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Glucocorticoid–endocannabinoid interactions in the prelimbic cortex mediate stress-potentiated reinstatement of cocaine seeking
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Abstracts / Drug and Alcohol Dependence 146 (2015) e34–e117
(AUC = .81); drugs (illicit or prescription) 84% and 89% (AUC = .86). Sensitivity was lower for prescription drugs (57%) than for illicit drugs (78%). For detecting a substance use disorder, sensitivity and specificity were: tobacco 100% and 73% (AUC = .87); alcohol 93% and 64% (AUC = .79); drugs 85% and 82% (AUC = .84). Conclusions: The SUBS accurately identified unhealthy tobacco, alcohol, and drug use in this primary care sample, and had high sensitivity but lower specificity for identifying substance use disorders. Individuals screening positive on the SUBS should receive further assessment. Our findings support use of the SUBS for substance use screening in primary care, but additional tools may be needed for prescription drugs. Financial support: NIDA K23 DA030395 NIH/NCATS UL1 TR000038. http://dx.doi.org/10.1016/j.drugalcdep.2014.09.468 Osmotic-release methylphenidate randomized controlled trial for adolescents with attention-deficit/hyperactivity disorders and substance use disorders: A missing data sensitivity analysis Sterling McPherson, Mary Rose Mamey, Celestina Barbosa-Leiker, Sean M. Murphy, John Roll Washington State University, Spokane, WA, United States Aims: To examine sensitivity to missing data procedures on treatment effects in a randomized controlled trial (RCT) of osmoticrelease methylphenidate (OROS) for adolescents with co-occurring attention-deficit/hyperactivity disorder (ADHD) and substance use disorders (SUD). Methods: Data came from a National Drug Abuse Treatment Clinical Trials Network study (N = 303, Riggs et al., 2011), which evaluated the safety/efficacy of a 16-week RCT of OROS vs. placebo in adolescents (aged 13-18) with ADHD who were also receiving cognitive behavioral therapy for their SUD. The two primary outcomes were clinician-reported ADHD symptoms and self-reported past 28 days of substance use (SU). We fit a parallel growth model and assessed the effect sizes assuming missing at random (MAR) compared to two missing not at random (MNAR) models; Diggle–Kenward (DK) selection model and Wu–Carroll (WC) selection model. Results: Our MAR model found no significant treatment effect on ADHD or SU, and the effect sizes were small for both ADHD and SU (d = 0.16, 0.10, respectively). The MNAR DK model also produced non-significant treatment effects with similar effect sizes of ADHD (d = 0.03) and SU (d = 0.11). The MNAR WC model evidenced a significant effect of OROS relative to placebo on SU, and the effect sizes for both ADHD (d = 2.11) and SU (d = 1.09) were larger than reported in the other models. Conclusions: While the MAR model and one MNAR model found similarly sized effects as the original RCT, the second MNAR model produced different results for both of the outcomes. This sensitivity analysis highlights an important need for future RCTs of co-morbid mental illness and SUDs to carefully evaluate the missing data assumptions made when assessing treatment effects. Financial support: Life Science Discovery Fund (Roll, PI), NIDA Clinical Trials Network Pacific Northwest Node (5 U10 DA01371410; Donovan and Roll, Co-PIs), Pilot Study Support Program at the Center for Advancing Longitudinal Drug Abuse Research (CALDAR; P30DA016383; McPherson, PI). http://dx.doi.org/10.1016/j.drugalcdep.2014.09.469
Glucocorticoid–endocannabinoid interactions in the prelimbic cortex mediate stress-potentiated reinstatement of cocaine seeking Jayme R. McReynolds 1 , Oliver Vranjkovic 1 , Evan N. Graf 1 , Cecilia J. Hillard 2 , John R. Mantsch 1 1 Biomedical Sciences, Marquette University, Milwaukee, WI, United States 2 Pharmacology & Toxicology, Medical College of Wisconsin, Milwaukee, WI, United States
Aims: Under certain self-administration conditions, stress alone does not reinstate cocaine seeking. However, stress, such as electric footshock stress (EFS), can potentiate reinstatement when paired with a low dose of cocaine and this effect is corticosteronedependent. Corticosterone (CORT) may exert its action through an interaction with the endocannbinoid (eCB) system as cannabinoid receptor 1 (CB1R) dependent effects on neurotransmission in the medial prefrontal cortex, a region that is critical for reinstatement, are dependent upon glucocorticoids. The current study examined the involvement of the CB1R, specifically in the prelimbic cortex (PLC), in stress-potentiated reinstatement of cocaine seeking. Methods: Male Sprague–Dawley rats self-administered cocaine (0.5 mg/kg/inf) 14 × 2 h/day on a FR4 schedule. Rats underwent extinction followed by stress-potentiated reinstatement tests, EFS + low dose cocaine (2.5 mg/kg i.p.). To test the involvement of the PLC, rats were given an intra-PLC infusion of CORT (0.05 ffJg/.03 ffJL) instead of EFS 15 min prior to the low dose cocaine injection. To test the involvement of CB1R, rats were given a systemic injection of the CB1R antagonist, AM251 (0, 1, 3 mg/kg i.p.) 30 min prior or an intra- PLC infusion of AM251 (0, 0.3 ffJg/0.3 ffJL) 15 min prior to EFS. Results: EFS paired with a low dose of cocaine-induced reinstatement of cocaine seeking whereas either given alone did not. This effect was mimicked when intra-PLC infusions of CORT were paired with low dose cocaine suggesting CORT actions in the PLC mediate stress-potentiated reinstatement. Systemic AM251 blocked stress-potentiated reinstatement. Furthermore, preliminary data suggests that intra-PLC AM251 also blocks stresspotentiated reinstatement. Conclusions: Taken together, these data suggest that corticosterone actions in the PLC, likely through an interaction with the eCB system, mediate stress-potentiated reinstatement. Financial support: NIH grant DA015758 to John Mantsch. http://dx.doi.org/10.1016/j.drugalcdep.2014.09.470 Transitions in polydrug use among heroin and methamphetamine injectors in Tijuana, Mexico Meredith C. Meacham 1,2 , Karla D. Wagner 1 , Timothy Mackey 1 , T.L. Patterson 1 , Steffanie Strathdee 1 , Scott Roesch 2 1
University of California, San Diego, La Jolla, CA, United States 2 San Diego State University, San Diego, CA, United States Aims: Although most people who inject drugs (PWID) in Tijuana primarily inject heroin, use of methamphetamine and co-injection of meth and heroin is also common. We examined patterns and transitions in polydrug use to inform prevention and treatment of drug use and its health and social consequences. Methods: PWID residing in Tijuana aged ≥ 18 years were recruited through respondent driven sampling from 2006 to
Abstracts / Drug and Alcohol Dependence 146 (2015) e34–e117
(AUC = .81); drugs (illicit or prescription) 84% and 89% (AUC = .86). Sensitivity was lower for prescription drugs (57%) than for illicit drugs (78%). For detecting a substance use disorder, sensitivity and specificity were: tobacco 100% and 73% (AUC = .87); alcohol 93% and 64% (AUC = .79); drugs 85% and 82% (AUC = .84). Conclusions: The SUBS accurately identified unhealthy tobacco, alcohol, and drug use in this primary care sample, and had high sensitivity but lower specificity for identifying substance use disorders. Individuals screening positive on the SUBS should receive further assessment. Our findings support use of the SUBS for substance use screening in primary care, but additional tools may be needed for prescription drugs. Financial support: NIDA K23 DA030395 NIH/NCATS UL1 TR000038. http://dx.doi.org/10.1016/j.drugalcdep.2014.09.468 Osmotic-release methylphenidate randomized controlled trial for adolescents with attention-deficit/hyperactivity disorders and substance use disorders: A missing data sensitivity analysis Sterling McPherson, Mary Rose Mamey, Celestina Barbosa-Leiker, Sean M. Murphy, John Roll Washington State University, Spokane, WA, United States Aims: To examine sensitivity to missing data procedures on treatment effects in a randomized controlled trial (RCT) of osmoticrelease methylphenidate (OROS) for adolescents with co-occurring attention-deficit/hyperactivity disorder (ADHD) and substance use disorders (SUD). Methods: Data came from a National Drug Abuse Treatment Clinical Trials Network study (N = 303, Riggs et al., 2011), which evaluated the safety/efficacy of a 16-week RCT of OROS vs. placebo in adolescents (aged 13-18) with ADHD who were also receiving cognitive behavioral therapy for their SUD. The two primary outcomes were clinician-reported ADHD symptoms and self-reported past 28 days of substance use (SU). We fit a parallel growth model and assessed the effect sizes assuming missing at random (MAR) compared to two missing not at random (MNAR) models; Diggle–Kenward (DK) selection model and Wu–Carroll (WC) selection model. Results: Our MAR model found no significant treatment effect on ADHD or SU, and the effect sizes were small for both ADHD and SU (d = 0.16, 0.10, respectively). The MNAR DK model also produced non-significant treatment effects with similar effect sizes of ADHD (d = 0.03) and SU (d = 0.11). The MNAR WC model evidenced a significant effect of OROS relative to placebo on SU, and the effect sizes for both ADHD (d = 2.11) and SU (d = 1.09) were larger than reported in the other models. Conclusions: While the MAR model and one MNAR model found similarly sized effects as the original RCT, the second MNAR model produced different results for both of the outcomes. This sensitivity analysis highlights an important need for future RCTs of co-morbid mental illness and SUDs to carefully evaluate the missing data assumptions made when assessing treatment effects. Financial support: Life Science Discovery Fund (Roll, PI), NIDA Clinical Trials Network Pacific Northwest Node (5 U10 DA01371410; Donovan and Roll, Co-PIs), Pilot Study Support Program at the Center for Advancing Longitudinal Drug Abuse Research (CALDAR; P30DA016383; McPherson, PI). http://dx.doi.org/10.1016/j.drugalcdep.2014.09.469
Glucocorticoid–endocannabinoid interactions in the prelimbic cortex mediate stress-potentiated reinstatement of cocaine seeking Jayme R. McReynolds 1 , Oliver Vranjkovic 1 , Evan N. Graf 1 , Cecilia J. Hillard 2 , John R. Mantsch 1 1 Biomedical Sciences, Marquette University, Milwaukee, WI, United States 2 Pharmacology & Toxicology, Medical College of Wisconsin, Milwaukee, WI, United States
Aims: Under certain self-administration conditions, stress alone does not reinstate cocaine seeking. However, stress, such as electric footshock stress (EFS), can potentiate reinstatement when paired with a low dose of cocaine and this effect is corticosteronedependent. Corticosterone (CORT) may exert its action through an interaction with the endocannbinoid (eCB) system as cannabinoid receptor 1 (CB1R) dependent effects on neurotransmission in the medial prefrontal cortex, a region that is critical for reinstatement, are dependent upon glucocorticoids. The current study examined the involvement of the CB1R, specifically in the prelimbic cortex (PLC), in stress-potentiated reinstatement of cocaine seeking. Methods: Male Sprague–Dawley rats self-administered cocaine (0.5 mg/kg/inf) 14 × 2 h/day on a FR4 schedule. Rats underwent extinction followed by stress-potentiated reinstatement tests, EFS + low dose cocaine (2.5 mg/kg i.p.). To test the involvement of the PLC, rats were given an intra-PLC infusion of CORT (0.05 ffJg/.03 ffJL) instead of EFS 15 min prior to the low dose cocaine injection. To test the involvement of CB1R, rats were given a systemic injection of the CB1R antagonist, AM251 (0, 1, 3 mg/kg i.p.) 30 min prior or an intra- PLC infusion of AM251 (0, 0.3 ffJg/0.3 ffJL) 15 min prior to EFS. Results: EFS paired with a low dose of cocaine-induced reinstatement of cocaine seeking whereas either given alone did not. This effect was mimicked when intra-PLC infusions of CORT were paired with low dose cocaine suggesting CORT actions in the PLC mediate stress-potentiated reinstatement. Systemic AM251 blocked stress-potentiated reinstatement. Furthermore, preliminary data suggests that intra-PLC AM251 also blocks stresspotentiated reinstatement. Conclusions: Taken together, these data suggest that corticosterone actions in the PLC, likely through an interaction with the eCB system, mediate stress-potentiated reinstatement. Financial support: NIH grant DA015758 to John Mantsch. http://dx.doi.org/10.1016/j.drugalcdep.2014.09.470 Transitions in polydrug use among heroin and methamphetamine injectors in Tijuana, Mexico Meredith C. Meacham 1,2 , Karla D. Wagner 1 , Timothy Mackey 1 , T.L. Patterson 1 , Steffanie Strathdee 1 , Scott Roesch 2 1
University of California, San Diego, La Jolla, CA, United States 2 San Diego State University, San Diego, CA, United States Aims: Although most people who inject drugs (PWID) in Tijuana primarily inject heroin, use of methamphetamine and co-injection of meth and heroin is also common. We examined patterns and transitions in polydrug use to inform prevention and treatment of drug use and its health and social consequences. Methods: PWID residing in Tijuana aged ≥ 18 years were recruited through respondent driven sampling from 2006 to