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Poster Abstracts
Conference Abstracts / Alcohol 42 (2008) 303-341
329
P88
P90
The developmental expression of DISC1 is altered by increases in cAMP signaling but not by chronic ethanol exposure Patrick J. Mulholland and L. Judson Chandler, Medical University of South Carolina, Charleston, SC, USA
The role of serotonin in alcoholism and stress: The inconsistent results of pharmacotherapy of serotonergic drugs for alcoholism George A. Kenna, Brown University, Providence RI, USA
Disrupted-in-Schizophrenia 1 (DISC1) is a multifunctional scaffold protein involved in brain development, cognition, and cAMP signaling, and is differentially expressed in various isoforms across multiple subcellular compartments. Interestingly, postmortem analysis of human alcoholic brain tissue has observed enhance nuclear localization of an isoform of DISC1. Since alterations in processes associated with cAMP signaling likely contribute to differences in responses to both stress and alcohol in the adult and developing brain, we characterized the subcellular changes in DISC1 expression in cortex across development, after chronic increases and decreases in synaptic activity, after chronic elevation of cAMP-PDE4 signaling, and following prolonged alcohol exposure. At various times throughout development, cytosolic and membrane fractions were prepared from high-density cortical neurons or rodent cortex. Expression of multiple DISC1 isoforms significantly changed in both fractions across development in both primary cortical neurons and in rodent cortex. Changes in activity induced by prolonged treatment of cultures with NMDA, tetrodotoxin, the NMDA receptor antagonist APV, or alcohol did not modify developmental expression of DISC1. In contrast, chronic treatment with either the PDE4 inhibitor rolipram or the adenylyl cyclase activator forskolin produced marked alterations in DISC1 developmental expression. The findings from this study suggest that DISC1 expression during development is not altered in response to changes in synaptic activity or by exposure to alcohol. The current study demonstrates that developmental expression of DISC1 in cortex temporally correlated with a heightened period of synaptogenesis and was sensitive to alterations in cAMP-PDE4 signaling but not to chronic changes in synaptic activity or chronic alcohol exposure.
P89 A longitudinal study on the relationship between alcohol craving and the hypothalamic-pituitary-thyroid and volume-regulating hormones L. Leggio, A. Ferrulli, S. Cardone, N. Malandrino, A. Mirijello, C. D’Angelo, L. Vonghia, A. Miceli, E. Capristo, G. Gasbarrini, G.A. Kenna, R.M. Swift, G. Addolorato, Brown University, Providence (RI) and Catholic University of Rome, Rome (IT) Appetite peptides as ghrelin and insulin have shown to be significantly correlated with alcohol craving and particularly with the compulsive component of alcohol craving. More recently, similar data have been found for the thyroid-related hormones, suggesting a role of the hypothalamic-pituitary-thyroid (HPT) axis in alcohol dependence. Furthermore, thyroid hormones seem to be correlated with anxiety levels in actively drinking alcohol dependent patients. Since craving and anxiety share common neurobiological pathway, it could be conceivable a the possible role of the HPT axis on alcohol craving via anxiety. Interestingly, alcohol craving seems also influenced by volume intake. Consistently, the renin-aldosterone axis seems able to influence the obsessive component of craving in medium-term abstinent patients. All together, these data suggest that different groups of hormones (volumeregulating vs feeding-related hormones) could influence different neurobiological pathways (respectively obsessive vs compulsive craving) and could reflect the overlap between alcohol-seeking behaviour and different appetite pathways (respectively salt vs sweet appetite). In summary, the possible role of appetite peptides in alcohol addiction supports the role of the hypothalamic-pituitary axis in the neurobiology of alcohol dependence. Since these peptides may also play a role in mediating neuroendocrine and behavioral responses to stressors, their possible role as a link between alcoholism and stress will be also discussed.
Numerous studies suggest that serotonergic (5-HT) mechanisms are associated with the development of alcohol dependence (AD) however, studies evaluating 5-HT medications in populations of (AD) individuals have produced conflicting efficacy. One hypothesis suggests that 5-HT response may be based on a polymorphism of the 5’-HTTLPR promoter region of the 5-HT re-uptake transporter. These alleles have been classified as genotypes: LL, SS and SL, with the LL variant putatively associated with early onset alcoholism (EOA) and the SS/SL variants associated with late onset alcoholism (LOA). The aim of this study was to match and mismatch LL or SS/SL alleles to ondansteron and sertraline. Fifteen non-treatment-seeking AD individuals were randomized based on their genotype (LL or SS/SL) into one of two counterbalanced arms: participants in the first arm (LL) first received either 200mg/day of sertraline or ondansetron 0.5mg/day for three weeks followed by an alcohol self-administration experiment (ASAE), then received placebo for three weeks followed by a second ASAE. Participants then received the alternate drug for three weeks followed by a third ASAE. Participants in the second arm (SS/SL) received the same medications. At time 1 there is support for ondansetron significantly improving drinking outcomes for LL carriers, compared to sertraline. This is true for the ASAE volume consumed (100% reduction and t = 2.35), and for the naturalistic assessment of drinks per drinking day during the 7 days prior to each ASAE (79% reduction and t = 4.34). Compared to ondansetron for SS/SL carriers, outcomes at time 1 for sertraline and SS/SL carriers are in the opposite direction than hypoth-esized. Overall, subjects reduced drinking across their participation in the trial. This study suggests that ondansetron may reduce alcohol consumption in AD individuals who have LL alleles. By contrast there was no support that sertraline reduces alcohol use in individuals who have SS or SL alleles. The study also supports the use of the ASAE as a method to delineate mechanisms of action. Evidence is growing to suggest that alcoholism in some may be influenced by a gene x socio-environmental interaction making pharmacological treatment with SSRIa in these patients complex as evidenced by the inconsistent results of previous studies. Researchers must consider and assess potential underlying typologies assocated with genetic and socio-environmental influences that may contribute to successful treatment of AD in future trials.
P91 Do cytokines contribute to stress-induced sensitization of withdrawal-induced anxiety? GR Breese, DJ Knapp, DH Overstreet, M Navarro, M Huang, and TA Wills, Bowles Center for Alcohol Studies, University of North Carolina School of Medicine, Chapel Hill, NC, USA It was recently found that stress, which sensitizes ethanol-withdrawalinduced anxiety, not only activated the HPA axis, but also increased the cytokine, tumor necrosis factor-α (TNFα), in brain. Since the cytokine antagonist α-melanocyte stimulating hormone (α-MSH) is reduced in brain by repeated ethanol withdrawals, it was considered whether cytokines could contribute to the repeated stress sensitization of anxiety observed during withdrawal from ethanol (Neuropsychopharmacology. 29: 470, 2004). When cytokine activity was increased in brain by 2 weekly lipopolysaccharide (LPS) or TNFα exposures prior to 5 days of 4.5% ethanol diet, both treatments sensitized the anxiety induced by ethanol withdrawal (Neuropsychopharmacology. 33:867, 2008). A challenge with a subsequent 5 days of ethanol diet 16 days after completion of the cytokine/ethanol withdrawal exposure also caused an increase in anxiety during ethanol withdrawal—evidence for induction of a persistent adaptive change reminiscent of that seen with the stress/withdrawal protocol. Importantly, flumazenil (5 mg/kg; IP) and αMSH (200 ng; ICV) blocked the sensitization of withdrawal-induce anxiety by these protocols. These data support the need for future investigations to define links cytokines and stress may have to the negative affect that facilitates relapse of alcoholics to drinking. [Support by AA14949 & AA11605]
329
P88
P90
The developmental expression of DISC1 is altered by increases in cAMP signaling but not by chronic ethanol exposure Patrick J. Mulholland and L. Judson Chandler, Medical University of South Carolina, Charleston, SC, USA
The role of serotonin in alcoholism and stress: The inconsistent results of pharmacotherapy of serotonergic drugs for alcoholism George A. Kenna, Brown University, Providence RI, USA
Disrupted-in-Schizophrenia 1 (DISC1) is a multifunctional scaffold protein involved in brain development, cognition, and cAMP signaling, and is differentially expressed in various isoforms across multiple subcellular compartments. Interestingly, postmortem analysis of human alcoholic brain tissue has observed enhance nuclear localization of an isoform of DISC1. Since alterations in processes associated with cAMP signaling likely contribute to differences in responses to both stress and alcohol in the adult and developing brain, we characterized the subcellular changes in DISC1 expression in cortex across development, after chronic increases and decreases in synaptic activity, after chronic elevation of cAMP-PDE4 signaling, and following prolonged alcohol exposure. At various times throughout development, cytosolic and membrane fractions were prepared from high-density cortical neurons or rodent cortex. Expression of multiple DISC1 isoforms significantly changed in both fractions across development in both primary cortical neurons and in rodent cortex. Changes in activity induced by prolonged treatment of cultures with NMDA, tetrodotoxin, the NMDA receptor antagonist APV, or alcohol did not modify developmental expression of DISC1. In contrast, chronic treatment with either the PDE4 inhibitor rolipram or the adenylyl cyclase activator forskolin produced marked alterations in DISC1 developmental expression. The findings from this study suggest that DISC1 expression during development is not altered in response to changes in synaptic activity or by exposure to alcohol. The current study demonstrates that developmental expression of DISC1 in cortex temporally correlated with a heightened period of synaptogenesis and was sensitive to alterations in cAMP-PDE4 signaling but not to chronic changes in synaptic activity or chronic alcohol exposure.
P89 A longitudinal study on the relationship between alcohol craving and the hypothalamic-pituitary-thyroid and volume-regulating hormones L. Leggio, A. Ferrulli, S. Cardone, N. Malandrino, A. Mirijello, C. D’Angelo, L. Vonghia, A. Miceli, E. Capristo, G. Gasbarrini, G.A. Kenna, R.M. Swift, G. Addolorato, Brown University, Providence (RI) and Catholic University of Rome, Rome (IT) Appetite peptides as ghrelin and insulin have shown to be significantly correlated with alcohol craving and particularly with the compulsive component of alcohol craving. More recently, similar data have been found for the thyroid-related hormones, suggesting a role of the hypothalamic-pituitary-thyroid (HPT) axis in alcohol dependence. Furthermore, thyroid hormones seem to be correlated with anxiety levels in actively drinking alcohol dependent patients. Since craving and anxiety share common neurobiological pathway, it could be conceivable a the possible role of the HPT axis on alcohol craving via anxiety. Interestingly, alcohol craving seems also influenced by volume intake. Consistently, the renin-aldosterone axis seems able to influence the obsessive component of craving in medium-term abstinent patients. All together, these data suggest that different groups of hormones (volumeregulating vs feeding-related hormones) could influence different neurobiological pathways (respectively obsessive vs compulsive craving) and could reflect the overlap between alcohol-seeking behaviour and different appetite pathways (respectively salt vs sweet appetite). In summary, the possible role of appetite peptides in alcohol addiction supports the role of the hypothalamic-pituitary axis in the neurobiology of alcohol dependence. Since these peptides may also play a role in mediating neuroendocrine and behavioral responses to stressors, their possible role as a link between alcoholism and stress will be also discussed.
Numerous studies suggest that serotonergic (5-HT) mechanisms are associated with the development of alcohol dependence (AD) however, studies evaluating 5-HT medications in populations of (AD) individuals have produced conflicting efficacy. One hypothesis suggests that 5-HT response may be based on a polymorphism of the 5’-HTTLPR promoter region of the 5-HT re-uptake transporter. These alleles have been classified as genotypes: LL, SS and SL, with the LL variant putatively associated with early onset alcoholism (EOA) and the SS/SL variants associated with late onset alcoholism (LOA). The aim of this study was to match and mismatch LL or SS/SL alleles to ondansteron and sertraline. Fifteen non-treatment-seeking AD individuals were randomized based on their genotype (LL or SS/SL) into one of two counterbalanced arms: participants in the first arm (LL) first received either 200mg/day of sertraline or ondansetron 0.5mg/day for three weeks followed by an alcohol self-administration experiment (ASAE), then received placebo for three weeks followed by a second ASAE. Participants then received the alternate drug for three weeks followed by a third ASAE. Participants in the second arm (SS/SL) received the same medications. At time 1 there is support for ondansetron significantly improving drinking outcomes for LL carriers, compared to sertraline. This is true for the ASAE volume consumed (100% reduction and t = 2.35), and for the naturalistic assessment of drinks per drinking day during the 7 days prior to each ASAE (79% reduction and t = 4.34). Compared to ondansetron for SS/SL carriers, outcomes at time 1 for sertraline and SS/SL carriers are in the opposite direction than hypoth-esized. Overall, subjects reduced drinking across their participation in the trial. This study suggests that ondansetron may reduce alcohol consumption in AD individuals who have LL alleles. By contrast there was no support that sertraline reduces alcohol use in individuals who have SS or SL alleles. The study also supports the use of the ASAE as a method to delineate mechanisms of action. Evidence is growing to suggest that alcoholism in some may be influenced by a gene x socio-environmental interaction making pharmacological treatment with SSRIa in these patients complex as evidenced by the inconsistent results of previous studies. Researchers must consider and assess potential underlying typologies assocated with genetic and socio-environmental influences that may contribute to successful treatment of AD in future trials.
P91 Do cytokines contribute to stress-induced sensitization of withdrawal-induced anxiety? GR Breese, DJ Knapp, DH Overstreet, M Navarro, M Huang, and TA Wills, Bowles Center for Alcohol Studies, University of North Carolina School of Medicine, Chapel Hill, NC, USA It was recently found that stress, which sensitizes ethanol-withdrawalinduced anxiety, not only activated the HPA axis, but also increased the cytokine, tumor necrosis factor-α (TNFα), in brain. Since the cytokine antagonist α-melanocyte stimulating hormone (α-MSH) is reduced in brain by repeated ethanol withdrawals, it was considered whether cytokines could contribute to the repeated stress sensitization of anxiety observed during withdrawal from ethanol (Neuropsychopharmacology. 29: 470, 2004). When cytokine activity was increased in brain by 2 weekly lipopolysaccharide (LPS) or TNFα exposures prior to 5 days of 4.5% ethanol diet, both treatments sensitized the anxiety induced by ethanol withdrawal (Neuropsychopharmacology. 33:867, 2008). A challenge with a subsequent 5 days of ethanol diet 16 days after completion of the cytokine/ethanol withdrawal exposure also caused an increase in anxiety during ethanol withdrawal—evidence for induction of a persistent adaptive change reminiscent of that seen with the stress/withdrawal protocol. Importantly, flumazenil (5 mg/kg; IP) and αMSH (200 ng; ICV) blocked the sensitization of withdrawal-induce anxiety by these protocols. These data support the need for future investigations to define links cytokines and stress may have to the negative affect that facilitates relapse of alcoholics to drinking. [Support by AA14949 & AA11605]