Scanning Sex, Stress and Substance Abuse Susceptibility: Neural Correlates of Vulnerability to Abuse Drugs.

Despite decades of research, it is still not understood why some individuals are vulnerable to drug addiction while others are resilient. Susceptibility to use and abuse drugs appears to arise from a complex set of interacting variables. It is known that environmental (e.g. stress exposure), trait (e.g. impulsiveness) and genetic factors all contribute to substance abuse risk, however, the biological mechanisms that underlie this risk are not well understood. Though some research has indicated abnormalities in dopaminergic and opioidergic activity in current and former drug addicts, such as lower D2 receptor availability and higher mu-opioid receptor availability within the ventral striatum, it cannot be determined whether such abnormalities represented predisposing factors to drug use or were a consequence of drug consumption or addiction processes. Studying non-drug using individuals who carry factors that have historically been shown to place them at higher risk for substance use and abuse represents a preferable alternative to studying drug addicts. In these studies, we examined the relationships between several susceptibility factors, specifically exposure to recent life stress, genetic variation at the oxytocin gene (OXT), and trait impulsiveness with measures of dopaminergic and opioidergic functioning in healthy, non-drug using subjects utilizing positron emission tomography (PET). The results of these studies are as follows: First, utilizing mu-opioid receptor agonist radiotracer [11C]carfentanil we observed significantly higher regional mu-opioid receptor concentrations and greater stress-induced endogenous opioid system activation in individuals exhibiting high levels of trait impulsiveness. Second, in scans using the D2/D3 dopamine receptor antagonist radiotracer [11C]raclopride, we observed significant differences in stress-induced dopaminergic activity between men and women throughout the striatum. In addition, we noted a significant interaction between sex and environmental stress in the nucleus accumbens. Finally, we observed that single nucleotide polymorphisms (SNPs) located on chromosome 20 upstream of OXT were associated with dopaminergic and behavioral responses to a stressor, but only in women. The data obtained from these studies are broadly relevant for addiction research and provides original information regarding the mechanisms which may underlie individual risk to use and abuse drugs.Ph.D.NeuroscienceUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/75798/1/tiflove_1.pd

Ink from longfin inshore squid, Doryteuthis pealeii, as a chemical and visual defense against two predatory fishes, summer flounder, Paralichthys dentatus, and sea catfish, Ariopsis felis

Author Posting. © Marine Biological Laboratory, 2013. This article is posted here by permission of Marine Biological Laboratory for personal use, not for redistribution. The definitive version was published in Biological Bulletin 225 (2013): 152-160.Chemical and visual defenses are used by many organisms to avoid being approached or eaten by predators. An example is inking molluscs—including gastropods such as sea hares and cephalopods such as squid, cuttlefish, and octopus—which release a colored ink upon approach or attack. Previous work showed that ink can protect molluscs through a combination of chemical, visual, and other effects. In this study, we examined the effects of ink from longfin inshore squid, Doryteuthis pealeii, on the behavior of two species of predatory fishes, summer flounder, Paralichthys dentatus, and sea catfish, Ariopsis felis. Using a cloud assay, we found that ink from longfin inshore squid affected the approach phase of predation by summer flounder, primarily through its visual effects. Using a food assay, we found that the ink affected the consummatory and ingestive phase of predation of both sea catfish and summer flounder, through the ink's chemical properties. Fractionation of ink showed that most of its deterrent chemical activity is associated with melanin granules, suggesting that either compounds adhering to these granules or melanin itself are the most biologically active. This work provides the basis for a comparative approach to identify deterrent molecules from inking cephalopods and to examine neural mechanisms whereby these chemicals affect behavior of fish, using the sea catfish as a chemosensory model.Our project was supported by National Science Foundation grant IOS-1036742 and REU supplements IOS-1338385, IOS 1234038, and IOS-1130244; by The Plum Foundation John E. Dowling Fellowship Fund and the Colwin Endowed Summer Research Fellowship Fund from the Marine Biological Laboratory; and by a Second Century Initiative graduate fellowship from Georgia State University

Development and initial validation of a rock climbing craving questionnaire (RCCQ)

Conceptual similarities have been identified between experiences of extreme sports athletes and those with drug and behavioural addictions. Evidence suggests rock climbers experience craving and other withdrawal-like states when abstinent from their sport. However, no studies have attempted to quantitatively measure the craving experienced by participants of any extreme sports. Such a measure could allow a greater understanding of the craving experienced by extreme sports athletes and a comparison of these across sports (e.g., surfing) and activities (e.g., drug-use). Therefore, using validated craving measures as a template, the aim of the two studies outlined here was to design and preliminarily validate a subjective multidimensional inventory that could be used to measure craving in the sports of rock-climbing and mountaineering (“RCCQ”). The aim of the first study was to investigate the factor structure of a preliminary measure of craving. Climbers (n = 407) completed the RCCQ. A 3-factor model explained 53.65% of the total variance in item scores. All 3 factors comprised 5 items each, which were conceptually labelled as “urge to climb” “negative reinforcement” and “positive reinforcement”. The aim of the second study was to validate the 15-item 3-factor RCCQ resulting from study one using confirmatory factor analysis. Climbers (n = 254) completed the questionnaire under a climbing-related cue condition or a cue-neutral condition. Confirmatory factor analysis (CFA) revealed a good model fit and that all individual parameter estimates were significant and standard errors were within reasonable limits once item 13 was removed from Factor 1. Study one supports the multi-dimensional nature of rock climbing craving and shows parallels with substance-related craving in reflecting intention and positive (desire) and negative (withdrawal) reinforcement. Study two confirms this factor structure and gives initial validation to the measure with evidence that these factors are sensitive to cue exposure. Given the preliminary nature of the data, any practical implications are tentative. However, if as shown here, craving for climbing (and potentially other extreme sports) is similar to that experienced by drug-users and addicts, there is the potential that climbing and other extreme sports could be used as a replacement therapy for drug users

Risk for opioid misuse in chronic pain patients is associated with endogenous opioid system dysregulation

µ-Opioid receptors (MOR) are a major target of endogenous and exogenous opioids, including opioid pain medications. The µ-opioid neurotransmitter system is heavily implicated in the pathophysiology of chronic pain and opioid use disorder and, as such, central measures of µ-opioid system functioning are increasingly being considered as putative biomarkers for risk to misuse opioids. To explore the relationship between MOR system function and risk for opioid misuse, 28 subjects with chronic nonspecific back pain completed a clinically validated measure of opioid misuse risk, the Pain Medication Questionnaire (PMQ), and were subsequently separated into high (PMQ > 21) and low (PMQ ≤ 21) opioid misuse risk groups. Chronic pain patients along with 15 control participants underwent two separate [11C]-carfentanil positron emission tomography scans to explore MOR functional measures: one at baseline and one during a sustained pain-stress challenge, with the difference between the two providing an indirect measure of stress-induced endogenous opioid release. We found that chronic pain participants at high risk for opioid misuse displayed higher baseline MOR availability within the right amygdala relative to those at low risk. By contrast, patients at low risk for opioid misuse showed less pain-induced activation of MOR-mediated, endogenous opioid neurotransmission in the nucleus accumbens. This study links human in vivo MOR system functional measures to the development of addictive disorders and provides novel evidence that MORs and µ-opioid system responsivity may underlie risk to misuse opioids among chronic pain patients.publishedVersionPeer reviewe

Reduced basal ganglia μ-opioid receptor availability in trigeminal neuropathic pain: A pilot study

Abstract Background Although neuroimaging techniques have provided insights into the function of brain regions involved in Trigeminal Neuropathic Pain (TNP) in humans, there is little understanding of the molecular mechanisms affected during the course of this disorder. Understanding these processes is crucial to determine the systems involved in the development and persistence of TNP. Findings In this study, we examined the regional μ-opioid receptor (μOR) availability in vivo (non-displaceable binding potential BPND) of TNP patients with positron emission tomography (PET) using the μOR selective radioligand [11C]carfentanil. Four TNP patients and eight gender and age-matched healthy controls were examined with PET. Patients with TNP showed reduced μOR BPND in the left nucleus accumbens (NAc), an area known to be involved in pain modulation and reward/aversive behaviors. In addition, the μOR BPND in the NAc was negatively correlated with the McGill sensory and total pain ratings in the TNP patients. Conclusions Our findings give preliminary evidence that the clinical pain in TNP patients can be related to alterations in the endogenous μ-opioid system, rather than only to the peripheral pathology. The decreased availability of μORs found in TNP patients, and its inverse relationship to clinical pain levels, provide insights into the central mechanisms related to this condition. The results also expand our understanding about the impact of chronic pain on the limbic system.http://deepblue.lib.umich.edu/bitstream/2027.42/112555/1/12990_2012_Article_533.pd

Personality Trait Predictors of Placebo Analgesia and Neurobiological Correlates

Personality traits have been shown to interact with environmental cues to modulate biological responses including treatment responses, and potentially having a role in the formation of placebo effects. Here, we assessed psychological traits in 50 healthy controls as to their capacity to predict placebo analgesic effects, placebo-induced activation of μ-opioid neurotransmission and changes in cortisol plasma levels during a sustained experimental pain challenge (hypertonic saline infused in the masseter muscle) with and without placebo administration. Statistical analyses showed that an aggregate of scores from Ego-Resiliency, NEO Altruism, NEO Straightforwardness (positive predictors) and NEO Angry Hostility (negative predictor) scales accounted for 25% of the variance in placebo analgesic responses. Molecular imaging showed that subjects scoring above the median in a composite of those trait measures also presented greater placebo-induced activation of μ-opioid neurotransmission in the subgenual and dorsal anterior cingulate cortex (ACC), orbitofrontal cortex, insula, nucleus accumbens, amygdala and periaqueductal gray (PAG). Endogenous opioid release in the dorsal ACC and PAG was positively correlated with placebo-induced reductions in pain ratings. Significant reductions in cortisol levels were observed during placebo administration and were positively correlated with decreases in pain ratings, μ-opioid system activation in the dorsal ACC and PAG, and as a trend, negatively with NEO Angry Hostility scores. Our results show that personality traits explain a substantial proportion of the variance in placebo analgesic responses and are further associated with activations in endogenous opioid neurotransmission, and as a trend cortisol plasma levels. This initial data, if replicated in larger sample, suggest that simple trait measures easily deployable in the field could be utilized to reduce variability in clinical trials, but may also point to measures of individual resiliency in the face of aversive stimuli such as persistent pain and potentially other stressors

Enteropathy-associated T cell lymphoma subtypes are characterized by loss of function of SETD2

Enteropathy-associated T cell lymphoma (EATL) is a lethal, and the most common, neoplastic complication of celiac disease. Here, we defined the genetic landscape of EATL through whole-exome sequencing of 69 EATL tumors. SETD2 was the most frequently silenced gene in EATL (32% of cases). The JAK-STAT pathway was the most frequently mutated pathway, with frequent mutations in STAT5B as well as JAK1 , JAK3 , STAT3 , and SOCS1 . We also identified mutations in KRAS , TP53 , and TERT . Type I EATL and type II EATL (monomorphic epitheliotropic intestinal T cell lymphoma) had highly overlapping genetic alterations indicating shared mechanisms underlying their pathogenesis. We modeled the effects of SETD2 loss in vivo by developing a T cell–specific knockout mouse. These mice manifested an expansion of γδ T cells, indicating novel roles for SETD2 in T cell development and lymphomagenesis. Our data render the most comprehensive genetic portrait yet of this uncommon but lethal disease and may inform future classification schemes

NETosis in Alzheimer's Disease

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the progressive deterioration of cognitive functions. Its neuropathological features include amyloid-\u3b2 (A\u3b2) accumulation, the formation of neurofibrillary tangles, and the loss of neurons and synapses. Neuroinflammation is a well-established feature of AD pathogenesis, and a better understanding of its mechanisms could facilitate the development of new therapeutic approaches. Recent studies in transgenic mouse models of AD have shown that neutrophils adhere to blood vessels and migrate inside the parenchyma. Moreover, studies in human AD subjects have also shown that neutrophils adhere and spread inside brain vessels and invade the parenchyma, suggesting these cells play a role in AD pathogenesis. Indeed, neutrophil depletion and the therapeutic inhibition of neutrophil trafficking, achieved by blocking LFA-1 integrin in AD mouse models, significantly reduced memory loss and the neuropathological features of AD. We observed that neutrophils release neutrophil extracellular traps (NETs) inside blood vessels and in the parenchyma of AD mice, potentially harming the blood-brain barrier and neural cells. Furthermore, confocal microscopy confirmed the presence of NETs inside the cortical vessels and parenchyma of subjects with AD, providing more evidence that neutrophils and NETs play a role in AD-related tissue destruction. The discovery of NETs inside the AD brain suggests that these formations may exacerbate neuro-inflammatory processes, promoting vascular and parenchymal damage during AD. The inhibition of NET formation has achieved therapeutic benefits in several models of chronic inflammatory diseases, including autoimmune diseases affecting the brain. Therefore, the targeting of NETs may delay AD pathogenesis and offer a novel approach for the treatment of this increasingly prevalent disease

Effects of alcohol preload on attentional bias towards cocaine-related cues

Background Drug and alcohol users have an ‘attentional bias’ for substance-related cues, which is likely to reflect the incentive-motivational properties of those cues. Furthermore, administration of an alcohol preload increases attentional bias for alcohol and tobacco-related cues in heavy drinkers and tobacco smokers, respectively. The present study investigated attentional bias for cocaine cues in cocaine users and non-users following administration of either alcohol or placebo. Method Thirty-two regular cocaine users and 40 non-users took part. Participants were administered alcohol or placebo, and administration was double blind. After drink administration, a Visual Probe task and Modified Stroop task were used to assess attentional bias. Subjective craving and alcohol outcome expectancies were also measured. Results There was a significant interaction between group and drink type on the visual probe task indicating that cocaine users who had received alcohol had increased attentional bias for cocaine pictures compared to non-users and cocaine users who received placebo. The cocaine Stroop revealed no differences between cocaine users and non-users, and no effects of alcohol in either group. Conclusions Alcohol preload in regular cocaine users increases attentional bias for cocaine cues. However, cocaine users who received placebo did not show attentional bias for cocaine stimuli. Future research should investigate the effects of alcohol preload on attentional bias in cocaine-dependent individuals

Neuronal Deletion of Caspase 8 Protects against Brain Injury in Mouse Models of Controlled Cortical Impact and Kainic Acid-Induced Excitotoxicity

system. mice demonstrated superior survival, reduced seizure severity, less apoptosis, and reduced caspase 3 processing. Uninjured aged knockout mice showed improved learning and memory, implicating a possible role for caspase 8 in cognitive decline with aging.Neuron-specific deletion of caspase 8 reduces brain damage and improves post-traumatic functional outcomes, suggesting an important role for this caspase in pathophysiology of acute brain trauma