DNA methylation is altered with extended access to cocaine during abstinence

s / Drug and Alcohol Dependence 140 (2014) e169–e251 e179 Aprepitant in each of two sessions using a psychological stressor, and in each of two session using a physiologic stressor. During each session, measures of cocaine and alcohol craving were gathered both preand post-stressor. Results: Compared to placebo, Aprepitant significantly reduced cocaine craving during the physiologic stress sessions, asmeasured using the Cocaine Craving Questionnaires (CCQ). These craving reductions were driven by subjects’ decreased expectations about positive outcomes fromcocaine use, and occurred atmultiple timepoints post-stressor (ps < .05). Compared to placebo, Aprepitant also reduced alcohol craving during the physiologic stress sessions, as measured by the Alcohol Craving Questionnaire (ACQ). These craving reductionsweredrivenby subjects’ decreased expectations about relief of withdrawal from drinking, and occurred at multiple timepoints post stressor (ps = .05). There were no parallel reductions in cocaine or alcohol craving during the psychological stress sessions. Conclusions: These results demonstrate that the NK1 antagonist Aprepitant reduced stress-induced cocaine and alcohol craving under conditions of physiological stress, but not under conditions of psychological stress. The reductions in cocaine craving relate primarily to decreases in expectations about positive outcomes from cocaine use. In contrast, reductions in alcohol craving relate to decreases in expectations about relief from withdrawal or dysphoria. Taken together, these suggest that Aprepitant may have a differentmechanismofaction inalcoholdependenceand incocaine dependence. Financial support: Support for this study was provided by P50DA012756 and K01DA025073. http://dx.doi.org/10.1016/j.drugalcdep.2014.02.501 DNA methylation is altered with extended access to cocaine during abstinence Kyle Ploense1,2, A. Carr1, T. Bredy2, Y. Sun3, Tod E. Kippin1 1 Psychological and Brain Sciences, UCSB, Santa Barbara, CA, United States 2 Queensland Brain Institute, Saint Lucia, QLD, Australia 3 Psychiatry and Biobehavioral Sciences, UCLA, Los Angeles, CA, United States Aims: DNA methylation is a key determinant of gene expression and is implicated inneuroplasticity relevant to addiction.Here, we examine DNA methylation within the dorsal medial prefrontal cortex (dmPFC) following limitedor prolonged-access to cocaine self-administration and varying periods of forced cocaine abstinence. Methods: Rats were fitted with IV catheters and allowed to lever press for saline, limited-access (1h/day) to cocaine, or prolonged-access (6h/day) to cocaine for 15 sessions. Then, dmPFC was collected at either 1, 14, or 60 days of abstinence from self-administration. As reported previously, only prolongedaccess rats exhibited escalated cocaine intake across sessions and had intake substantially higher than the limited-access group. MeDIP-CHIP and qPCR analyses of dmPFC tissue revealed dramatic and extremely gene-specific changes in DNA methylation/demethylation within promoter regions and flanking the transcription start site (TSS) across groups. Results: The region flanking TSS in the gene Npas4 exhibited dynamic changes in DNA methylation following limited and prolonged-access that varied in response to treatment as well as length of abstinence. After 1 day of abstinence, the prolongedaccess group was trending towards increased methylation at TSS, at 14 days after treatment only the prolonged-access group exhibited decreasedmethylation surrounding TSS,whereas after 60 days post-treatment there was a reversal and the limited and prolonged access groups exhibited dramatically increased methylation from the control. Conclusions: These results demonstrate that cocaine selfadministration alters DNA methylation dynamically over the course of abstinence, as well as the transcription of mRNA in both limited and prolonged access to cocaine. The present findings provide a possible molecular mechanism mediating the enduring nature of cocaine addiction during abstinence. Financial support: The research was supported by grants from NARSAD and NIH (R21DA027115). http://dx.doi.org/10.1016/j.drugalcdep.2014.02.502 The impact of state-level education policy, taxation, income disparity and political ideology on tobacco use in two nationally representative samples Andrew D. Plunk, W. Tate, L. Bierut, R. Grucza Washington University, St. Louis, MO, United States Aims: Math and science education may be linked to improved health decision making. State-by-state increases in graduation requirements in the mid ‘80s and early ‘90s offer an opportunity to explore this potential effect. To this end, we used two nationally representative samples to examine the effects of higher math and science coursework requirements on smoking initiation, defined as ever smoking 100 cigarettes; we also included several state-level covariates that couldaffect educationquality and funding: cigarette tax rate, political ideology and income disparity. Methods: Four waves (1999, 2001, 2003 and 2006) of the Tobacco Use Supplement of the Current Population Survey (TUSCPS) and eleven administrations (1998–2008) of the Behavioral Risk-Factor Surveillance System (BRFSS) were paired with statelevel graduation requirement data. Analyses were conditioned on high school graduation; 16,364 TUS-CPS and 54,661 BRFSS respondents met inclusion criteria and graduated during the period of interest (1980–1999). Logistic regression was used to model the effect of graduation requirement on smoking initiation. Results: Higher math and science graduation requirements were associated with lower odds of smoking initiation for both samples, which persisted after including additional state-level covariates and in stratified analyses based on race/ethnicity and sex. Associations forwhites of both sexeswere likely driving results for the full samples, although confidence intervals for all subgroup analyses overlapped. For example, white BRFSS respondents who were exposed to the highest requirementswere at 8% lower odds to have initiated smoking compared to thosewith the lowest requirements (OR= .92, CI [.87, .95], p< .001). Conclusions: Our findings support a significant association between increasing math and science education at the high school level and smoking initiation, independent of further educational attainment and state-level characteristics such as cigarette taxation, income disparity and political ideology. Financial support: NIDA T32DA07313, K02DA021237, R21DA026 and R01DA031288. http://dx.doi.org/10.1016/j.drugalcdep.2014.02.503