression'.

Strain differences in behavioral inhibition in a Go/No-go task demonstrated using 15 inbred mouse strains.

BACKGROUND: High levels of impulsivity have been associated with a number of substance abuse disorders including alcohol abuse. Research has not yet revealed whether these high levels predate the development of alcohol abuse. METHODS: The current study examined impulsivity in 15 inbred strains of mice (A/HeJ, AKR/J, BALB/cJ, C3H/HeJ, C57BL/6J, C57L/J, C58/J, CBA/J, DBA/1J, DBA/2J, NZB/B1NJ, PL/J, SJL/J, SWR/J, and 129P3/J) using a Go/No-go task, which was designed to measure a subject's ability to inhibit a behavior. Numerous aspects of response to ethanol and other drugs of abuse have been examined in these strains. RESULTS: There were significant strain differences in the number of responses made during the No-go signal (false alarms) and the extent to which strains responded differentially during the Go and No-go signals (d'). The rate of responding prior to the cue did not differ among strains, although there was a statistically significant correlation between false alarms and precue responding that was not related to basal activity level. Interstrain correlations suggested that false alarms and rate of responding were associated with strain differences in ethanol-related traits from the published literature. CONCLUSIONS: The results of this study do support a link between innate level of impulsivity and response to ethanol and are consistent with a genetic basis for some measures of behavioral inhibition.

Response bias is unaffected by delay length in a delay discounting paradigm.

This study examined the contribution of response bias to measures of delay discounting in Long-Evans rats (n=8) using the adjusting amount procedure. Under this procedure, we assessed preference for 150microl of 10% sucrose solution delivered following a delay over a variable-amount alternative delivered immediately. Bias was calculated based on relative preference when reinforcers were delivered immediately from both alternatives. We extended this assessment procedure to examine preference when rewards from both alternatives were equally delayed (2, 4, 8, or 16s) in addition to assessing a traditional delay discounting function. Relative preference was similar across delays and slightly larger than 150microl. These results indicate that response bias was stable and suggests a relative aversion for the adjusting alternative, which may be due to the variability in reward size associated with that alternative.

Lobeline effects on tonic and methamphetamine-induced dopamine release.

The mechanisms of interaction between lobeline and the dopamine transporter (DAT) or the vesicular monoamine transporter (VMAT-2) are not clear. The goal of this study was to elucidate the effects of lobeline on these transporters in a cell system co-expressing the DAT and VMAT-2. Lobeline caused release of [(3)H]dopamine to a similar extent as reserpine (VMAT-2 inhibitor), but was less efficacious than methamphetamine or dopamine. Additionally, lobeline decreased the [(3)H]dopamine-releasing effects of methamphetamine, unlike reserpine which increased release by methamphetamine. These results suggest that lobeline has unique properties at the DAT and VMAT-2 which may make it useful as a pharmacotherapeutic to treat methamphetamine abuse.

Mouse lines selected for alcohol consumption differ on certain measures of impulsivity.

BACKGROUND: Alcoholics and heavy drinkers score higher on measures of impulsivity than nonalcoholics and light drinkers. This may be due to factors that predate drug exposure (e.g. genetics) or to neuroadaptations associated with exposure to alcohol. The aim of this study was to examine the role of genetics by comparing impulsivity in short-term selected lines of mice bred to voluntarily drink either high (STDRHI2) or low (STDRLO2) amounts of 10% ethanol. METHODS: Independent sets of mice completed 2 experiments designed to measure impulsivity. Using the adjusting amount procedure, we examined preference for smaller, sooner rewards over larger but delayed rewards (delay discounting). This task determines the amount of immediate sucrose equivalent to the discounted value of a 20 microl sucrose reward given following a specific delay (0, 2, 4, 8, or 12 seconds). Using a Go/No-go task, we examined the ability of mice to inhibit nose-poking in response to specific cues. These tasks are commonly used to assess different aspects of impulsive behavior, and provide measures that are not highly correlated. RESULTS: No significant differences were found between STDRHI2 and STDRLO2 mice in delay discounting. In the Go/No-go task, STDRHI2 mice made more responses during the pre-cue period without committing more false alarms, compared with STDRLO2 mice. CONCLUSIONS: The results suggest that short-term selective breeding for high relative alcohol consumption may also select for animals that have impaired response inhibition.