Pub Date : 2018-07-01Epub Date: 2018-06-04DOI: 10.1111/acer.13774
Samuel F Acuff, Kathryn E Soltis, Ashley A Dennhardt, Kristoffer S Berlin, James G Murphy
Background: Heavy drinking among college students is a significant public health concern that can lead to profound social and health consequences, including alcohol use disorder. Behavioral economics posits that low future orientation and high valuation of alcohol (alcohol demand) combined with deficits in alternative reinforcement increase the likelihood of alcohol misuse. Despite this, no study has examined the incremental utility of all 3 variables simultaneously in a comprehensive model.
Methods: This study uses structural equation modeling to test the associations between behavioral economic variables-alcohol demand (latent), future orientation (measured with a delay discounting task and the Consideration of Future Consequences [CFC] scale), and proportionate substance-related reinforcement-and alcohol consumption and problems among 393 heavy drinking college students. Two models are tested as follows: (i) an iteration of the reinforcer pathology model that includes an interaction between future orientation and alcohol demand; and (ii) an alternative model evaluating the interconnectedness of behavioral economic variables in predicting problematic alcohol use.
Results: The interaction effects in Model 1 were nonsignificant. Model 2 suggests that greater alcohol demand and proportionate substance-related reinforcement are associated with greater alcohol consumption and problems. Furthermore, CFC was associated with alcohol-related problems and lower proportionate substance-related reinforcement but was not significantly associated with alcohol consumption or alcohol demand. Finally, greater proportionate substance-related reinforcement was associated with greater alcohol demand.
Conclusions: Our results support the validity of the behavioral economic reinforcer pathology model as applied to young adult heavy drinking.
{"title":"Evaluating Behavioral Economic Models of Heavy Drinking Among College Students.","authors":"Samuel F Acuff, Kathryn E Soltis, Ashley A Dennhardt, Kristoffer S Berlin, James G Murphy","doi":"10.1111/acer.13774","DOIUrl":"https://doi.org/10.1111/acer.13774","url":null,"abstract":"<p><strong>Background: </strong>Heavy drinking among college students is a significant public health concern that can lead to profound social and health consequences, including alcohol use disorder. Behavioral economics posits that low future orientation and high valuation of alcohol (alcohol demand) combined with deficits in alternative reinforcement increase the likelihood of alcohol misuse. Despite this, no study has examined the incremental utility of all 3 variables simultaneously in a comprehensive model.</p><p><strong>Methods: </strong>This study uses structural equation modeling to test the associations between behavioral economic variables-alcohol demand (latent), future orientation (measured with a delay discounting task and the Consideration of Future Consequences [CFC] scale), and proportionate substance-related reinforcement-and alcohol consumption and problems among 393 heavy drinking college students. Two models are tested as follows: (i) an iteration of the reinforcer pathology model that includes an interaction between future orientation and alcohol demand; and (ii) an alternative model evaluating the interconnectedness of behavioral economic variables in predicting problematic alcohol use.</p><p><strong>Results: </strong>The interaction effects in Model 1 were nonsignificant. Model 2 suggests that greater alcohol demand and proportionate substance-related reinforcement are associated with greater alcohol consumption and problems. Furthermore, CFC was associated with alcohol-related problems and lower proportionate substance-related reinforcement but was not significantly associated with alcohol consumption or alcohol demand. Finally, greater proportionate substance-related reinforcement was associated with greater alcohol demand.</p><p><strong>Conclusions: </strong>Our results support the validity of the behavioral economic reinforcer pathology model as applied to young adult heavy drinking.</p>","PeriodicalId":7410,"journal":{"name":"Alcoholism, clinical and experimental research","volume":"42 7","pages":"1304-1314"},"PeriodicalIF":3.2,"publicationDate":"2018-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1111/acer.13774","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36095731","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
G. Beaudet, S. Valable, J. Bourgine, V. Lelong-Boulouard, L. Lanfumey, T. Freret, M. Boulouard, E. Paizanis
BACKGROUND Binge drinking is popular and highly prevalent in teenagers. However, the long-term cognitive and neurobiological consequences of such practices are not yet fully understood. In this context, we therefore assessed in mice whether a chronic intermittent alcohol (CIA) exposure in adolescence had long-term consequences on object discrimination and memory performances, emotional behaviors, brain activity, and morphology. METHODS C57BL/6JRj mice were treated with either saline or ethanol (EtOH) (2 g/kg/d, i.p., from postnatal days [PND] 30 to PND 44 every other day). The day following the last administration or later in adulthood (PND 71) mice were tested for different behavioral tests (novel object recognition, spontaneous alternation, light-dark box, elevated plus-maze, actimeter test), to assess object recognition, working memory performances, anxiety-like behavior, and locomotor activity. We also investigated neuronal activation of hippocampus, prefrontal and perirhinal cortices, and anatomical changes using immediate-early gene expression and longitudinal brain magnetic resonance imaging. RESULTS Our results showed that adolescent mice exposed to CIA present a critical and persistent impairment of short-term object recognition performances. By contrast, spatial working memory was not impaired, nor was anxiety-like behavior. This altered object discrimination was associated with a biphasic change in neuronal activity in the hippocampus but without morphological changes. Indeed, c-Fos expression was specifically increased in the dorsal dentate gyrus (DG) of the hippocampus after the binge exposure, but then became significantly lower in adulthood both in the DG and the CA1 part of the hippocampus compared with adult saline pretreated mice. CONCLUSIONS These findings provide evidence for adolescent vulnerability to the effects of intermittent binge EtOH exposure on object discrimination and hippocampal activity with long-lasting consequences.
{"title":"Long-Lasting Effects of Chronic Intermittent Alcohol Exposure in Adolescent Mice on Object Recognition and Hippocampal Neuronal Activity.","authors":"G. Beaudet, S. Valable, J. Bourgine, V. Lelong-Boulouard, L. Lanfumey, T. Freret, M. Boulouard, E. Paizanis","doi":"10.1111/acer.13256","DOIUrl":"https://doi.org/10.1111/acer.13256","url":null,"abstract":"BACKGROUND\u0000Binge drinking is popular and highly prevalent in teenagers. However, the long-term cognitive and neurobiological consequences of such practices are not yet fully understood. In this context, we therefore assessed in mice whether a chronic intermittent alcohol (CIA) exposure in adolescence had long-term consequences on object discrimination and memory performances, emotional behaviors, brain activity, and morphology.\u0000\u0000\u0000METHODS\u0000C57BL/6JRj mice were treated with either saline or ethanol (EtOH) (2 g/kg/d, i.p., from postnatal days [PND] 30 to PND 44 every other day). The day following the last administration or later in adulthood (PND 71) mice were tested for different behavioral tests (novel object recognition, spontaneous alternation, light-dark box, elevated plus-maze, actimeter test), to assess object recognition, working memory performances, anxiety-like behavior, and locomotor activity. We also investigated neuronal activation of hippocampus, prefrontal and perirhinal cortices, and anatomical changes using immediate-early gene expression and longitudinal brain magnetic resonance imaging.\u0000\u0000\u0000RESULTS\u0000Our results showed that adolescent mice exposed to CIA present a critical and persistent impairment of short-term object recognition performances. By contrast, spatial working memory was not impaired, nor was anxiety-like behavior. This altered object discrimination was associated with a biphasic change in neuronal activity in the hippocampus but without morphological changes. Indeed, c-Fos expression was specifically increased in the dorsal dentate gyrus (DG) of the hippocampus after the binge exposure, but then became significantly lower in adulthood both in the DG and the CA1 part of the hippocampus compared with adult saline pretreated mice.\u0000\u0000\u0000CONCLUSIONS\u0000These findings provide evidence for adolescent vulnerability to the effects of intermittent binge EtOH exposure on object discrimination and hippocampal activity with long-lasting consequences.","PeriodicalId":7410,"journal":{"name":"Alcoholism, clinical and experimental research","volume":"43 1","pages":"2591-2603"},"PeriodicalIF":3.2,"publicationDate":"2016-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73024858","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BACKGROUND Driver age and blood alcohol concentration are both important factors in predicting driving risk; however, little is known regarding the joint import of these factors on neural activity following socially relevant alcohol doses. We examined age and alcohol effects on brain oscillations during simulated driving, focusing on 2 region-specific frequency bands implicated in task performance and attention: parietal alpha power (PAP; 8 to 12 Hz) and frontal theta power (FTP; 4 to 7 Hz). METHODS Participants included 80 younger (aged 25 to 35 years) and 40 older (aged 55 to 70 years) community-dwelling, moderate drinkers. Participants consumed placebo, low, or moderate doses of alcohol designed to achieve target peak breath alcohol concentrations of 0, 0.04, or 0.065 g/dl, respectively. Electrophysiological measures were recorded during engagement in a simulated driving task involving 4 scenarios of varied environmental complexity. RESULTS A main effect of age was detected in FTP, but neither an alcohol effect nor interactions were observed. For PAP, an age-by-alcohol interaction was detected. Relative to placebo controls, older and younger participants receiving low-dose (0.04 g/dl) alcohol evinced divergent PAP alterations, with a pattern of higher power among older participants and lower power among younger participants. This interaction was noted across the varied environmental contexts. CONCLUSIONS These findings are consistent with the hypothesis that compared with younger individuals, older drivers may be differentially susceptible to alcohol effects. While these age-by-alcohol interactions in neural activity are provocative, further investigation exploring the mechanisms and behavioral correlates of these effects will be crucial in determining their behavioral impact.
{"title":"Effects of Age and Acute Moderate Alcohol Administration on Neurophysiology During Simulated Driving.","authors":"B. Lewis, J. Boissoneault, I. Frazier, S. Nixon","doi":"10.1111/acer.13243","DOIUrl":"https://doi.org/10.1111/acer.13243","url":null,"abstract":"BACKGROUND\u0000Driver age and blood alcohol concentration are both important factors in predicting driving risk; however, little is known regarding the joint import of these factors on neural activity following socially relevant alcohol doses. We examined age and alcohol effects on brain oscillations during simulated driving, focusing on 2 region-specific frequency bands implicated in task performance and attention: parietal alpha power (PAP; 8 to 12 Hz) and frontal theta power (FTP; 4 to 7 Hz).\u0000\u0000\u0000METHODS\u0000Participants included 80 younger (aged 25 to 35 years) and 40 older (aged 55 to 70 years) community-dwelling, moderate drinkers. Participants consumed placebo, low, or moderate doses of alcohol designed to achieve target peak breath alcohol concentrations of 0, 0.04, or 0.065 g/dl, respectively. Electrophysiological measures were recorded during engagement in a simulated driving task involving 4 scenarios of varied environmental complexity.\u0000\u0000\u0000RESULTS\u0000A main effect of age was detected in FTP, but neither an alcohol effect nor interactions were observed. For PAP, an age-by-alcohol interaction was detected. Relative to placebo controls, older and younger participants receiving low-dose (0.04 g/dl) alcohol evinced divergent PAP alterations, with a pattern of higher power among older participants and lower power among younger participants. This interaction was noted across the varied environmental contexts.\u0000\u0000\u0000CONCLUSIONS\u0000These findings are consistent with the hypothesis that compared with younger individuals, older drivers may be differentially susceptible to alcohol effects. While these age-by-alcohol interactions in neural activity are provocative, further investigation exploring the mechanisms and behavioral correlates of these effects will be crucial in determining their behavioral impact.","PeriodicalId":7410,"journal":{"name":"Alcoholism, clinical and experimental research","volume":"26 1","pages":"2519-2527"},"PeriodicalIF":3.2,"publicationDate":"2016-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85452184","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
P. Thompson, N. Hill-Kapturczak, M. Lopez-Cruzan, L. Alvarado, A. Dwivedi, M. Javors
BACKGROUND Phosphatidylethanol (PEth) is a metabolite of ethanol (EtOH), and its concentration in whole blood samples is a direct biomarker of alcohol consumption. Because PEth is also present in the brain and incorporated in lipid membranes, it can be used to classify deceased individuals on alcohol consumption status at the time of death. The purpose of this study was to detect PEth homologs in postmortem brains of individuals known to have had alcohol use disorder (AUD) and to determine the relationship between serum alcohol at the time of death and PEth in the cerebellum (CE) and orbital frontal cortex (OFC). METHODS Postmortem brain was collected and stored according to standard protocol. Psychiatric symptoms experienced prior to death were obtained by next of kin psychological autopsy to categorize subjects. Thirty male subjects were chosen for analyses: 10 with AUD with positive serum EtOH levels present at time of autopsy (AUD-W), 10 with AUD without positive serum EtOH levels (AUD-WO), and 10 controls. PEth 16:0/18:1 and 16:0/18:2 were quantified in 50 mg of CE and OFC of human postmortem brain using HPLC and mass spectrometric detection (triple quadrupole). RESULTS Results of this study were as follows: (i) PEth 16:0/18:1 and 16:0/18:2 were detected in the CE and OFC of all subjects diagnosed with AUD, (ii) PEth 16:0/18:1 levels were about 10-fold higher than PEth 16:0/18:2 in all subjects and both areas of brain, (iii) AUD-W subjects had higher PEth homolog levels in CE and OFC than controls and AUD-WO subjects, (iv) PEth 16:0/18:1, but not PEth 16:0/18:2, levels in CE and OFC of AUD-W subjects correlated significantly with serum EtOH levels at the time of death. CONCLUSIONS Quantification of combined PEth homolog levels in postmortem human brain is a good candidate as a diagnostic factor to classify drinking status, especially for those with AUD at the time of death. For alcohol research studies with postmortem brain, verification of drinking status is essential.
{"title":"Phosphatidylethanol in Postmortem Brain and Serum Ethanol at Time of Death.","authors":"P. Thompson, N. Hill-Kapturczak, M. Lopez-Cruzan, L. Alvarado, A. Dwivedi, M. Javors","doi":"10.1111/acer.13254","DOIUrl":"https://doi.org/10.1111/acer.13254","url":null,"abstract":"BACKGROUND\u0000Phosphatidylethanol (PEth) is a metabolite of ethanol (EtOH), and its concentration in whole blood samples is a direct biomarker of alcohol consumption. Because PEth is also present in the brain and incorporated in lipid membranes, it can be used to classify deceased individuals on alcohol consumption status at the time of death. The purpose of this study was to detect PEth homologs in postmortem brains of individuals known to have had alcohol use disorder (AUD) and to determine the relationship between serum alcohol at the time of death and PEth in the cerebellum (CE) and orbital frontal cortex (OFC).\u0000\u0000\u0000METHODS\u0000Postmortem brain was collected and stored according to standard protocol. Psychiatric symptoms experienced prior to death were obtained by next of kin psychological autopsy to categorize subjects. Thirty male subjects were chosen for analyses: 10 with AUD with positive serum EtOH levels present at time of autopsy (AUD-W), 10 with AUD without positive serum EtOH levels (AUD-WO), and 10 controls. PEth 16:0/18:1 and 16:0/18:2 were quantified in 50 mg of CE and OFC of human postmortem brain using HPLC and mass spectrometric detection (triple quadrupole).\u0000\u0000\u0000RESULTS\u0000Results of this study were as follows: (i) PEth 16:0/18:1 and 16:0/18:2 were detected in the CE and OFC of all subjects diagnosed with AUD, (ii) PEth 16:0/18:1 levels were about 10-fold higher than PEth 16:0/18:2 in all subjects and both areas of brain, (iii) AUD-W subjects had higher PEth homolog levels in CE and OFC than controls and AUD-WO subjects, (iv) PEth 16:0/18:1, but not PEth 16:0/18:2, levels in CE and OFC of AUD-W subjects correlated significantly with serum EtOH levels at the time of death.\u0000\u0000\u0000CONCLUSIONS\u0000Quantification of combined PEth homolog levels in postmortem human brain is a good candidate as a diagnostic factor to classify drinking status, especially for those with AUD at the time of death. For alcohol research studies with postmortem brain, verification of drinking status is essential.","PeriodicalId":7410,"journal":{"name":"Alcoholism, clinical and experimental research","volume":"9 1","pages":"2557-2562"},"PeriodicalIF":3.2,"publicationDate":"2016-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82325809","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
S. Bergeson, Michelle A. Nipper, Jeremiah P. Jensen, M. Helms, D. Finn
BACKGROUND The chronic intermittent ethanol (CIE) paradigm is valuable for screening compounds for efficacy to reduce drinking traits related to alcohol use disorder (AUD), as it measures alcohol consumption and preference under physical dependence conditions. Air control-treated animals allow simultaneous testing of similarly treated, nondependent animals. As a consequence, we used CIE to test the hypothesis that tigecycline, a semisynthetic tetracycline similar to minocycline and doxycycline, would reduce alcohol consumption regardless of dependence status. METHODS Adult C57BL/6J female and male mice were tested for tigecycline efficacy to reduce ethanol (EtOH) consumption using a standard CIE paradigm. The ability of tigecycline to decrease 2-bottle choice of 15% EtOH (15E) versus water intake in dependent (CIE vapor) and nondependent (air-treated) male and female mice was tested after 4 cycles of CIE vapor or air exposure using a within-subjects design and a dose-response. Drug doses of 0, 40, 60, 80, and 100 mg/kg in saline were administered intraperitoneally (0.01 ml/g body weight) and in random order, with a 1-hour pretreatment time. Baseline 15E intake was re-established prior to administration of subsequent injections, with a maximum of 2 drug injections tested per week. RESULTS Tigecycline was found to effectively reduce high alcohol consumption in both dependent and nondependent female and male mice. CONCLUSIONS Our data suggest that tigecycline may be a promising drug with novel pharmacotherapeutic characteristics for the treatment of mild-to-severe AUD in both sexes.
{"title":"Tigecycline Reduces Ethanol Intake in Dependent and Nondependent Male and Female C57BL/6J Mice.","authors":"S. Bergeson, Michelle A. Nipper, Jeremiah P. Jensen, M. Helms, D. Finn","doi":"10.1111/acer.13251","DOIUrl":"https://doi.org/10.1111/acer.13251","url":null,"abstract":"BACKGROUND\u0000The chronic intermittent ethanol (CIE) paradigm is valuable for screening compounds for efficacy to reduce drinking traits related to alcohol use disorder (AUD), as it measures alcohol consumption and preference under physical dependence conditions. Air control-treated animals allow simultaneous testing of similarly treated, nondependent animals. As a consequence, we used CIE to test the hypothesis that tigecycline, a semisynthetic tetracycline similar to minocycline and doxycycline, would reduce alcohol consumption regardless of dependence status.\u0000\u0000\u0000METHODS\u0000Adult C57BL/6J female and male mice were tested for tigecycline efficacy to reduce ethanol (EtOH) consumption using a standard CIE paradigm. The ability of tigecycline to decrease 2-bottle choice of 15% EtOH (15E) versus water intake in dependent (CIE vapor) and nondependent (air-treated) male and female mice was tested after 4 cycles of CIE vapor or air exposure using a within-subjects design and a dose-response. Drug doses of 0, 40, 60, 80, and 100 mg/kg in saline were administered intraperitoneally (0.01 ml/g body weight) and in random order, with a 1-hour pretreatment time. Baseline 15E intake was re-established prior to administration of subsequent injections, with a maximum of 2 drug injections tested per week.\u0000\u0000\u0000RESULTS\u0000Tigecycline was found to effectively reduce high alcohol consumption in both dependent and nondependent female and male mice.\u0000\u0000\u0000CONCLUSIONS\u0000Our data suggest that tigecycline may be a promising drug with novel pharmacotherapeutic characteristics for the treatment of mild-to-severe AUD in both sexes.","PeriodicalId":7410,"journal":{"name":"Alcoholism, clinical and experimental research","volume":"194 1","pages":"2491-2498"},"PeriodicalIF":3.2,"publicationDate":"2016-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83118229","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Joseph M. Martinez, J. A. Groot, D. Curtis, C. L. Allison, P. Marquardt, Ashley N Holmes, David S. Edwards, David R. M. Trotter, P. Syapin, D. Finn, S. Bergeson
BACKGROUND Alcohol use disorder (AUD) is a spectrum disorder characterized by mild to severe symptoms, including potential withdrawal signs upon cessation of consumption. Approximately five hundred thousand patients with AUD undergo clinically relevant episodes of withdrawal annually (New Engl J Med, 2003, 348, 1786). Recent evidence indicates potential for drugs that alter neuroimmune pathways as new AUD therapies. We have previously shown the immunomodulatory drugs, minocycline and tigecycline, were effective in reducing ethanol (EtOH) consumption in both the 2-bottle choice and drinking-in-the-dark paradigms. Here, we test the hypothesis that tigecycline, a tetracycline derivative, will reduce the severity of EtOH withdrawal symptoms in a common acute model of alcohol withdrawal (AWD) using a single anesthetic dose of EtOH in seizure sensitive DBA/2J (DBA) mice. METHODS Naïve adult female and male DBA mice were given separate injections of 4 g/kg i.p. EtOH with vehicle or tigecycline (0, 20, 40, or 80 mg/kg i.p.). The 80 mg/kg dose was tested at 3 time points (0, 4, and 7 hours) post EtOH treatment. Handling-induced convulsions (HICs) were measured before and then over 12 hours following EtOH injection. HIC scores and areas under the curve were tabulated. In separate mice, blood EtOH concentrations (BECs) were measured at 2, 4, and 7 hours postinjection of 4 g/kg i.p. EtOH in mice treated with 0 and 80 mg/kg i.p. tigecycline. RESULTS AWD symptom onset, peak magnitude, and overall HIC severity were reduced by tigecycline drug treatment compared to controls. Tigecycline treatment was effective regardless of timing throughout AWD, with earlier treatment showing greater efficacy. Tigecycline showed a dose-responsive reduction in acute AWD convulsions, with no sex differences in efficacy. Importantly, tigecycline did not affect BECs over a time course of elimination. CONCLUSIONS Tigecycline effectively reduced AWD symptoms in DBA mice at all times and dosages tested, making it a promising lead compound for development of a novel pharmacotherapy for AWD. Further studies are needed to determine the mechanism of tigecycline action.
{"title":"Effective Reduction of Acute Ethanol Withdrawal by the Tetracycline Derivative, Tigecycline, in Female and Male DBA/2J Mice.","authors":"Joseph M. Martinez, J. A. Groot, D. Curtis, C. L. Allison, P. Marquardt, Ashley N Holmes, David S. Edwards, David R. M. Trotter, P. Syapin, D. Finn, S. Bergeson","doi":"10.1111/acer.13259","DOIUrl":"https://doi.org/10.1111/acer.13259","url":null,"abstract":"BACKGROUND\u0000Alcohol use disorder (AUD) is a spectrum disorder characterized by mild to severe symptoms, including potential withdrawal signs upon cessation of consumption. Approximately five hundred thousand patients with AUD undergo clinically relevant episodes of withdrawal annually (New Engl J Med, 2003, 348, 1786). Recent evidence indicates potential for drugs that alter neuroimmune pathways as new AUD therapies. We have previously shown the immunomodulatory drugs, minocycline and tigecycline, were effective in reducing ethanol (EtOH) consumption in both the 2-bottle choice and drinking-in-the-dark paradigms. Here, we test the hypothesis that tigecycline, a tetracycline derivative, will reduce the severity of EtOH withdrawal symptoms in a common acute model of alcohol withdrawal (AWD) using a single anesthetic dose of EtOH in seizure sensitive DBA/2J (DBA) mice.\u0000\u0000\u0000METHODS\u0000Naïve adult female and male DBA mice were given separate injections of 4 g/kg i.p. EtOH with vehicle or tigecycline (0, 20, 40, or 80 mg/kg i.p.). The 80 mg/kg dose was tested at 3 time points (0, 4, and 7 hours) post EtOH treatment. Handling-induced convulsions (HICs) were measured before and then over 12 hours following EtOH injection. HIC scores and areas under the curve were tabulated. In separate mice, blood EtOH concentrations (BECs) were measured at 2, 4, and 7 hours postinjection of 4 g/kg i.p. EtOH in mice treated with 0 and 80 mg/kg i.p. tigecycline.\u0000\u0000\u0000RESULTS\u0000AWD symptom onset, peak magnitude, and overall HIC severity were reduced by tigecycline drug treatment compared to controls. Tigecycline treatment was effective regardless of timing throughout AWD, with earlier treatment showing greater efficacy. Tigecycline showed a dose-responsive reduction in acute AWD convulsions, with no sex differences in efficacy. Importantly, tigecycline did not affect BECs over a time course of elimination.\u0000\u0000\u0000CONCLUSIONS\u0000Tigecycline effectively reduced AWD symptoms in DBA mice at all times and dosages tested, making it a promising lead compound for development of a novel pharmacotherapy for AWD. Further studies are needed to determine the mechanism of tigecycline action.","PeriodicalId":7410,"journal":{"name":"Alcoholism, clinical and experimental research","volume":"19 1","pages":"2499-2505"},"PeriodicalIF":3.2,"publicationDate":"2016-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89368861","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
P. Syapin, Joseph M. Martinez, D. Curtis, P. Marquardt, C. L. Allison, J. A. Groot, Carol Baby, Yazan M. Al-Hasan, Ismael Segura, Matthew J Scheible, Katy T Nicholson, J. Redondo, David R. M. Trotter, David S. Edwards, S. Bergeson
BACKGROUND New pharmacotherapies to treat alcohol use disorders (AUD) are needed. Given the complex nature of AUD, there likely exist multiple novel drug targets. We, and others, have shown that the tetracycline drugs, minocycline and doxycycline, reduced ethanol (EtOH) drinking in mice. To test the hypothesis that suppression of high EtOH consumption is a general property of tetracyclines, we screened several derivatives for antidrinking activity using the Drinking-In-the-Dark (DID) paradigm. Active drugs were studied further using the dose-response relationship. METHODS Adult female and male C57BL/6J mice were singly housed and the DID paradigm was performed using 20% EtOH over a 4-day period. Mice were administered a tetracycline or its vehicle 20 hours prior to drinking. Water and EtOH consumption was measured daily. Body weight was measured at the start of drug injections and after the final day of the experiment. Blood was collected for EtOH content measurement immediately following the final bout of drinking. RESULTS Seven tetracyclines were tested at a 50 mg/kg dose. Only minocycline and tigecycline significantly reduced EtOH drinking, and doxycycline showed a strong effect size trend toward reduced drinking. Subsequent studies with these 3 drugs revealed a dose-dependent decrease in EtOH consumption for both female and male mice, with sex differences in efficacy. Minocycline and doxycycline reduced water intake at higher doses, although to a lesser degree than their effects on EtOH drinking. Tigecycline did not negatively affect water intake. The rank order of potency for reduction in EtOH consumption was minocycline > doxycycline > tigecycline, indicating efficacy was not strictly related to their partition coefficients or distribution constants. CONCLUSIONS Due to its effectiveness in reducing high EtOH consumption coupled without an effect on water intake, tigecycline was found to be the most promising lead tetracycline compound for further study toward the development of a new pharmacotherapy for the treatment of AUD.
{"title":"Effective Reduction in High Ethanol Drinking by Semisynthetic Tetracycline Derivatives.","authors":"P. Syapin, Joseph M. Martinez, D. Curtis, P. Marquardt, C. L. Allison, J. A. Groot, Carol Baby, Yazan M. Al-Hasan, Ismael Segura, Matthew J Scheible, Katy T Nicholson, J. Redondo, David R. M. Trotter, David S. Edwards, S. Bergeson","doi":"10.1111/acer.13253","DOIUrl":"https://doi.org/10.1111/acer.13253","url":null,"abstract":"BACKGROUND\u0000New pharmacotherapies to treat alcohol use disorders (AUD) are needed. Given the complex nature of AUD, there likely exist multiple novel drug targets. We, and others, have shown that the tetracycline drugs, minocycline and doxycycline, reduced ethanol (EtOH) drinking in mice. To test the hypothesis that suppression of high EtOH consumption is a general property of tetracyclines, we screened several derivatives for antidrinking activity using the Drinking-In-the-Dark (DID) paradigm. Active drugs were studied further using the dose-response relationship.\u0000\u0000\u0000METHODS\u0000Adult female and male C57BL/6J mice were singly housed and the DID paradigm was performed using 20% EtOH over a 4-day period. Mice were administered a tetracycline or its vehicle 20 hours prior to drinking. Water and EtOH consumption was measured daily. Body weight was measured at the start of drug injections and after the final day of the experiment. Blood was collected for EtOH content measurement immediately following the final bout of drinking.\u0000\u0000\u0000RESULTS\u0000Seven tetracyclines were tested at a 50 mg/kg dose. Only minocycline and tigecycline significantly reduced EtOH drinking, and doxycycline showed a strong effect size trend toward reduced drinking. Subsequent studies with these 3 drugs revealed a dose-dependent decrease in EtOH consumption for both female and male mice, with sex differences in efficacy. Minocycline and doxycycline reduced water intake at higher doses, although to a lesser degree than their effects on EtOH drinking. Tigecycline did not negatively affect water intake. The rank order of potency for reduction in EtOH consumption was minocycline > doxycycline > tigecycline, indicating efficacy was not strictly related to their partition coefficients or distribution constants.\u0000\u0000\u0000CONCLUSIONS\u0000Due to its effectiveness in reducing high EtOH consumption coupled without an effect on water intake, tigecycline was found to be the most promising lead tetracycline compound for further study toward the development of a new pharmacotherapy for the treatment of AUD.","PeriodicalId":7410,"journal":{"name":"Alcoholism, clinical and experimental research","volume":"96 1","pages":"2482-2490"},"PeriodicalIF":3.2,"publicationDate":"2016-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80975950","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ashley Acheson, S. L. Lake, B. Bray, Yuanyuan Liang, C. Mathias, Stacy R. Ryan, N. Charles, D. Dougherty
BACKGROUND Problem substance use often begins in adolescence. This vulnerability likely stems, at least partially, from relatively rapid increases in sensation seeking occurring in early to mid-adolescence and more gradual improvements in impulse control occurring through later adolescence. Better understanding how these processes develop in high-risk youth may lead to enhanced substance use disorder treatment and prevention strategies. METHODS We characterized trajectories of self-reported impulsivity and sensation seeking in 305 FH+ youths who at minimum had a father with a history of alcohol or other drug use disorders and 81 youths with no family histories of substance use disorders (FH-). Assessments started at ages 10 to 12 and continued at 6-month intervals for up to 42 months. In addition, a subset of 58 FH+ youths who began alcohol or other drug use before age 15 (FH+ Users) were compared to 58 FH+ propensity-matched adolescents who did not initiate substance use before age 15 (FH+ Non-Users). RESULTS Compared to FH- youths at preadolescence, FH+ youths reported higher general impulsivity and higher impulsivity related to poor planning and attention. Over time, there were no differential effects of FH status on changes in impulsivity or sensation seeking across adolescence. FH+ Users had smaller decreases in general impulsivity and impulsivity related to restlessness and fidgeting across adolescence than FH+ Non-Users. FH+ Users also had greater increases in sensation seeking across adolescence than FH+ Non-Users. CONCLUSIONS Increased impulsivity in FH+ youths may make them less able to regulate sensation seeking drives that peak in adolescence, which may contribute to their high risk for developing substance use disorders. Additionally, FH+ adolescents who initiate early use may be at increased risk in part due to increased impulsivity coupled with greater increases in sensation seeking.
{"title":"Early Adolescent Trajectories of Impulsiveness and Sensation Seeking in Children of Fathers with Histories of Alcohol and Other Substance Use Disorders.","authors":"Ashley Acheson, S. L. Lake, B. Bray, Yuanyuan Liang, C. Mathias, Stacy R. Ryan, N. Charles, D. Dougherty","doi":"10.1111/acer.13235","DOIUrl":"https://doi.org/10.1111/acer.13235","url":null,"abstract":"BACKGROUND\u0000Problem substance use often begins in adolescence. This vulnerability likely stems, at least partially, from relatively rapid increases in sensation seeking occurring in early to mid-adolescence and more gradual improvements in impulse control occurring through later adolescence. Better understanding how these processes develop in high-risk youth may lead to enhanced substance use disorder treatment and prevention strategies.\u0000\u0000\u0000METHODS\u0000We characterized trajectories of self-reported impulsivity and sensation seeking in 305 FH+ youths who at minimum had a father with a history of alcohol or other drug use disorders and 81 youths with no family histories of substance use disorders (FH-). Assessments started at ages 10 to 12 and continued at 6-month intervals for up to 42 months. In addition, a subset of 58 FH+ youths who began alcohol or other drug use before age 15 (FH+ Users) were compared to 58 FH+ propensity-matched adolescents who did not initiate substance use before age 15 (FH+ Non-Users).\u0000\u0000\u0000RESULTS\u0000Compared to FH- youths at preadolescence, FH+ youths reported higher general impulsivity and higher impulsivity related to poor planning and attention. Over time, there were no differential effects of FH status on changes in impulsivity or sensation seeking across adolescence. FH+ Users had smaller decreases in general impulsivity and impulsivity related to restlessness and fidgeting across adolescence than FH+ Non-Users. FH+ Users also had greater increases in sensation seeking across adolescence than FH+ Non-Users.\u0000\u0000\u0000CONCLUSIONS\u0000Increased impulsivity in FH+ youths may make them less able to regulate sensation seeking drives that peak in adolescence, which may contribute to their high risk for developing substance use disorders. Additionally, FH+ adolescents who initiate early use may be at increased risk in part due to increased impulsivity coupled with greater increases in sensation seeking.","PeriodicalId":7410,"journal":{"name":"Alcoholism, clinical and experimental research","volume":"15 1","pages":"2622-2630"},"PeriodicalIF":3.2,"publicationDate":"2016-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82771518","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
S. Bergeson, H. Blanton, Joseph M. Martinez, D. Curtis, C. Sherfey, Brandon L Seegmiller, P. Marquardt, J. A. Groot, C. L. Allison, C. Bezboruah, J. Guindon
Background Physicians have long reported that patients with chronic pain show higher tendencies for alcohol use disorder (AUD), and AUD patients appear to have higher pain sensitivities. The goal of this study was to test 2 hypotheses: (i) binge alcohol consumption increases inflammatory pain and mechanical and cold sensitivities; and (ii) tigecycline is an effective treatment for alcohol‐mediated‐increased pain behaviors and sensitivities. Both female and male mice were used to test the additional hypothesis that important sex differences in the ethanol (EtOH)‐related traits would be seen. Methods “Drinking in the Dark” (DID) alcohol consuming and nondrinking control, female and male, adult C57BL/6J mice were evaluated for inflammatory pain behaviors and for the presence of mechanical and cold sensitivities. Inflammatory pain was produced by intraplantar injection of formalin (10 μl, 2.5% in saline). For cold sensation, a 20 μl acetone drop was used. Mechanical withdrawal threshold was measured by an electronic von Frey anesthesiometer. Efficacy of tigecycline (80 mg/kg i.p.) to reduce DID‐related pain responses and sensitivity was tested. Results DID EtOH consumption increased inflammatory pain behavior, while it also produced sustained mechanical and cold sensitivities in both females and males. Tigecycline produced antinociceptive effects in males; a pro‐nociceptive effect was seen in females in the formalin test. Likewise, the drug reduced both mechanical and cold sensitivities in males, but females showed an increase in sensitivity in both tests. Conclusions Our results demonstrated that binge drinking increases pain, touch, and thermal sensations in both sexes. In addition, we have identified sex‐specific effects of tigecycline on inflammatory pain, as well as mechanical and cold sensitivities. The development of tigecycline as an AUD pharmacotherapy may need consideration of its pro‐nociceptive action in females. Further studies are needed to investigate the mechanism underlying the sex‐specific differences in nociception.
{"title":"Binge Ethanol Consumption Increases Inflammatory Pain Responses and Mechanical and Cold Sensitivity: Tigecycline Treatment Efficacy Shows Sex Differences","authors":"S. Bergeson, H. Blanton, Joseph M. Martinez, D. Curtis, C. Sherfey, Brandon L Seegmiller, P. Marquardt, J. A. Groot, C. L. Allison, C. Bezboruah, J. Guindon","doi":"10.1111/acer.13252","DOIUrl":"https://doi.org/10.1111/acer.13252","url":null,"abstract":"Background Physicians have long reported that patients with chronic pain show higher tendencies for alcohol use disorder (AUD), and AUD patients appear to have higher pain sensitivities. The goal of this study was to test 2 hypotheses: (i) binge alcohol consumption increases inflammatory pain and mechanical and cold sensitivities; and (ii) tigecycline is an effective treatment for alcohol‐mediated‐increased pain behaviors and sensitivities. Both female and male mice were used to test the additional hypothesis that important sex differences in the ethanol (EtOH)‐related traits would be seen. Methods “Drinking in the Dark” (DID) alcohol consuming and nondrinking control, female and male, adult C57BL/6J mice were evaluated for inflammatory pain behaviors and for the presence of mechanical and cold sensitivities. Inflammatory pain was produced by intraplantar injection of formalin (10 μl, 2.5% in saline). For cold sensation, a 20 μl acetone drop was used. Mechanical withdrawal threshold was measured by an electronic von Frey anesthesiometer. Efficacy of tigecycline (80 mg/kg i.p.) to reduce DID‐related pain responses and sensitivity was tested. Results DID EtOH consumption increased inflammatory pain behavior, while it also produced sustained mechanical and cold sensitivities in both females and males. Tigecycline produced antinociceptive effects in males; a pro‐nociceptive effect was seen in females in the formalin test. Likewise, the drug reduced both mechanical and cold sensitivities in males, but females showed an increase in sensitivity in both tests. Conclusions Our results demonstrated that binge drinking increases pain, touch, and thermal sensations in both sexes. In addition, we have identified sex‐specific effects of tigecycline on inflammatory pain, as well as mechanical and cold sensitivities. The development of tigecycline as an AUD pharmacotherapy may need consideration of its pro‐nociceptive action in females. Further studies are needed to investigate the mechanism underlying the sex‐specific differences in nociception.","PeriodicalId":7410,"journal":{"name":"Alcoholism, clinical and experimental research","volume":"82 1","pages":"2506 - 2515"},"PeriodicalIF":3.2,"publicationDate":"2016-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89087510","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
P. Kamat, C. J. Mallonee, Akash K. George, S. Tyagi, N. Tyagi
Alcohol is the most socially accepted addictive drug. Alcohol consumption is associated with some health problems such as neurological, cognitive, behavioral deficits, cancer, heart, and liver disease. Mechanisms of alcohol-induced toxicity are presently not yet clear. One of the mechanisms underlying alcohol toxicity has to do with its interaction with amino acid homocysteine (Hcy), which has been linked with brain neurotoxicity. Elevated Hcy impairs with various physiological mechanisms in the body, especially metabolic pathways. Hcy metabolism is predominantly controlled by epigenetic regulation such as DNA methylation, histone modifications, and acetylation. An alteration in these processes leads to epigenetic modification. Therefore, in this review, we summarize the role of Hcy metabolism abnormalities in alcohol-induced toxicity with epigenetic adaptation and their influences on cerebrovascular pathology.
{"title":"Homocysteine, Alcoholism, and Its Potential Epigenetic Mechanism.","authors":"P. Kamat, C. J. Mallonee, Akash K. George, S. Tyagi, N. Tyagi","doi":"10.1111/acer.13234","DOIUrl":"https://doi.org/10.1111/acer.13234","url":null,"abstract":"Alcohol is the most socially accepted addictive drug. Alcohol consumption is associated with some health problems such as neurological, cognitive, behavioral deficits, cancer, heart, and liver disease. Mechanisms of alcohol-induced toxicity are presently not yet clear. One of the mechanisms underlying alcohol toxicity has to do with its interaction with amino acid homocysteine (Hcy), which has been linked with brain neurotoxicity. Elevated Hcy impairs with various physiological mechanisms in the body, especially metabolic pathways. Hcy metabolism is predominantly controlled by epigenetic regulation such as DNA methylation, histone modifications, and acetylation. An alteration in these processes leads to epigenetic modification. Therefore, in this review, we summarize the role of Hcy metabolism abnormalities in alcohol-induced toxicity with epigenetic adaptation and their influences on cerebrovascular pathology.","PeriodicalId":7410,"journal":{"name":"Alcoholism, clinical and experimental research","volume":"55 1","pages":"2474-2481"},"PeriodicalIF":3.2,"publicationDate":"2016-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76044552","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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