Clare J. Wilhelm

Rats bred for high alcohol drinking are more sensitive to delayed and probabilistic outcomes

Alcoholics and heavy drinkers score higher on measures of impulsivity than nonalcoholics and light drinkers. This may be because of factors that predate drug exposure (e.g. genetics). This study examined the role of genetics by comparing impulsivity measures in ethanol‐naive rats selectively bred based on their high [high alcohol drinking (HAD)] or low [low alcohol drinking (LAD)] consumption of ethanol. Replicates 1 and 2 of the HAD and LAD rats, developed by the University of Indiana Alcohol Research Center, completed two different discounting tasks. Delay discounting examines sensitivity to rewards that are delayed in time and is commonly used to assess ‘choice’ impulsivity. Probability discounting examines sensitivity to the uncertain delivery of rewards and has been used to assess risk taking and risk assessment. High alcohol drinking rats discounted delayed and probabilistic rewards more steeply than LAD rats. Discount rates associated with probabilistic and delayed rewards were weakly correlated, while bias was strongly correlated with discount rate in both delay and probability discounting. The results suggest that selective breeding for high alcohol consumption selects for animals that are more sensitive to delayed and probabilistic outcomes. Sensitivity to delayed or probabilistic outcomes may be predictive of future drinking in genetically predisposed individuals.

D4 receptor deficiency in mice has limited effects on impulsivity and novelty seeking

Alleles of the human dopamine D(4) receptor (D(4)R) gene (DRD4.7) have repeatedly been found to correlate with novelty seeking, substance abuse, pathological gambling, and attention-deficit hyperactivity disorder (ADHD). If these various psychopathologies are a result of attenuated D(4)R-mediated signaling, mice lacking D(4)Rs (D(4)KO) should be more impulsive than wild-type (WT) mice and exhibit more novelty seeking. However, in our study, D(4)KO and WT mice showed similar levels of impulsivity as measured by delay discounting performance and response inhibition on a Go/No-go test, suggesting that D(4)R-mediated signaling may not affect impulsivity. D(4)KO mice were more active than WT mice in the first 5 min of a novel open field test, suggesting greater novelty seeking. For both genotypes, more impulsive mice habituated less in the novel open field. These data suggest that the absence of D(4)Rs is not sufficient to cause psychopathologies associated with heightened impulsivity and novelty seeking.

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.

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.

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.

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.

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 S100β 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.

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-Ab/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.

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.