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Stress, coping, and alcohol use in young adulthood
242
Abstracts / Alcohol 60 (2017) 203e243
human literature. Ultimately, future studies will explore the biological underpinnings of how alcohol affects established relationships and potentially lead to alternatives to current treatments. P165 TLR3 ACTIVATION INCREASES VOLUNTARY ALCOHOL CONSUMPTION Anna S. Warden, Adriana DaCosta, Yuri A. Blednov, R. Dayne Mayfield, R. Adron Harris. University of Texas at Austin, Austin, TX, USA Emerging evidence suggests that activation of neuroimmune pathways (i.e. toll-like receptor pathway) can regulate chronic ethanol consumption. TLRs initiate pro- and anti-inflammatory responses via two intracellular signaling transduction cascades: (1) MyD88-dependent and (2) TRIFdependent pathways. All TLRs signal through MyD88 except TLR3, which can signal through both pathways. Previously our lab has shown that activation of MyD88-dependent signaling with lipopolysaccharide increases voluntary ethanol consumption and preference in mice. Moreover, we have shown that chronic ethanol consumption alters expression of the TRIF-dependent pathway. However, the effect of TLR3 activation on voluntary ethanol consumption is currently unknown. Therefore, we measured the effects of TLR3 agonist polyinosinic-polycytidylic acid (Poly I:C) on ethanol intake and preference in C57BL6/J male mice. We measured intake of 15% or 20% v/v ethanol in an every-other-day two-bottle choice drinking paradigm while administering Poly I:C every four days. Poly I:C increased ethanol consumption and preference in C57BL6/J in a dosedependent manner. Poly I:C did not alter total fluid intake or preference for saccharin (0.0008% or 0.0033%). Poly I:C induced gene expression changes were determined by quantitative PCR. There were significant increases in expression of TRIF-dependent, MyD88-dependent, and proinflammatory signaling genes in the prefrontal cortex, nucleus accumbens, and amygdala. Our results provide novel evidence that TLR3 activation has a role in regulating voluntary ethanol consumption. We suggest that inhibition of TLR3 signaling may be an unexplored target for medication development to reduce excessive alcohol consumption. Supported by grants: U01 AA020926, P01 AA020683, AA013520, AA006399. P166 STRESS, COPING, AND ALCOHOL USE IN YOUNG ADULTHOOD Helene R. White, Kristen G. Anderson, Jordan Beardslee. Rutgers Center of Alcohol Studies, Piscataway, NJ, USA; Reed College, Portland, OR, USA; University of Pittsburgh Medical Center, Pittsburgh, PA, USA Higher levels of coping motives are associated with higher frequency and quantity of alcohol use, and higher levels of stress may exacerbate this association. Few studies have looked at the associations among drinking, coping motives, and stress in a single study. In this study, we examined whether perceived level of stress moderated the association between drinking coping motives and alcohol use in a community sample of young adult men. Data came from alcohol users who were interviewed at mean age 26 (N ¼ 344) and again at mean age 29 (N ¼ 333). Past year frequency and quantity of drinking were assessed as outcomes. Motives and perceived levels of stress were assessed by validated instruments. Race was controlled in the analyses. Hierarchical regression analyses indicated that, at both ages, stronger coping motives were significantly related to greater frequency and quantity of alcohol use. Stress was significantly related to alcohol quantity at age 29 but not at age 26 and not to alcohol frequency at either age. Stress did not moderate the effects of coping on either outcome. Overall, the results indicate a strong concurrent association between coping motives and alcohol use among young adult men. These associations remain strong regardless of perceived stress level. Interventions to challenge coping motives are needed for young men throughout young adulthood. P167 THE ACUTE ALCOHOL TRANSCRIPTOME PARALLELS THAT OF RAPID ANTIDEPRESSANTS S.A. Wolfe, C.F. Heaney, F. Niere, S.P. Farris, R.D. Mayfield, R.A. Harris, K.F. Raab-Graham. University of Texas at Austin, Austin, TX, USA
Alcohol and depression display a strong comorbidity, and it is thought that self-medication with alcohol often occurs in depressed individuals. We aim to identify synaptic changes that are common to both alcohol and antidepressants to elucidate the molecular basis of the self-medication hypothesis. We found that acute alcohol exposure alters the function of the GABABR in hippocampal dendrites that leads to increased dendritic calcium signaling and downstream activation of translation (Wolfe et al., Nat. Comm., 2016). This same pathway has linked to actions of the rapid-antidepressant Ro-25-6981, and with antidepressant-like behavioral changes 24hrs after ethanol treatment. To further this research we used RNASequencing to profile the transcriptome of hippocampal synaptoneurosomes from mice treated acutely with alcohol (2.5g/kg) or Ro-25-6981 (10mg/kg). We will compare genes that are differentially expressed with each treatment and identify expression changes that occur with both acute alcohol and rapid antidepressant administration. These data further our understanding of the similarities between molecular changes that co-occur with alcohol and rapid antidepressants, allowing us to identify pathways and genes that may be targetable for treatment. Supported by: NIH-NIAAA pilot grant, NSF IOS-1355158, DoD USAMRMC Award W81XWH-14-10061; and U01 AA020926, P01 AA020683, AA013520, AA006399. P168 HISTONE METHYLATION INVOLVEMENT IN LASTING MEMORY DEFICITS AND ETHANOL SENSITIVITY AFTER BINGE ETHANOL IN ADOLESCENTS Jennifer T. Wolstenholme. Virginia Commonwealth University, Richmond, VA, USA Alcohol use in teens primarily occurs in binges and is associated with cognitive impairments, reduced white matter content, and synaptic pruning in the frontal cortex. Binge drinking in adolescence increases the rewarding aspects of ethanol while decreasing its aversive properties, enabling higher consumption and risk for alcohol use disorders. Indeed, drinking at an early age increases risk for adult dependence. Ongoing brain development, particularly regarding prefrontal cortex (PFC) myelination and synaptic connectivity, may make adolescent drinkers highly vulnerable to lasting consequences of binge ethanol. However, the molecular mechanisms underlying ethanol-induced changes in PFC development are not fully understood. To uncover these long-term adaptive and maladaptive responses to adolescent ethanol, we dosed DBA2/J mice with binge ethanol (4g/kg, i.g.) intermittently from PND29-42 and measured genomic PFC transcriptional expression. Behavioral sensitivity to acute ethanol was assessed during adolescence and in adulthood to measure immediate and persistent effects of adolescent binge ethanol. As adults, mice were also tested for memory deficits. Binge ethanol decreased adolescent PFC myelin expression and led to lasting memory deficits in the object recognition test and greater ethanol sensitivity in adulthood. Genomic profiling of transcripts in PFC identified decreased expression of genes involved in histone demethylation at H3K9 and H3K36. We hypothesize that this may be a switch for future transcriptional changes that underlie the behavioral changes lasting into adulthood. These findings have important implications for addiction risk in humans and are beginning to identify underlying mechanisms and processes for how ethanol disrupts frontal cortex development. P170 THE ROLE OF THE PERIAQUEDUCTAL GRAY AREA IN MALADAPTIVE EMOTIONAL AND BEHAVIORAL RESPONSES STEMMING FROM ALCOHOL DEPENDENCE Emily Lowery-Gionta, Huiling Wang, Leandro Vendruscolo, Dylan Sucich, Brendan Tunstall, Lisa Thomas, Marisela Morales, George F. Koob. NIDA/NIH, Baltimore, MD, USA; NIAAA/NIH, Rockville, MD, USA Adaptations in key brain regions developed over the course of alcohol dependence perpetuate the disorder by inducing negative affective states that drive compensatory, compulsory alcohol drinking. The Periaqueductal Gray Area (PAG) is a midbrain region that coordinates emotional and behavioral responses to aversive stimuli through connections with the extended amygdala, a cluster of coordinated regions that modulate alcohol dependence-related emotional and behavioral phenotypes. Here, we
Abstracts / Alcohol 60 (2017) 203e243
human literature. Ultimately, future studies will explore the biological underpinnings of how alcohol affects established relationships and potentially lead to alternatives to current treatments. P165 TLR3 ACTIVATION INCREASES VOLUNTARY ALCOHOL CONSUMPTION Anna S. Warden, Adriana DaCosta, Yuri A. Blednov, R. Dayne Mayfield, R. Adron Harris. University of Texas at Austin, Austin, TX, USA Emerging evidence suggests that activation of neuroimmune pathways (i.e. toll-like receptor pathway) can regulate chronic ethanol consumption. TLRs initiate pro- and anti-inflammatory responses via two intracellular signaling transduction cascades: (1) MyD88-dependent and (2) TRIFdependent pathways. All TLRs signal through MyD88 except TLR3, which can signal through both pathways. Previously our lab has shown that activation of MyD88-dependent signaling with lipopolysaccharide increases voluntary ethanol consumption and preference in mice. Moreover, we have shown that chronic ethanol consumption alters expression of the TRIF-dependent pathway. However, the effect of TLR3 activation on voluntary ethanol consumption is currently unknown. Therefore, we measured the effects of TLR3 agonist polyinosinic-polycytidylic acid (Poly I:C) on ethanol intake and preference in C57BL6/J male mice. We measured intake of 15% or 20% v/v ethanol in an every-other-day two-bottle choice drinking paradigm while administering Poly I:C every four days. Poly I:C increased ethanol consumption and preference in C57BL6/J in a dosedependent manner. Poly I:C did not alter total fluid intake or preference for saccharin (0.0008% or 0.0033%). Poly I:C induced gene expression changes were determined by quantitative PCR. There were significant increases in expression of TRIF-dependent, MyD88-dependent, and proinflammatory signaling genes in the prefrontal cortex, nucleus accumbens, and amygdala. Our results provide novel evidence that TLR3 activation has a role in regulating voluntary ethanol consumption. We suggest that inhibition of TLR3 signaling may be an unexplored target for medication development to reduce excessive alcohol consumption. Supported by grants: U01 AA020926, P01 AA020683, AA013520, AA006399. P166 STRESS, COPING, AND ALCOHOL USE IN YOUNG ADULTHOOD Helene R. White, Kristen G. Anderson, Jordan Beardslee. Rutgers Center of Alcohol Studies, Piscataway, NJ, USA; Reed College, Portland, OR, USA; University of Pittsburgh Medical Center, Pittsburgh, PA, USA Higher levels of coping motives are associated with higher frequency and quantity of alcohol use, and higher levels of stress may exacerbate this association. Few studies have looked at the associations among drinking, coping motives, and stress in a single study. In this study, we examined whether perceived level of stress moderated the association between drinking coping motives and alcohol use in a community sample of young adult men. Data came from alcohol users who were interviewed at mean age 26 (N ¼ 344) and again at mean age 29 (N ¼ 333). Past year frequency and quantity of drinking were assessed as outcomes. Motives and perceived levels of stress were assessed by validated instruments. Race was controlled in the analyses. Hierarchical regression analyses indicated that, at both ages, stronger coping motives were significantly related to greater frequency and quantity of alcohol use. Stress was significantly related to alcohol quantity at age 29 but not at age 26 and not to alcohol frequency at either age. Stress did not moderate the effects of coping on either outcome. Overall, the results indicate a strong concurrent association between coping motives and alcohol use among young adult men. These associations remain strong regardless of perceived stress level. Interventions to challenge coping motives are needed for young men throughout young adulthood. P167 THE ACUTE ALCOHOL TRANSCRIPTOME PARALLELS THAT OF RAPID ANTIDEPRESSANTS S.A. Wolfe, C.F. Heaney, F. Niere, S.P. Farris, R.D. Mayfield, R.A. Harris, K.F. Raab-Graham. University of Texas at Austin, Austin, TX, USA
Alcohol and depression display a strong comorbidity, and it is thought that self-medication with alcohol often occurs in depressed individuals. We aim to identify synaptic changes that are common to both alcohol and antidepressants to elucidate the molecular basis of the self-medication hypothesis. We found that acute alcohol exposure alters the function of the GABABR in hippocampal dendrites that leads to increased dendritic calcium signaling and downstream activation of translation (Wolfe et al., Nat. Comm., 2016). This same pathway has linked to actions of the rapid-antidepressant Ro-25-6981, and with antidepressant-like behavioral changes 24hrs after ethanol treatment. To further this research we used RNASequencing to profile the transcriptome of hippocampal synaptoneurosomes from mice treated acutely with alcohol (2.5g/kg) or Ro-25-6981 (10mg/kg). We will compare genes that are differentially expressed with each treatment and identify expression changes that occur with both acute alcohol and rapid antidepressant administration. These data further our understanding of the similarities between molecular changes that co-occur with alcohol and rapid antidepressants, allowing us to identify pathways and genes that may be targetable for treatment. Supported by: NIH-NIAAA pilot grant, NSF IOS-1355158, DoD USAMRMC Award W81XWH-14-10061; and U01 AA020926, P01 AA020683, AA013520, AA006399. P168 HISTONE METHYLATION INVOLVEMENT IN LASTING MEMORY DEFICITS AND ETHANOL SENSITIVITY AFTER BINGE ETHANOL IN ADOLESCENTS Jennifer T. Wolstenholme. Virginia Commonwealth University, Richmond, VA, USA Alcohol use in teens primarily occurs in binges and is associated with cognitive impairments, reduced white matter content, and synaptic pruning in the frontal cortex. Binge drinking in adolescence increases the rewarding aspects of ethanol while decreasing its aversive properties, enabling higher consumption and risk for alcohol use disorders. Indeed, drinking at an early age increases risk for adult dependence. Ongoing brain development, particularly regarding prefrontal cortex (PFC) myelination and synaptic connectivity, may make adolescent drinkers highly vulnerable to lasting consequences of binge ethanol. However, the molecular mechanisms underlying ethanol-induced changes in PFC development are not fully understood. To uncover these long-term adaptive and maladaptive responses to adolescent ethanol, we dosed DBA2/J mice with binge ethanol (4g/kg, i.g.) intermittently from PND29-42 and measured genomic PFC transcriptional expression. Behavioral sensitivity to acute ethanol was assessed during adolescence and in adulthood to measure immediate and persistent effects of adolescent binge ethanol. As adults, mice were also tested for memory deficits. Binge ethanol decreased adolescent PFC myelin expression and led to lasting memory deficits in the object recognition test and greater ethanol sensitivity in adulthood. Genomic profiling of transcripts in PFC identified decreased expression of genes involved in histone demethylation at H3K9 and H3K36. We hypothesize that this may be a switch for future transcriptional changes that underlie the behavioral changes lasting into adulthood. These findings have important implications for addiction risk in humans and are beginning to identify underlying mechanisms and processes for how ethanol disrupts frontal cortex development. P170 THE ROLE OF THE PERIAQUEDUCTAL GRAY AREA IN MALADAPTIVE EMOTIONAL AND BEHAVIORAL RESPONSES STEMMING FROM ALCOHOL DEPENDENCE Emily Lowery-Gionta, Huiling Wang, Leandro Vendruscolo, Dylan Sucich, Brendan Tunstall, Lisa Thomas, Marisela Morales, George F. Koob. NIDA/NIH, Baltimore, MD, USA; NIAAA/NIH, Rockville, MD, USA Adaptations in key brain regions developed over the course of alcohol dependence perpetuate the disorder by inducing negative affective states that drive compensatory, compulsory alcohol drinking. The Periaqueductal Gray Area (PAG) is a midbrain region that coordinates emotional and behavioral responses to aversive stimuli through connections with the extended amygdala, a cluster of coordinated regions that modulate alcohol dependence-related emotional and behavioral phenotypes. Here, we