| 1. |
- Schwandt, Melanie L., et al.
(författare)
-
Gene-Environment Interactions and Response to Social Intrusion in Male and Female Rhesus Macaques
- 2010
-
Ingår i: Biological Psychiatry. - : Elsevier BV. - 0006-3223 .- 1873-2402. ; 67:4, s. 323-330
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Genetic factors interact with environmental stressors to moderate risk for human psychopathology, but sex may also be an important mediating factor. Different strategies for coping with environmental stressors have evolved in males and females, and these differences may underlie the differential prevalence of certain types of psychopathology in the two sexes. In this study, we investigated the possibility of sex-specific gene-environment interactions in a nonhuman primate model of response to social threat. Methods: Rhesus macaques (77 males and 106 females) were exposed to an unfamiliar conspecific. Using factor analysis, we identified three behavioral factors characterizing the response to social threat. Monkeys were genotyped for the serotonin transporter-linked polymorphism (5-HTTLPR), and the effects of genotype, early life stress, and sex on behavioral responses were evaluated. Results: Factor analysis produced five factors: High-Risk Aggression, Impulsivity/Novelty-Seeking, Gregariousness/Boldness, Harm Avoidance, and Redirected Aggression. Overall, males displayed higher levels of High-Risk Aggression and Gregariousness/Boldness than females. Levels of High-Risk Aggression in males carrying the s allele were significantly higher if they were also exposed to early adversity in the form of peer rearing. Conclusions: Our findings support those from studies in humans suggesting that males are more vulnerable to externalizing or aggression-related disorders. The results highlight the importance of interactions that exist among behavior, genes, and the environment and suggest that sex differences in vulnerability to psychopathology may be grounded in our evolutionary history.
|
|
| 2. |
- Gowin, Joshua L., et al.
(författare)
-
The Effect of Varenicline on the Neural Processing of Fearful Faces and the Subjective Effects of Alcohol in Heavy Drinkers
- 2016
-
Ingår i: Alcoholism. - : WILEY-BLACKWELL. - 0145-6008 .- 1530-0277. ; 40:5, s. 979-987
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Pharmacotherapies for alcohol use disorder have been shown to reduce hazardous drinking and improve overall health. The effect sizes for the effectiveness of these medications, however, are small, underscoring the need to expand the range of therapeutics and develop personalized treatment approaches. Recent studies have suggested that varenicline, an 42-nicotinic partial agonist widely used for smoking cessation, can help alcoholics reduce drinking, but the neurocognitive underpinnings of its effectiveness remain largely unexplored. Methods: In this double-blind study, 32 heavy drinkers were randomized to receive varenicline (2 mg/d) or placebo. After 2 weeks of dosing, participants underwent functional MRI scans, during which they viewed images of faces with either neutral or fearful expressions at baseline and following an intravenous alcohol infusion to a target breath alcohol concentration of 80 mg%. Blood oxygen level-dependent (BOLD) response was analyzed with Analysis of Functional Neuroimaging software. Linear mixed-effects models were used to examine the effects of facial expression (fearful vs. neutral) and medication (placebo vs. varenicline) on BOLD response. The effect of medication on measures of subjective response to alcohol was also examined. Results: Results indicated a significant facial expression-by-medication interaction in the left amygdala. The groups showed equivalent activation to neutral faces, but, whereas the placebo group showed increased activation to fearful faces, the varenicline group showed no change in activation. Amygdala activation to fearful faces correlated with number of drinks in the previous 90 days and Obsessive Compulsive Drinking Scale scores. There was no effect of varenicline on subjective response to alcohol. Conclusions: Our results indicate that varenicline may disrupt amygdala response to fearful faces in heavy drinkers. Further, amygdala activation correlated with alcohol consumption, suggesting that the effects of varenicline may be related to aspects of drinking behavior. These results suggest that amygdala response to fearful faces may be developed as a biomarker of the effectiveness of medications being developed for the treatment of alcohol use disorder.
|
|
| 3. |
- Lee, Ji Soo, et al.
(författare)
-
Genetic Association and Expression Analyses of the Phosphatidylinositol-4-Phosphate 5-Kinase (PIP5K1C) Gene in Alcohol Use DisorderRelevance for Pain Signaling and Alcohol Use
- 2018
-
Ingår i: Alcoholism. - : WILEY. - 0145-6008 .- 1530-0277. ; 42:6, s. 1034-1043
-
Tidskriftsartikel (refereegranskat)abstract
- BackgroundThe gene encoding phosphatidylinositol-4-phosphate 5-kinase (PIP5K1C) has been recently implicated in pain regulation. Interestingly, a recent cross-tissue and cross-phenotypic epigenetic analysis identified the same gene in alcohol use disorder (AUD). Given the high comorbidity between AUD and chronic pain, we hypothesized that genetic variation in PIP5K1C might contribute to susceptibility to AUD. MethodsWe conducted a case-control association study of genetic variants in PIP5K1C. Association analyses of 16 common PIP5K1C single nucleotide polymorphisms (SNPs) were conducted in cases and controls of African (427 cases and 137 controls) and European ancestry (488 cases and 324 controls) using standard methods. In addition, given the prominent role of the opioid system in pain signaling, we investigated the effects of acute alcohol exposure on PIP5K1C expression in humanized transgenic mice for the -opioid receptor that included the OPRM1 A118G polymorphism, a widely used mouse model to study analgesic response to opioids in pain. PIP5K1C expression was measured in the thalamus and basolateral amygdala (BLA) in mice after short-term administration (single 2g/kg dose) of alcohol or saline using immunohistochemistry and analyzed by 2-way analysis of variance. ResultsIn the case-control association study using an NIAAA discovery sample, 8 SNPs in PIP5K1C were significantly associated with AUD in the African ancestry (AA) group (pamp;lt;0.05 after correction; rs4807493, rs10405681, rs2074957, rs10432303, rs8109485, rs1476592, rs10419980, and rs4432372). However, a replication analysis using an independent sample (N=3,801) found no significant associations after correction for multiple testing. In the humanized transgenic mouse model with the OPRM1 polymorphism, PIP5K1C expression was significantly different between alcohol and saline-treated mice, regardless of genotype, in both the thalamus (pamp;lt;0.05) and BLA (pamp;lt;0.01). ConclusionsOur discovery sample shows that genetic variants in PIP5K1C are associated with AUD in the AA group, and acute alcohol exposure leads to up-regulation of PIP5K1C, potentially explaining a mechanism underlying the increased risk for chronic pain conditions in individuals with AUD.
|
|
| 4. |
- Spagnolo, Primavera A., et al.
(författare)
-
Striatal Dopamine Release in Response to Morphine: A [C-11]Raclopride Positron Emission Tomography Study in Healthy Men
- 2019
-
Ingår i: Biological Psychiatry. - : ELSEVIER SCIENCE INC. - 0006-3223 .- 1873-2402. ; 86:5, s. 356-364
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Preclinical and human positron emission tomography studies have produced inconsistent results regarding the effects of opioids on mesolimbic dopamine (DA). Here, we quantify striatal DA release (measured by [C-11]raclopride displacement) in response to an intravenous infusion of morphine, and its relationship with morphine-induced subjective effects, in healthy, nondependent opioid-experienced participants. METHODS: Fifteen healthy male participants were initially included. Sessions were on separate days. On session 1, participants received intravenous morphine (10 mg/70 kg) in the clinic to ensure tolerability. Participants without adverse reactions (n = 10) then received intravenous morphine and placebo (saline) sessions, in counterbalanced order, while undergoing [C-11]raclopride positron emission tomography scans. Subjective and physiological responses were assessed. Region-of-interest and voxelwise image analyses were used to assess changes in [C-11]raclopride nondisplaceable binding potential. RESULTS: Morphine produced marked subjective and physiological effects and induced a significant decrease in [C-11]raclopride nondisplaceable binding potential, particularly in the nucleus accumbens and globus pallidus, where the change in [C-11]raclopride nondisplaceable binding potential was approximately 9%. However, the subjective effects of morphine did not show a simple pattern of correlation with DA release. CONCLUSIONS: This is, to our knowledge, the first study providing in vivo human evidence that DA transmission in the ventral striatum is affected by morphine. Further studies are required to fully delineate the DA contribution to the reinforcing effects of opioids.
|
|
| 5. |
- Baker, Maggie, et al.
(författare)
-
Early rearing history influences oxytocin receptor epigenetic regulation in rhesus macaques
- 2017
-
Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : NATL ACAD SCIENCES. - 0027-8424 .- 1091-6490. ; 114:44, s. 11769-11774
-
Tidskriftsartikel (refereegranskat)abstract
- Adaptations to stress can occur through epigenetic processes and may be a conduit for informing offspring of environmental challenge. We employed ChIP-sequencing for H3K4me3 to examine effects of early maternal deprivation (peer-rearing, PR) in archived rhesus macaque hippocampal samples (male, n = 13). Focusing on genes with roles in stress response and behavior, we assessed the effects of rearing on H3K4me3 binding by ANOVA. We found decreased H3K4me3 binding at genes critical to behavioral stress response, the most robust being the oxytocin receptor gene OXTR, for which we observed a corresponding decrease in RNA expression. Based on this finding, we performed behavioral analyses to deter mine whether a gain-of-function nonsynonymous OXTR SNP inter acted with early stress to influence relevant behavioral stress reactivity phenotypes (n = 194), revealing that this SNP partially rescued the PR phenotype. PR infants exhibited higher levels of separation anxiety and arousal in response to social separation, but infants carrying the alternative OXTR allele did not exhibit as great a separation response. These data indicate that the oxytocin system is involved in social-separation response and suggest that epigenetic down-modulation of OXTR could contribute to behavior al differences observed in PR animals. Epigenetic changes at OXTR may represent predictive adaptive responses that could impart readiness to respond to environmental challenge or maintain proximity to a caregiver but also contribute to behavioral pathology. Our data also demonstrate that OXTR polymorphism can permit animals to partially overcome the detrimental effects of early maternal deprivation, which could have translational implications for human psychiatric disorders.
|
|
| 6. |
- Cortes, Carlos R., et al.
(författare)
-
Insula Sensitivity to Unfairness in Alcohol Use Disorder
- 2018
-
Ingår i: Alcohol and Alcoholism. - : OXFORD UNIV PRESS. - 0735-0414 .- 1464-3502. ; 53:3, s. 201-208
-
Tidskriftsartikel (refereegranskat)abstract
- Aims: Social decision making has recently been evaluated in alcohol use disorder (AUD) using the ultimatum game (UG) task, suggesting a possible deficit in aversive emotion regulation elicited by the unfairness during this task. Despite the relevance to relapse of this possible faulty regulation, the brain correlates of the UG in AUD are unknown. Methods: In total, 23 AUD and 27 healthy controls (HC) played three consecutive fMRI runs of the UG, while behavioral and brain responses were recorded. Results: Overall, acceptance rate of unfair offers did not differ between groups, but there was a difference in the rate of behavioral change across runs. We found significant anterior insula (aINS) activation in both groups for both fair and unfair conditions, but only HC showed a trend towards increased activation during unfair vs. fair offers. There were not overall whole-brain between-group significant differences. We found a trend of signal attenuation, instead of an increase, in the aINS for AUD when compared to HC during the third run, which is consistent with our recent findings of selective insula atrophy in AUD. Conclusion: We found differential group temporal dynamics of behavioral response in the UG. The HC group had a low acceptance rate for unfair offers in the first two runs that increased markedly for the third run; whereas the AUD group was consistent in their rejection of unfair offers across the three runs. We found a strong significant decrease in neural response across runs for both groups. Short summary: This fMRI study of UG in alcohol use disorder found behavioral group differences in acceptance rate across runs, which together with significant BOLD-signal decrease across runs in UG-related regions in both groups, highlights the impairment of strategy in AUD and the effect of repetitive exposure to unfairness in this task.
|
|
| 7. |
- Kwako, Laura E., et al.
(författare)
-
The Corticotropin Releasing Hormone-1 (CRH1) Receptor Antagonist Pexacerfont in Alcohol Dependence: A Randomized Controlled Experimental Medicine Study
- 2015
-
Ingår i: Neuropsychopharmacology. - : Nature Publishing Group: Open Access Hybrid Model Option A. - 0893-133X .- 1740-634X. ; 40:5, s. 1053-1063
-
Tidskriftsartikel (refereegranskat)abstract
- Extensive preclinical data implicate corticotropin-releasing hormone (CRH), acting through its CRH1 receptor, in stress- and dependence-induced alcohol seeking. We evaluated pexacerfont, an orally available, brain penetrant CRH1 antagonist for its ability to suppress stress-induced alcohol craving and brain responses in treatment seeking alcohol-dependent patients in early abstinence. Fifty-four anxious alcohol-dependent participants were admitted to an inpatient unit at the NIH Clinical Center, completed withdrawal treatment, and were enrolled in a double-blind, randomized, placebo-controlled study with pexacerfont (300 mg/day for 7 days, followed by I 00 mg/day for 23 days). After reaching steady state, participants were assessed for alcohol craving in response to stressful or alcohol-related cues, neuroendocrine responses to these stimuli, and functional magnetic resonance imaging (fMRI) responses to alcohol-related stimuli or stimuli with positive or negative emotional valence. A separate group of 10 patients received open-label pexacerfont following the same dosing regimen and had cerebrospinal fluid sampled to estimate central nervous system exposure. Pexacerfont treatment had no effect on alcohol craving, emotional responses, or anxiety. There was no effect of pexacerfont on neural responses to alcohol-related or affective stimuli. These results were obtained despite drug levels in cerebrospinal fluid (CSF) that predict close to 90% central CRH1 receptor occupancy. CRH1 antagonists have been grouped based on their receptor dissociation kinetics, with pexacerfont falling in a category characterized by fast dissociation. Our results may indicate that antagonists with slow offset are required for therapeutic efficacy. Alternatively, the extensive preclinical data on CRH1 antagonism as a mechanism to suppress alcohol seeking may not translate to humans.
|
|
| 8. |
- Lee, Mary R., et al.
(författare)
-
The novel ghrelin receptor inverse agonist PF-5190457 administered with alcohol: preclinical safety experiments and a phase 1b human laboratory study
- 2020
-
Ingår i: Molecular Psychiatry. - : NATURE PUBLISHING GROUP. - 1359-4184 .- 1476-5578. ; 25:2, s. 461-475
-
Tidskriftsartikel (refereegranskat)abstract
- Rodent studies indicate that ghrelin receptor blockade reduces alcohol consumption. However, no ghrelin receptor blockers have been administered to heavy alcohol drinking individuals. Therefore, we evaluated the safety, tolerability, pharmacokinetic (PK), pharmacodynamic (PD) and behavioral effects of a novel ghrelin receptor inverse agonist, PF-5190457, when co-administered with alcohol. We tested the effects of PF-5190457 combined with alcohol on locomotor activity, loss-of-righting reflex (a measure of alcohol sedative actions), and on blood PF-5190457 concentrations in rats. Then, we performed a single-blind, placebo-controlled, within-subject human study with PF-5190457 (placebo/0 mg b.i.d., 50 mg b.i.d., 100 mg b.i.d.). Twelve heavy drinkers during three identical visits completed an alcohol administration session, subjective assessments, and an alcohol cue-reactivity procedure, and gave blood samples for PK/PD testing. In rats, PF-5190457 did not interact with the effects of alcohol on locomotor activity or loss-of-righting reflex. Alcohol did not affect blood PF-5190457 concentrations. In humans, all adverse events were mild or moderate and did not require discontinuation or dose reductions. Drug dose did not alter alcohol concentration or elimination, alcohol-induced stimulation or sedation, or mood during alcohol administration. Potential PD markers of PF-5190457 were acyl-to-total ghrelin ratio and insulin-like growth factor-1. PF-5190457 (100 mg b.i.d.) reduced alcohol craving during the cue-reactivity procedure. This study provides the first translational evidence of safety and tolerability of the ghrelin receptor inverse agonist PF-5190457 when co-administered with alcohol. PK/PD/behavioral findings support continued research of PF-5190457 as a potential pharmacological agent to treat alcohol use disorder.
|
|
| 9. |
- Persson, Anna, et al.
(författare)
-
Concurrent Treatment of PTSD and Substance Use Disorders Using Prolonged Exposure ( COPE): A Pilot Study in Alcohol-dependent Women
- 2017
-
Ingår i: Journal of addiction medicine. - : LIPPINCOTT WILLIAMS & WILKINS. - 1932-0620 .- 1935-3227. ; 11:2, s. 119-125
-
Tidskriftsartikel (refereegranskat)abstract
- Objectives: Posttraumatic stress disorder (PTSD) and substance use disorders are highly comorbid. Effective treatments are largely lacking. This pilot study evaluated the safety and feasibility of a novel intervention, Concurrent Treatment of PTSD and Substance Use Disorders Using Prolonged Exposure (COPE), in preparation for a randomized controlled trial. Methods: Twenty-two treatment-seeking women with current DSM-IV-TR PTSD and alcohol dependence (AD) were recruited. Participants received COPE. Safety and feasibility were evaluated, as were efficacy-related outcomes: PTSD and depression symptom severity, alcohol use, craving, and dependence severity. Results: No adverse events occurred. COPE was implemented in routine clinical practice. Among the assessed women, 95.8% were eligible to participate. Treatment attendance and completion were higher than in previous studies. Post treatment, all efficacy-related outcomes, including PTSD and depression symptom severity, alcohol use, craving, and dependence severity, were significantly reduced. Conclusions: COPE was safe and feasible to use. Concerns that trauma-focused, exposure-based therapy might promote relapse in this population appear unwarranted. Our findings provide initial evidence suggestive of COPE efficacy for comorbid PTSD and AD in women. These results provide a strong rationale for investigating the efficacy of COPE for comorbid PTSD and AD in women in a randomized controlled trial.
|
|
| 10. |
- Schwandt, Melanie L., et al.
(författare)
-
PPAR gamma activation by pioglitazone does not suppress cravings for alcohol, and is associated with a risk of myopathy in treatment seeking alcohol dependent patients: a randomized controlled proof of principle study
- 2020
-
Ingår i: Psychopharmacology. - : SPRINGER. - 0033-3158 .- 1432-2072. ; 237, s. 2367-2380
-
Tidskriftsartikel (refereegranskat)abstract
- Rationale Proinflammatory processes have been implicated in alcohol addiction, craving, and relapse, while studies in experimental animals have suggested that activation of peroxisome proliferator-activated receptor gamma (PPAR gamma) inhibits proinflammatory signaling. Accordingly, it is hypothesized that medications with PPAR gamma activity may have therapeutic potential in alcohol dependence. Objectives We conducted a double-blind, placebo-controlled mechanistic proof of principle study in alcohol-dependent inpatients to investigate the effect of pioglitazone on alcohol craving. Methods Participants were treated for withdrawal, if needed, and then randomized to pioglitazone (target dose 45 mg/day) or placebo. Once at target dose, they completed two experimental manipulations: guided imagery, which used personalized auditory scripts to induce alcohol cravings, and a low-dose challenge with i.v. lipopolysaccharide (LPS; 0.8 ng/kg) or placebo, on two separate sessions, in counterbalanced order. Behavioral and endocrine responses as well as CSF levels of proinflammatory cytokines were evaluated. Results The study was prematurely terminated after randomization of 16 subjects, following an independent review that established a high risk of myopathy in the active treatment group. Analysis of those who completed the study indicated that pioglitazone was associated with elevated, rather than suppressed alcohol cravings in response to alcohol-associated stimuli. LPS did not induce cravings for alcohol and thus did not lend itself to evaluating pioglitazone effects; however, pioglitazone increased the neuroendocrine stress response to LPS. CSF levels of IL-6, TNF-alpha, or MCP-1 were unaffected by pioglitazone treatment. Conclusions Both safety and efficacy biomarker data suggest that pioglitazone lacks potential as a medication for the treatment of alcohol dependence.
|
|
