Gene variants of the dopaminergic system are associated with non ...

Abstracts / Drug and Alcohol Dependence 171 (2017) e2–e226

The tobacco status project: Three month outcomes for a randomized controlled trial of a Facebook smoking cessation intervention for young adults Danielle Ramo 1,∗ , Johannes Thrul 1 , Kevin Delucchi 1 , S.M. Hall 1 , P. Ling 1 , A. Belohlavek 1 , Shirley Zhao 1 , Beomyun Han 1 , J. Prochaska 2 1 2

UCSF, San Francisco, CA, United States Stanford University, Stanford, CA, United States

Aims: Social media represents a promising strategy to deliver evidence-based smoking cessation treatment. We present outcomes from a trial testing the efficacy of a Facebook smoking cessation intervention for young adults. Methods: Young adult smokers (N = 501; age 18–25) were recruited online and randomized to either the 3 month Tobacco Status Project (TSP) intervention or a referral to a smoking cessation website (Smokefree.gov; control). TSP included assignment to a private Facebook group tailored to readiness to quit smoking, daily Facebook contacts, weekly live counseling sessions, and for those ready to quit, 6 additional Cognitive Behavioral Therapy counseling sessions. Results: The sample was 73% non-Hispanic White and 55% female with 87% daily smokers, 48% smoking 10 or fewer cigarettes per day, and averaging 2.8 years smoking (SD = .6); 30% were in precontemplation (no intention to quit in the next 6 months); 49% contemplation (intending to quit in the next 6 months), and 21% preparation (intending to quit in the next 30 days) for quitting smoking. Three-month follow-up rate was 70% (67% treatment, 74% control; 2 = .124, P = .14). Verified smoking 7-day point prevalence abstinence was significantly higher for TSP than control at treatment end (8.3% vs 3.3%; odds ratio [OR] = 2.52; 95% confidence interval [CI] = 1.56, 4.04; P < .0001). A greater proportion of TSP participants reduced the number of cigarettes they smoked in the past week by at least half from baseline to 3 months (52.7% vs. 38.8%; OR = 1.82; 95% CI = 1.33, 2.49; P = .0002). There were no differences in likelihood of having made a quit attempt during treatment or readiness to quit smoking in the next month across groups. Conclusions: A novel Facebook intervention is associated with biochemically-verified abstinence from tobacco and reduction of smoking at 3 months. Social media intervention could be disseminated widely and expanded to address additional health risks. Financial support: K23 DA032578, P50 DA09253. http://dx.doi.org/10.1016/j.drugalcdep.2016.08.474 Pre-clinical abuse testing applications in drug development Jovita Randall-Thompson ∗ , Michael Klein Controlled Substance Staff, Food and Drug Administration, Silver Spring, MD, United States Aims: An abuse potential assessment for a new drug being developed (under IND or NDA) comprises of a mosaic collection of information and data. The drug’s chemical, pharmacological and pharmacokinetic studies should be described independently. The research results from these interdisciplinary studies need to be interconnected. Studies consist of a full screening of the drug’s receptor binding affinity and receptor functioning activity assayed on neurotransmitter systems associated with abuse potential. This information is collected early in drug development. The determination of whether to conduct additional studies to further elucidate the drug’s abuse potential may often be partially based on such

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information. However, a novel mechanism of action can often leave grounds of uncertainty of the relative abuse risk of the drug from an overall behavioral and social perspective. There are circumstances when a change in a marketed drug product’s dosage form may impact the abuse potential of the active principle ingredient. Under such circumstances, uncertainty is not often addressed until a preclinical abuse study, such as drug discrimination and selfadministration, is conducted. Furthermore, there are cases when a human assessment may be needed, yet this does not nullify conducting of a pre-clinical abuse assessment. As a “stepping-stone”, the pre-clinical abuse assessment provides information concerning effects of drug dose and appropriate selection of comparator drug and assists in planning the course of human assessment of the drug. Conclusions: The relevance of pre-clinical abuse studies in understanding a drug’s risk of abuse should not be underestimated. The role and parameters of these studies as it relates to abuse assessment planning in drug development will be discussed. Financial support: Financial support provided by the Food and Drug Administration. http://dx.doi.org/10.1016/j.drugalcdep.2016.08.475 Gene variants of the dopaminergic system are associated with non-dependent heroin use and heroin dependence Matthew Randesi 1,∗ , Orna Levran 1 , Jurg Ott 1 , Peter Blanken 2 , Wim van den Brink 2 , Jan M. van Ree 2 , Mary Jeanne Kreek 1 1 The Rockefeller University, New York, NY, United States 2 Central Committee on the Treatment of Heroin Addicts, Utrecht, Netherlands

Aims: To determine whether specific variants in genes of the dopamine system are associated with non-dependent heroin use and heroin dependence in a population that includes subjects who self-exposed to heroin without becoming addicted, methadonemaintained heroin dependents, and heroin-dependent subjects in heroin-assisted treatment. Methods: The study was limited to subjects of Dutch Caucasian ancestry. Four subject groups were collected: non-dependent heroin users (NOD) [n = 198]; opioid-dependent (OD) patients in methadone maintenance treatment (MMT) [n = 204]; opioiddependent MMT-resistant patients in heroin-assisted treatment (HAT) [n = 196]; and healthy controls (HC) with no history of heroin use [n = 197]. A total of 118 variants in 13 genes were genotyped using an Illumina GoldenGate array. To establish the role of the dopamine genes in (a) non-dependent heroin use, and (b) heroin dependence, the following groups were compared: (a) HC vs NOD; (b1) HC vs OD and (b2) NOD vs OD. Results: Eleven SNPs in 7 genes showed nominally significant association (p < 0.05) with non-dependent heroin use and dependence. In the comparison of healthy controls vs opioid dependent subjects, the association of SNP rs2073837, located in the dopamine beta-hydroxylase gene (DBH), with heroin dependence was experiment-wise significant (OR = 4.27; pcorrected = 0.0388). DBH converts dopamine to norepinephrine. SNP rs2073837 has previously been shown to be associated with attention deficient hyperactivity disorder (ADHD). Conclusions: This study contributes to our understanding of the role of genetic variation in the dopaminergic system with heroin dependence. Further studies are warranted to confirm and elucidate the role of these variants in the vulnerability to illicit drug use and drug addiction.

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Abstracts / Drug and Alcohol Dependence 171 (2017) e2–e226

Financial support: Supported by grants from the Adelson Medical Research Foundation, NIDA grant P50-DA005130 (MJK), a special supplement to R01-DA012848 (MJK) and a grant from the Netherlands Ministry of Health, Welfare and Sports.

Distress tolerance among substance users associated with connectivity between the MFG and VMPFC/SGACC during a distress tolerance task

http://dx.doi.org/10.1016/j.drugalcdep.2016.08.476

Elizabeth Danielle Reese 1,∗ , Ryan Patrick Bell 1 , Jennifer Youngshin Yi 1 , Thomas Ross 2 , Elliot Stein 2 , Stacey B. Daughters 1

Vulnerability to glutamate excitotoxicity is sexually dimorphic in rats exposed to chronic social defeat stress: Relevance to astrocytic glutamate-glutamine cycle Virginie Rappeneau 1,∗ , Amanda Blaker 2 , Jeffrey R. Petro 1 , Bryan K. Yamamoto 2 , Akiko Shimamoto 1 1

Neuroscience and Pharmacology, Meharry Medical College, Nashville, TN, United States 2 Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN, United States Aims: Functional role of astrocytes has been implicated in behavioral consequences of stress such as drug reinstatement in rodents. Astrocytic transporters eliminates excess glutamate (GLU) from extracellular space (ECS) to maintain GLU balance, and dysfunction in astrocytes may contribute to behavioral deficits by inducing GLU excitotoxicity. We and others have shown that drug taking is sexually dimorphic, and stress has a major impact on such sex differences. To determine a role of astrocytes on sex differences in stress-induced drug taking, we first examined sex differences in GLU elimination in the nucleus accumbens (NAc), a brain area associated with drug reinforcement. Methods: Adult male and female Long-Evans rats were randomly assigned to a 21-day chronic social defeat stress (CSDS) or non-CSDS groups. GLU accumulation in the ECS was determined in the NAc as well as its astrocytic product glutamine (GLN), using a no-net flux in vivo microdialysis. Protein levels and immunoreactivity of GFAP and GLT-1, two astrocytic markers, were quantified in the NAc and prefrontal cortex (PFC). Results: CSDS accumulated GLU in the NAc more in females (n = 7) than in males (n = 4) (regression analysis, p < 0.05). Moreover, CSDS disrupted a correlation of extracellular GLU and GLN in males that was associated with decreased GFAP protein level and cell density (n = 6). In females, however, while CSDS decreased GFAP (n = 6), it did not alter the GLU-GLN cycle. In the PFC, a major glutamatergic afferent to the NAc, CSDS produced a statistical sex difference in protein levels of GFAP (n = 6/group) (t Test, p < 0.05). CSDS did not affect GLT-1 protein levels in NAc or PFC in both sexes (n = 6/group). Conclusions: These observations indicate that effects of CSDS on glutamate elimination may be sexually dimorphic, possibly due to astrocytes. Financial support: G12MD00758/U54MD007593/ G12MD007586/U54CA163069/R24DA036420/S10RR0254970/ DA035499/DA007606. http://dx.doi.org/10.1016/j.drugalcdep.2016.08.477

1 Department of Psychology and Neuroscience, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States 2 Neuroimaging Research Branch, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, United States

Aims: Distress tolerance (DT), defined as the ability to persist in goal directed behavior while experiencing affective distress, is implicated in the development and maintenance of substance use disorders. While theory and evidence indicate that cortico-limbic neural dysfunction may account for deficits in distress tolerance, the neurobiological mechanisms of DT have yet to be examined. Methods: We modified a computerized DT task for use in functional magnetic resonance imaging (fMRI), the Paced Auditory Serial Addition Task (PASAT-M), and examined the neural correlates and functional connectivity of DT among a cohort of substance users (n = 21; regular cocaine and nicotine users) and healthy controls (n = 25). Results: Findings indicate deactivation and activation of corticolimbic structures in response to distress during the PASAT-M. Greater activation in a priori network ROIs, namely the right insula, anterior cingulate cortex (ACC), bilateral medial frontal gyrus (MFG), right inferior frontal gyrus (IFG), and right ventromedial prefrontal cortex (vmPFC) significantly predicted higher DT among substance users, but not healthy controls. In addition, greater taskspecific functional connectivity during distress between the right MFG and bilateral vmPFC/sgACC was associated with higher DT among substance users, but not healthy controls. Conclusions: The observed positive relationship between DT and neural activation in cortico-limbic structures, as well as functional connectivity between the rMFG and vmPFC/sgACC is in line with theory and research suggesting the importance of these structures for persisting in goal directed behavior while experiencing affective distress. Financial support: R21 DA02922, NIDA Intramural Research Program (IRP). http://dx.doi.org/10.1016/j.drugalcdep.2016.08.478 The “little brain” steps up: Cerebellar activity during successful inhibition predicts treatment outcome in cocaine patients Paul S. Regier ∗ , K. Jagannathan, Jesse Suh, Marina Goldman, Kyle Matthew Kampman, Teresa Franklin, Charles P. O’Brien, Anna Rose Childress Psychiatry, University of Pennsylvania, Philadelphia, PA, United States Aims: People with addiction face serious challenges when trying to regulate drug use. Research suggests that deficits in pre-frontal cortical regions may allow more “automation” behavior, helping to explain the high rates of relapse. Despite compromised pre-frontal cortex function, some individuals with addiction achieve abstinence. One intriguing possibility is that the cerebellum acts as a