CREB-BDNF pathway influences alcohol cue-elicited activation in drinkers.
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ABSTRACT:
SUBMITTER: Chen J
PROVIDER: S-EPMC4969622 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BACKGROUND:Positive alcohol expectancy (AE) contributes to excessive drinking. Many imaging studies have examined cerebral responses to alcohol cues and how these regional processes related to problem drinking. However, it remains unclear how AE relates to cue response and whether AE mediates the relationship between cue response and problem drinking. METHODS:A total of 61 nondependent drinkers were assessed with the Alcohol Expectancy Questionnaire and Alcohol Use Disorder Identification Test and underwent functional magnetic resonance imaging while exposed to alcohol and neutral cues. Imaging data were processed and analyzed with published routines, and mediation analyses were conducted to examine the interrelationships among global positive score of the Alcohol Expectancy Questionnaire, Alcohol Use Disorder Identification Test score, and regional responses to alcohol versus neutral cues. RESULTS:Alcohol as compared with neutral cues engaged the occipital, retrosplenial, and medial orbitofrontal cortex as well as the left caudate head and red nucleus. The bilateral thalamus showed a significant correlation in cue response and in left superior frontal cortical connectivity with global positive score in a linear regression. Mediation analyses showed that global positive score completely mediated the relationship between thalamic cue activity as well as superior frontal cortical connectivity and Alcohol Use Disorder Identification Test score. The alternative models that AE contributed to problem drinking and, in turn, thalamic cue activity and connectivity were not supported. CONCLUSIONS:The findings suggest an important role of the thalamic responses to alcohol cues in contributing to AE and at-risk drinking in nondependent drinkers. AEs may reflect a top-down modulation of the thalamic processing of alcohol cues, influencing the pattern of alcohol use.
| S-EPMC6500759 | biostudies-literature
Project description:BackgroundThere is a strong bidirectional relationship between the use of alcohol and cigarettes which results in various challenges for treating those who co-use both substances. While varenicline and naltrexone each have FDA-approval for nicotine and alcohol use disorder, respectively, there is evidence that their clinical benefit may extend across the two disorders. Critically, the effect of combined varenicline and naltrexone on neural reactivity to alcohol cues among heavy drinking smokers has not yet been studied. Probing the effect of the combination therapy on alcohol cue-reactivity may give insight to the mechanisms underlying its efficacy.MethodsForty-seven heavy drinking smokers enrolled in two medication studies were randomized to receive varenicline alone (n = 11), varenicline plus naltrexone (n = 11), or placebo (n = 25). Participants completed an fMRI alcohol cue-reactivity task and rated their in-scanner alcohol craving. Whole-brain analyses examined the effect of medication on alcohol cue-elicited neural response.ResultsVarenicline plus naltrexone attenuated alcohol cue-elicited activation in mesolimbic regions relative to varenicline alone and to placebo (Z > 2.3, p < 0.05). The combination varenicline and naltrexone group also endorsed lower in-scanner alcohol craving relative to varenicline alone group (p = 0.04).ConclusionsThese findings provide evidence for the benefit of combined therapy of varenicline and naltrexone over varenicline alone for the attenuation of alcohol cue-elicited neural activation. This study provides a preliminary proof-of-mechanism for this combination pharmacotherapy and suggests that naltrexone may be driving the reductions in cue-elicited alcohol craving in the brain. Further clinical studies using the combined therapy to treat heavy drinking smokers are warranted.
| S-EPMC9059649 | biostudies-literature
Project description:Changes in physiological arousal frequently accompany cognitive and affective challenges. Many studies employed cue exposure paradigms to investigate the neural processes underlying cue-elicited drug and alcohol craving. However, whether cue-elicited craving relates to changes in physiological arousal and the neural bases underlying the potential relationship remain unclear. Here we examined cerebral cue-related activations in relation to differences in skin conductance responses (SCR) recorded during alcohol vs. neutral cue blocks in 61 non-dependent alcohol drinkers (30 men). Imaging and skin conductance data were collected and processed with published routines. Mediation analyses were conducted to examine the inter-relationship between regional activities, cue-elicited craving, and SCR. The results showed higher SCR during alcohol than during neutral cue exposure. Despite no differences in drinking characteristics, men as compared to women demonstrated higher craving rating, and men but not women demonstrated a positive correlation between alcohol (vs. neutral) cue-evoked craving and SCR. Further, across subjects, thalamic cue activity was positively correlated with differences in SCR between alcohol and neutral cue blocks in men but not in women. Mediation analyses suggested that thalamic activity mediated the correlation between craving and SCR across men and women, and in men but not women alone. These findings substantiate physiological and neural correlates of alcohol cue response and suggest important sex differences in the physiological and neural processes of cue evoked craving. Centered on the intralaminar and mediodorsal subregions, the thalamic correlate may represent a neural target for behavioral or pharmacological therapy to decrease cue-elicited arousal and craving.
| S-EPMC6606341 | biostudies-literature
Project description:Clinical trials and human laboratory studies have established that varenicline can reduce rates of alcohol use among heavy drinkers. Less is known about the mechanisms by which varenicline has this effect on drinking behavior. Reactivity to alcohol cues is often cited as the primary cause of relapse among those being treated for alcohol use disorder, and several front-line treatments for alcohol use disorder work, at least in part, by minimizing cue-induced alcohol craving.The current double-blind, placebo-controlled human laboratory study tested the effects of varenicline on alcohol cue reactivity in a group of heavy-drinking adult smokers and nonsmokers.As part of a larger series of sequential human laboratory experiments testing the effects of varenicline on drinking outcomes, participants were assigned (between-participant) to receive either active varenicline (2 mg/day) or placebo. Following a titration period, participants (n = 77) attended a laboratory session during which they were exposed to alcohol and neutral cues using a standard cue reactivity paradigm.Alcohol cue exposure increased craving for alcohol in both medication groups. However, participants receiving varenicline showed a smaller increase in alcohol craving compared to participants receiving placebo. The medication effect did not differ between smokers and nonsmokers. Among smokers, alcohol cue exposure also increased tobacco craving. Varenicline did not attenuate this effect.Results support the use of varenicline for reducing alcohol use in heavy drinkers and identify a potential mechanism by which varenicline reduces drinking. Varenicline continues to show promise as a pharmacological treatment for alcohol use disorder.
| S-EPMC5709183 | biostudies-literature
Project description:BackgroundIbudilast, a novel neuroimmune modulator being studied to treat alcohol use disorder (AUD), was shown in a randomized controlled trial (NCT03489850) to reduce ventral striatum (VS) activation in response to visual alcohol cues. The present study extended this finding by probing the effects of ibudilast on alcohol cue-elicited functional connectivity (i.e., temporally correlated activation) with the VS seed. The study also tests the association between functional connectivity and alcohol use during the trial.MethodsNon-treatment-seeking participants (n = 45) with current alcohol use disorder were randomized to receive twice-daily dosing with either ibudilast (50 mg; n = 20) or placebo (n = 25). Upon reaching the target dosagee of the medication or placebo, participants completed a functional neuroimaging alcohol cue reactivity paradigm. Drinks per drinking day were assessed at baseline and daily during the 2-week trial.ResultsIbudilast reduced alcohol cue-elicited functional connectivity between the VS seed and reward-processing regions including the orbitofrontal and anterior cingulate cortices compared with placebo (p < 0.05). Cue-elicited functional connectivity was correlated with drinks per drinking day (R2 = 0.5351, p < 0.001), and ibudilast reduced this association in similar reward-processing regions compared with placebo.ConclusionsIbudilast's effects on drinking outcomes may be related to the attenuation of functional connectivity in frontostriatal circuits related to reward processing. These results provide an important proof of concept for this novel pharmacotherapy and support the clinical utility of incorporating neuroimaging-and especially functional connectivity-analyses into medication development.
| S-EPMC8602728 | biostudies-literature
Project description:Ibudilast, a neuroimmune modulator which selectively inhibits phosphodiesterases (PDE)-3, -4, -10, and -11, and macrophage migration inhibitory factor (MIF), shows promise as a novel pharmacotherapy for alcohol use disorder (AUD). However, the mechanisms of action underlying ibudilast's effects on the human brain remain largely unknown. Thus, the current study examined the efficacy of ibudilast to improve negative mood, reduce heavy drinking, and attenuate neural reward signals in individuals with AUD. Fifty-two nontreatment-seeking individuals with AUD were randomized to receive ibudilast (n = 24) or placebo (n = 28). Participants completed a 2-week daily diary study during which they filled out daily reports of their past day drinking, mood, and craving. Participants completed an functional magnetic resonance imaging (fMRI) alcohol cue-reactivity paradigm half-way through the study. Ibudilast did not have a significant effect on negative mood (β = -0.34, p = 0.62). However, ibudilast, relative to placebo, reduced the odds of heavy drinking across time by 45% (OR = 0.55, (95% CI: 0.30, 0.98)). Ibudilast also attenuated alcohol cue-elicited activation in the ventral striatum (VS) compared to placebo (F(1,44) = 7.36, p = 0.01). Alcohol cue-elicited activation in the VS predicted subsequent drinking in the ibudilast group (F(1,44) = 6.39, p = 0.02), such that individuals who had attenuated ventral striatal activation and took ibudilast had the fewest number of drinks per drinking day in the week following the scan. These findings extend preclinical and human laboratory studies of the utility of ibudilast to treat AUD and suggest a biobehavioral mechanism through which ibudilast acts, namely, by reducing the rewarding response to alcohol cues in the brain leading to a reduction in heavy drinking.
| S-EPMC8197758 | biostudies-literature
Project description:Despite apparent sex differences in the development and treatment of alcohol use disorder, relatively little is known about the underlying neural mechanisms. In this study, we therefore investigated neural cue-reactivity in a sample of male (n = 28) and female (n = 27) problem drinkers (matched on age and alcohol use severity) with an average alcohol use disorder identification test score of 12 which is indicative of a likely alcohol use disorder. Neural cue-reactivity data were extracted from four regions of interest: the ventral and dorsal striatum and the ventral and dorsal anterior cingulate cortex, with a significance level set at p < 0.05. While the cue-reactivity paradigm induced similar levels of self-reported craving in men and women, visual alcohol cues induced significantly stronger striatal activation in men compared to drinkers. While sex differences in ventral striatal cue-reactivity were partly explained by sex differences in alcohol intake, cannabis use, negative affect and anxiety, this was not the case for sex differences in dorsal striatal cue-reactivity. These results suggest that alcohol cues are differentially processed by men and women and that the neurobiological mechanisms behind cue-reactivity differ between the sexes. Consequently, paradigms using alcohol-related pictures may not be optimal to induce cue-reactivity in female drinkers and may not be optimal to measure neurobiological markers of alcohol use severity and relapse. Future alcohol cue-reactivity studies should, in addition to including both men and women, include different types of cues (e.g., stressors and imagery in addition to pictures) to assess sex differences in alcohol cue-reactivity.
| S-EPMC6767856 | biostudies-literature
Project description:There is increasing evidence that brain-derived neurotrophic factor (BDNF) impacts on the development of obesity. We are the first to test the hypothesis that BDNF levels might be associated with neural reactivity to food cues in patients suffering from obesity and healthy controls. We assessed visual food cue-induced neural response in 19 obese patients and 20 matched controls using functional magnetic resonance imaging and analyzed the associations between BDNF levels, food cue-reactivity and food craving. Whole-brain analysis in both groups revealed that food cues elicited higher neural activation in clusters of mesolimbic brain areas including the insula (food > neutral). Patients suffering from obesity showed a significant positive correlation between plasma BDNF levels and visual food cue-reactivity in the bilateral insulae. In addition, patients suffering from obesity with positive food cue-induced insula activation also reported significantly higher food craving than those with low cue-reactivity-an effect that was absent in normal weight participants. The present findings implicate that BDNF levels in patients suffering from obesity might be involved in food craving and obesity in humans. This highlights the importance to consider BDNF pathways when investigating obesity and obesity treatment.
| S-EPMC8236045 | biostudies-literature
Project description:Cue-elicited craving for alcohol is well established but extinction-based treatment to extinguish this response has generated only modest positive outcomes in clinical trials. Basic and clinical research suggests that D-cycloserine (DCS) enhances extinction to fear cues under certain conditions. However, it remains unclear whether DCS would also accelerate extinction of cue-elicited craving for alcohol. The goal of the current study was to examine whether, compared with placebo (PBO), DCS enhanced extinction of cue-elicited craving among treatment-seeking individuals with alcohol use disorders (AUDs). Participants were administered DCS (50 mg) or PBO 1 h before an alcohol extinction paradigm in a simulated bar environment on two occasions. The extinction procedures occurred 1 week apart and were fully integrated into outpatient treatment. Subjective craving for alcohol was the primary variable of interest. Follow-up cue reactivity sessions were conducted 1 week and 3 weeks later to ascertain persisting DCS effects. Drinking outcomes and tolerability were also examined. DCS was associated with augmented reductions in alcohol craving to alcohol cues during the first extinction session and these effects persisted through all subsequent sessions, suggesting facilitation of extinction. Participants in the DCS condition reported significant short-term reductions in drinking, although these did not persist to follow-up, and found the medication highly tolerable. These findings provide evidence that DCS enhances extinction of cue-elicited craving for alcohol in individuals with AUDs in the context of outpatient treatment. The potential clinical utility of DCS is discussed, including methodological considerations and context-dependent learning.
| S-EPMC4462604 | biostudies-literature
Project description:Amyloid-? (A?) is considered partially responsible for cognitive dysfunction in Alzheimer's disease (AD). Resveratrol is known as an anti-neurotoxicity potential natural product, however low blood-brain-barrier (BBB) permissibility and low oral-bioavailability (OB) are the main limitations on its clinical potential. In this study, we illustrated that Pterostilbene (PTS), a kind of resveratrol analog which showed higher scores on BBB and OB, could overcome A?-induced neurotoxicity in vitro and in vivo. In silico simulation indicated PTS binding with PDE4A may contribute to its anti-apoptosis and anti-neurotoxicity effects. Behavioral tests further confirmed PTS' potential of overcoming memory deficits in APP/PS1 mice (AD model). Interestingly, PTS also rescued the reducing in dendritic spine density in APP/PS1 mice based on Golgi-Cox staining. Besides, as results of reversing A?-induced decreases in cyclic-AMP level, PTS increased the pVASP, pCREB, BDNF, and PSD95 expression. Overall, PTS protects neurons against A?-induced neurotoxicity and cognitive dysfunction through regulating the PDE4A-CREB-BDNF pathway. Therefore, targeting on PDE4A, PTS would be a qualified natural product for alleviating A?-induced neurotoxicity in AD.
| S-EPMC6834512 | biostudies-literature