Double jeopardy: Comorbid obesity and cigarette smoking are linked to neurobiological alterations in inhibitory control during smoking cue exposure.

Obesity and cigarette smoking are two of the leading preventable causes of death in the United States. Research suggests that overlapping pathophysiology may contribute to obesity and nicotine use disorder (NUD), yet no studies have investigated the effect of obesity on neural response to reward stimuli in NUD. This study used arterial spin-labeled perfusion functional magnetic resonance imaging (fMRI) to examine neural responses during exposure to smoking versus nonsmoking cues in 79 treatment-seeking participants with NUD, 26 with normal weight, 28 with overweight, and 25 with obesity. Given that deficits in behavioral inhibitory control have been associated with both obesity and NUD, participants completed an affect-congruent Go/NoGo task to assess the effect of body mass index (BMI) on this construct in NUD. Analyses revealed that BMI was negatively associated with activation in the right dorsolateral prefrontal cortex (dlPFC) in response to smoking cues, with significantly reduced response in smokers with overweight and smokers with obesity compared with normal-weight smokers. In addition, greater commission errors on the Go/NoGo task were correlated with reduced neural response to smoking cues in the right dlPFC only among those with obesity. Together, these findings provide evidence that obesity in treatment-seeking NUDs is related to neurobiological alterations in inhibitory control over cue-potentiated behaviors, suggesting that smoking cessation may be more difficult in individuals with comorbid NUD and obesity than in those without, requiring treatment strategies tailored to meet their unique needs.

Brain intrinsic network connectivity in individuals with frequent tanning behavior.

BACKGROUND: Emergent studies suggest a bidirectional relationship between brain functioning and the skin. This neurocutaneous connection may be responsible for the reward response to tanning and, thus, may contribute to excessive tanning behavior. To date, however, this association has not yet been examined. OBJECTIVES: To explore whether intrinsic brain functional connectivity within the default mode network (DMN) is related to indoor tanning behavior. METHODS: Resting state functional connectivity (rsFC) was obtained in twenty adults (16 females) with a history of indoor tanning. Using a seed-based [(posterior cingulate cortex (PCC)] approach, the relationship between tanning severity and FC strength was assessed. Tanning severity was measured with symptom count from the Structured Clinical Interview for Tanning Abuse and Dependence (SITAD) and tanning intensity (lifetime indoor tanning episodes/years tanning). RESULTS: rsFC strength between the PCC and other DMN regions (left globus pallidus, left medial frontal gyrus, left superior frontal gyrus) is positively correlated with tanning symptom count. rsFC strength between the PCC and salience network regions (right anterior cingulate cortex, left inferior parietal lobe, left inferior temporal gyrus) is correlated with tanning intensity. CONCLUSION: Greater connectivity between tanning severity and DMN and salience network connectivity suggests that heightened self-awareness of salient stimuli may be a mechanism that underlies frequent tanning behavior. These findings add to the growing evidence of brain-skin connection and reflect dysregulation in the reward processing networks in those with frequent tanning.

fMRI study of neural sensitization to hedonic stimuli in long-term, daily cannabis users.

Although there is emergent evidence illustrating neural sensitivity to cannabis cues in cannabis users, the specificity of this effect to cannabis cues as opposed to a generalized hyper-sensitivity to hedonic stimuli has not yet been directly tested. Using fMRI, we presented 53 daily, long-term cannabis users and 68 non-using controls visual and tactile cues for cannabis, a natural reward, and, a sensory-perceptual control object to evaluate brain response to hedonic stimuli in cannabis users. The results showed an interaction between group and reward type such that the users had greater response during cannabis cues relative to natural reward cues (i.e., fruit) in the orbitofrontal cortex, striatum, anterior cingulate gyrus, and ventral tegmental area compared to non-users (cluster-threshold z = 2.3, P < 0.05). In the users, there were positive brain-behavior correlations between neural response to cannabis cues in fronto-striatal-temporal regions and subjective craving, marijuana-related problems, withdrawal symptoms, and levels of THC metabolites (cluster-threshold z = 2.3, P < 0.05). These findings demonstrate hyper-responsivity, and, specificity of brain response to cannabis cues in long-term cannabis users that are above that of response to natural reward cues. These observations are concordant with incentive sensitization models suggesting sensitization of mesocorticolimbic regions and disruption of natural reward processes following drug use. Although the cross-sectional nature of this study does not provide information on causality, the positive correlations between neural response and indicators of cannabis use (i.e., THC levels) suggest that alterations in the reward system are, in part, related to cannabis use. Hum Brain Mapp 37:3431-3443, 2016. © 2016 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.

The hyper-sentient addict: an exteroception model of addiction.

BACKGROUND: Exteroception involves processes related to the perception of environmental stimuli important for an organism's ability to adapt to its environment. As such, exteroception plays a critical role in conditioned response. In addiction, behavioral and neuroimaging studies show that the conditioned response to drug-related cues is often associated with alterations in brain regions including the precuneus/posterior cingulate cortex, an important node within the default mode network dedicated to processes such as self-monitoring. OBJECTIVE: This review aimed to summarize the growing, but largely fragmented, literature that supports a central role of exteroceptive processes in addiction. METHODS: We performed a systematic review of empirical research via PubMed and Google Scholar with keywords including 'addiction', 'exteroception', 'precuneus', and 'self-awareness', to identify human behavioral and neuroimaging studies that report mechanisms of self-awareness in healthy populations, and altered self-awareness processes, specifically exteroception, in addicted populations. RESULTS: Results demonstrate that exteroceptive processes play a critical role in conditioned cue response in addiction and serve as targets for interventions such as mindfulness training. Further, a hub of the default mode network, namely, the precuneus, is (i) consistently implicated in exteroceptive processes, and (ii) widely demonstrated to have increased activation and connectivity in addicted populations. CONCLUSION: Heightened exteroceptive processes may underlie cue-elicited craving, which in turn may lead to the maintenance and worsening of substance use disorders. An exteroception model of addiction provides a testable framework from which novel targets for interventions can be identified.

Baclofen-induced Changes in the Resting Brain Modulate Smoking Cue Reactivity: A Double-blind Placebo-controlled Functional Magnetic Resonance Imaging Study in Cigarette Smokers.

OBJECTIVE: Smoking cue-(SC) elicited craving can lead to relapse in SC-vulnerable individuals. Thus, identifying treatments that target SC-elicited craving is a top research priority. Reduced drug cue neural activity is associated with recovery and is marked by a profile of greater tonic (resting) activation in executive control regions, and increased connectivity between executive and salience regions. Evidence suggests the GABA-B agonist baclofen can reduce drug cue-elicited neural activity, potentially through its actions on the resting brain. Based on the literature, we hypothesize that baclofen's effects in the resting brain can predict its effects during SC exposure. METHODS: In this longitudinal, double blind, placebo-controlled neuropharmacological study 43 non-abstinent, sated treatment-seeking cigarette smokers (63% male) participated in an fMRI resting-state scan and a SC-reactivity task prior to (T1) and 3 weeks following randomization (T2; baclofen: 80 mg/day; n = 21). Subjective craving reports were acquired before and after SC exposure to explicitly examine SC-induced craving. RESULTS: Whole-brain full-factorial analysis revealed a group-by-time interaction with greater resting brain activation of the right dorsolateral prefrontal cortex (dlPFC) at T2 in the baclofen group (BAC) (pFWEcorr = 0.02), which was associated with reduced neural responses to SCs in key cue-reactive brain regions; the anterior ventral insula and ventromedial prefrontal cortex (pFWEcorr ＜ 0.01). BAC, but not the placebo group reported decreased SC-elicited craving (p = 0.02). CONCLUSION: Results suggest that baclofen mitigates the reward response to SCs through an increase in tonic activation of the dlPFC, an executive control region. Through these mechanisms, baclofen may offer SC-vulnerable smokers protection from SC-induced relapse.

Menstrual cycle phase modulates responses to smoking cues in the putamen: Preliminary evidence for a novel target.

BACKGROUND: The preclinical literature identifies the ventral striatum (VS) as a key player in drug-conditioned responses, guiding hypotheses examining neural substrates involved in human drug cue reactivity, including the study of sex differences. Men show a replicable response that includes the VS, while women's responses have been weaker and variable. New evidence suggests that the hormonal milieu modulates women's responses to drug cues in the dorsal striatum (DS), specifically, in the putamen. Here we tested the hypothesis that the hormonal milieu affects neural responses to smoking cues (SCs) in the putamen in women cigarette smokers. METHODS: We re-examined our three previous neuroimaging studies of the influence of sex and menstrual cycle (MC) phase effects on SC neuroactivity, incorporating the DS as a region of interest. RESULTS: As previously shown, men exhibited increased ventral medial prefrontal cortex (vmPFC) and VS/V pallidum responses, and women showed increased vmPFC responses that were greater in women during the follicular phase (high estradiol), compared to the luteal phase (high progesterone). Reducing the statistical threshold within luteal phase women revealed select deactivation of the putamen. CONCLUSIONS: These preliminary findings shed light upon factors that may modulate drug cue reactivity in women, specifically the influence of hormones on DS responses. Emerging literature suggests that manipulating the hormonal milieu may open a fundamental window into sex-specific treatment targets. More rigorous study of the brain substrates involved in drug cue reactivity and other reward-related behavior that may be influenced by sex and the hormonal milieu is imperative.

Cannabinoid Receptor 1 Gene by Cannabis Use Interaction on CB1 Receptor Density.

Background: Because delta-9-tetrahydrocannabinol (THC), the primary psychoactive ingredient in cannabis, binds to cannabinoid 1 (CB1) receptors, levels of CB1 protein could serve as a potential biomarker for response to THC. To date, available techniques to characterize CB1 expression and function in vivo are limited. In this study, we developed an assay to quantify CB1 in lymphocytes to determine how it relates to cannabis use in 58 daily cannabis users compared with 47 nonusers. Furthermore, we tested whether CB1 levels are associated with mutations in a single nucleotide polymorphism known to regulate CB1 functioning (i.e., rs2023239). Methods: Total protein concentration was analyzed through the Pierce BCA Protein assay kit. CB1 protein was quantified through CNR1 enzyme-linked immunosorbent assay (ELISA) kit from MyBioSource. CB1 concentration and total protein concentration were quantified and used to calculate a ratio of CB1 to total protein. Results: Inherent levels of peripheral lymphocyte CB1 were sufficient for quantification through ELISA without protein amplification. We found a group×genotype interaction such that users with the G allele had greater CB1 concentration than users with the A/A genotype, and a trend-level difference between genotypes in nonusers. Conclusions: This study demonstrates a minimally invasive technique of CB1 quantification that holds promise for the use of CB1 protein concentration, along with rs2023239 genotype, as a potential biomarker for susceptibility to cannabis use. These results suggest a gene (rs2023239 G)×environment (cannabis use) effect on CB1 density.

Identification of Trypanosoma brucei AdoMetDC Inhibitors Using a High-Throughput Mass Spectrometry-Based Assay.

Human African trypanosomiasis (HAT) is a fatal infectious disease caused by the eukaryotic pathogen Trypanosoma brucei (Tb). Available treatments are difficult to administer and have significant safety issues. S-Adenosylmethionine decarboxylase (AdoMetDC) is an essential enzyme in the parasite polyamine biosynthetic pathway. Previous attempts to develop TbAdoMetDC inhibitors into anti-HAT therapies failed due to poor brain exposure. Here, we describe a large screening campaign of two small-molecule libraries (∼400,000 compounds) employing a new high-throughput (∼7 s per sample) mass spectrometry-based assay for AdoMetDC activity. As a result of primary screening, followed by hit confirmation and validation, we identified 13 new classes of reversible TbAdoMetDC inhibitors with low-micromolar potency (IC50) against both TbAdoMetDC and T. brucei parasite cells. The majority of these compounds were >10-fold selective against the human enzyme. Importantly, compounds from four classes demonstrated high propensity to cross the blood-brain barrier in a cell monolayer assay. Biochemical analysis demonstrated that compounds from eight classes inhibited intracellular TbAdoMetDC in the parasite, although evidence for a secondary off-target component was also present. The discovery of several new TbAdoMetDC inhibitor chemotypes provides new hits for lead optimization programs aimed to deliver a novel treatment for HAT.

Sex Effects of Marijuana on Brain Structure and Function.

BACKGROUND: Tetrahydrocannabinol (Δ9-THC), the primary ingredient in marijuana, exerts its effects across several neurological and biological systems that interact with the endocrine system. Thus, differential effects of Δ9-THC are likely to exist based on sex and hormone levels. METHODS: We reviewed the existing literature to determine sex-based effects of Δ9-THC on neural structure and functioning. RESULTS: The literature demonstrates differences in male and female marijuana users on brain structure, reward processing, attention, motor coordination, and sensitivity to withdrawal. However, inconsistencies exist in the literature regarding how marijuana affects men and women differentially, and more work is needed to understand these mechanisms. While extant literature remains inconclusive, differentiation between male and female marijuana users is likely due to neurological sexual dimorphism and differential social factors at play during development and adulthood. CONCLUSIONS: Sex has important implications for marijuana use and the development of cannabis use disorders and should be considered in the development of prevention and treatment strategies.

Discriminability of personality profiles in isolated and Co-morbid marijuana and nicotine users.

Specific personality traits have been linked with substance use disorders (SUDs), genetic mechanisms, and brain systems. Thus, determining the specificity of personality traits to types of SUD can advance the field towards defining SUD endophenotypes as well as understanding the brain systems involved for the development of novel treatments. Disentangling these factors is particularly important in highly co morbid SUDs, such as marijuana and nicotine use, so treatment can occur effectively for both. This study evaluated personality traits that distinguish isolated and co-morbid use of marijuana and nicotine. To that end, we collected the NEO Five Factor Inventory in participants who used marijuana-only (n=59), nicotine-only (n=27), both marijuana and nicotine (n=28), and in non-using controls (n=28). We used factor analyses to identify personality profiles, which are linear combinations of the five NEO Factors. We then conducted Receiver Operating Characteristics (ROC) curve analysis to test accuracy of the personality factors in discriminating isolated and co-morbid marijuana and nicotine users from each other. ROC curve analysis distinguished the four groups based on their NEO personality patterns. Results showed that NEO Factor 2 (openness, extraversion, agreeableness) discriminated marijuana and marijuana+nicotine users from controls and nicotine-only users with high predictability. Additional ANOVA results showed that the openness dimension discriminated marijuana users from nicotine users. These findings suggest that personality dimensions distinguish marijuana users from nicotine users and should be considered in prevention strategies.

Mediating processes between stress and problematic marijuana use.

BACKGROUND: The literature widely reports that stress is associated with marijuana use, yet, to date, the path from stress to marijuana-related problems has not been tested. In this study, we evaluated whether negative affect mediates the relationship between stress and marijuana use. METHODS: To that end, we tested models to determine mediators between problems with marijuana use (via Marijuana Problem Scale), stress (via Early Life Stress Questionnaire, Perceived Stress Scale), and negative affect (via Beck Depression Inventory; Beck Anxiety Inventory) in 157 current heavy marijuana users. Mediation tests and bootstrap confidence intervals were carried out via the "Mediation" package in R. RESULTS: Depression and anxiety scores both significantly mediated the relationship between perceived stress and problematic marijuana use. Only depression significantly mediated the relationship between early life stress and problematic marijuana use. Early life stress, perceived stress and problematic marijuana use were significant only as independent variables and dependent variables. CONCLUSIONS: These findings demonstrate that (1) depression mediated both early life stress and perceived stress, and problematic marijuana use, and, (2) anxiety mediated perceived stress and problematic marijuana use. This mediation analysis represents a strong first step toward understanding the relationship between these variables; however, longitudinal studies are needed to determine causality between these variables. To conclude, addressing concomitant depression and anxiety in those who report either perceived stress or early life stress is important for the prevention of cannabis use disorders.

Combined effects of marijuana and nicotine on memory performance and hippocampal volume.

Combined use of marijuana (MJ) and tobacco is highly prevalent in today's population. Individual use of either substance is linked to structural brain changes and altered cognitive function, especially with consistent reports of hippocampal volume deficits and poorer memory performance. However, the combined effects of MJ and tobacco on hippocampal structure and on learning and memory processes remain unknown. In this study, we examined both the individual and combined effects of MJ and tobacco on hippocampal volumes and memory performance in four groups of adults taken from two larger studies: MJ-only users (n=36), nicotine-only (Nic-only, n=19), combined marijuana and nicotine users (MJ+Nic, n=19) and non-using healthy controls (n=16). Total bilateral hippocampal volumes and memory performance (WMS-III logical memory) were compared across groups controlling for total brain size and recent alcohol use. Results found MJ and MJ+Nic groups had smaller total hippocampal volumes compared to Nic-only and controls. No significant difference between groups was found between immediate and delayed story recall. However, the controls showed a trend for larger hippocampal volumes being associated with better memory scores, while MJ+Nic users showed a unique inversion, whereby smaller hippocampal volume was associated with better memory. Overall, results suggest abnormalities in the brain-behavior relationships underlying memory processes with combined use of marijuana and nicotine use. Further research will need to address these complex interactions between MJ and nicotine.

The Serotonin Link between Alcohol Use and Affective Disorders.

Serotonin is imperative for the normal operations in the central nervous system. The serotonergic circuitry is implicated in many neuronal processes, and, especially so in mechanisms of emotional regulation and reward. Although function in the serotonergic circuitry has been shown to be abnormal in many pathological states like depression, anxiety, and addiction, its ubiquitous nature complicates efforts to pinpoint the exact loci of pathology. This becomes especially relevant when these conditions occur together, which they do frequently. In this review, we examine the literature on the role of serotonin in depression, anxiety, and addiction, identifying commonalities between these disorders to elucidate the mechanisms at work when they are comorbid. Specifically, we examine the role of serotonergic receptors, transporters, and networks in incidences of alcohol dependence that is comorbid with depression to facilitate a deeper understanding of these mechanisms necessary for the development of more effective and personalized treatments.

Identification of a glycogen synthase kinase-3ß inhibitor that attenuates hyperactivity in CLOCK mutant mice.

Bipolar disorder is characterized by a cycle of mania and depression, which affects approximately 5 million people in the United States. Current treatment regimes include the so-called "mood-stabilizing drugs", such as lithium and valproate that are relatively dated drugs with various known side effects. Glycogen synthase kinase-3ß (GSK-3ß) plays a central role in regulating circadian rhythms, and lithium is known to be a direct inhibitor of GSK-3ß. We designed a series of second generation benzofuran-3-yl-(indol-3-yl)maleimides containing a piperidine ring that possess IC50 values in the range of 4 to 680 nM against human GSK-3ß. One of these compounds exhibits reasonable kinase selectivity and promising preliminary absorption, distribution, metabolism, and excretion (ADME) data. The administration of this compound at doses of 10 to 25 mg kg⁻¹ resulted in the attenuation of hyperactivity in amphetamine/chlordiazepoxide-induced manic-like mice together with enhancement of prepulse inhibition, similar to the effects found for valproate (400 mg kg⁻¹) and the antipsychotic haloperidol (1 mg kg⁻¹). We also tested this compound in mice carrying a mutation in the central transcriptional activator of molecular rhythms, the CLOCK gene, and found that the same compound attenuates locomotor hyperactivity in response to novelty. This study further demonstrates the use of inhibitors of GSK-3ß in the treatment of manic episodes of bipolar/mood disorders, thus further validating GSK-3ß as a relevant therapeutic target in the identification of new therapies for bipolar patients.