- Email: [email protected]
hyperactivity-disorder individuals treated with extended-release mixed amphetamine salts
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Abstract / Drug and Alcohol Dependence 156 (2015) e183–e245
Scientific writing seminar to help early-stage investigators publish research James Sorensen ∗ , Carmen L. Masson, Annesa Flentje, Michael Shopshire, Joseph Guydish Department of Psychiatry, University of California, San Francisco, San Francisco, CA, United States Aims: In the addictions field there is insufficient information on how to increase the writing productivity of early-stage investigators. Possible ways to increase productivity range from brief “check ins” (Edwards, 2002) to classes and formal writing groups (Gianaros, 2006). We found no published studies addressing this issue; thus we aimed to fill a knowledge gap by reporting outcomes of a scientific writing seminar for postdoctoral fellows offered over 14 years. Methods: 113 postdoctoral trainees participated in 14 cohorts of the writing workshop conducted from 1999 to 2012. Ongoing records of submission and publication rates were analyzed. The writing seminar, called the Writers’ Task Force, occurred annually in 10 sessions over five months. Offered through NIDA training and center grants, the focus was on drug abuse treatment and services research. The initial meeting framed expectations, modeled the review process used in the seminar, and had fellows commit to writing and reviewing their work in future sessions. Remaining meetings focused on fellows’ manuscripts, with copies distributed a week before, author presentation of issues, three critiques by colleagues, and discussion. The seminar sometimes included presentations on writing/publishing topics but emphasized the active processes of writing and review. Results: Of the 113 participants, 98 (87%) submitted a manuscript for publication, and 88 participants (78%) published their manuscript. Mean time to publication after the end of the writing seminar was 2.68 years (SD = 1.49), and the median time to publication was 2 years. Conclusions: In this evaluation there was no control group, and the submission and publication rates of these papers without the seminar is unknown. A scientific writing seminar may benefit writing productivity; more research is needed to compare this training model to other approaches. Financial Support: NIH P50DA09253, T32DA07250, U10DA015815, P50DA09253, R25DA035163. http://dx.doi.org/10.1016/j.drugalcdep.2015.07.560 Disruption of serotonin 5-HT2c receptor (5-HT2c R) interaction with protein phosphatase and tensin homologue (PTEN) results in distinct patterns of cortical phosphorylated extracellular-signal regulated kinase1/2 (pERK1/2 ) Claudia Soto 1,∗ , Noelle C. Anastasio 1 , Sarah E. Swinford-Jackson 1 , Robert G. Fox 1 , Huang C. Du 2 , Scott Gilbertson 2 , Kathryn A. Cunningham 1 1 Ctr Addiction Res, University of Texas Medical Branch, Galveston, TX, United States 2 Dep Chem, University of Houston, Houston, TX, United States
Aims: The 5-HT2C R in the medial prefrontal cortex (mPFC) mediates relapse vulnerability in preclinical studies of cocaine use disorder. The mechanisms through which the 5-HT2C R modulates mPFC signaling are understudied. The 5-HT2C R interacts with Gaq/11 leading to nuclear pERK1/2 translocation and also directly associates with -arrestin2 resulting in cytoplasmic pERK1/2 sequestration.
pERK1/2 subcellular localization dictates its functional impact on signal transduction. Protein:protein interactions emerge as a mechanism to shift 5-HT2C R signal transduction towards a given pathway and thereby regulate pERK1/2 subcellular distribution. Disruption of 5-HT2C R:PTEN by TAT-3L4F potentiates 5-HT2C R agonist-induced pERK1/2 in vitro. We tested the hypothesis that 5HT2C R stimulation and/or disruption of 5-HT2C R:PTEN results in distinct mPFC pERK1/2 subcellular distribution. Methods: Male Sprague-Dawley rats received saline, 5-HT2C R agonist WAY163909 (1 mg/kg), TAT-3L4F (10 mol/kg), or the combination of WAY163909 plus TAT-3L4F. The mPFC tissue was harvested (20 min post-treatment) and nuclear and cytoplasmic pERK1/2 levels evaluated by immunoblotting. Results: WAY163909 increased nuclear and cytoplasmic pERK1/2 vs saline (p < 0.05). TAT-3L4F increased cytoplasmic (p < 0.05), but not nuclear pERK1/2 . WAY163909 plus TAT-3L4F increased cytoplasmic (p < 0.05), but not nuclear, pERK1/2 . Conclusions: TAT-3L4F may sequester pERK1/2 in the cytoplasm through a ® arrestin2 -dependent mechanism while WAY163909 induces a distinct mPFC pERK1/2 subcellular distribution. These data also suggest that disruption of 5-HT2C R:PTEN may alter WAY163909-induced intracellular signaling pathways (i.e., shift in pERK1/2 from the nuclear to soluble fraction). Taken together, these data provide novel insight into the mechanisms through which 5-HT2C R modulates signaling in the mPFC. Financial Support: DA030977, DA020087, DA033374, DA0728. http://dx.doi.org/10.1016/j.drugalcdep.2015.07.561 Cigarette smoking trajectories among comorbid cocaine-dependent and attention deficit/hyperactivity-disorder individuals treated with extended-release mixed amphetamine salts Brian Sou 1,∗ , Andrew Glass 2 , Daniel J. Brooks 3 , Amy Mahony 3 , John J. Mariani 3 , John Grabowski 4 , Frances R. Levin 3 1 The Sophie Davis School of Biomedical Education, New York, NY, United States 2 Biostatistics, New York State Psychiatric Institute, New York, NY, United States 3 New York State Psychiatric Institute, New York, NY, United States 4 Psychiatry, University of Minnesota, New York, NY, United States
Aims: To determine whether cocaine use correlates with nicotine use in ADHD/cocaine dependent individuals, and to examine the effects of MAS-XR on smoking in this population. Methods: The original randomized, double-blind, 14-week placebo controlled trial was conducted at Columbia University and at the University of Minnesota. This secondary analysis targeted treatment seeking adults who met DSM-IV criteria for ADHD, used cocaine ≥4 times in the past month at consent, and were cigarette smokers (≥1 cigarette per day; ≥4 days per week). Participants were randomly assigned to MAS-XR (80 mg), MAS-XR (60 mg), or placebo (n = 37). This analysis combined the two active treatment arms (n = 61). Cigarette smoking was assessed via self-report. Linear mixed effects models were used to model cigarette smoking as a function of cocaine use and treatment interaction. Results: The correlation between cocaine use and smoking was significant for both the MAS-XR group and the placebo group (p < 0.0001). Patients smoked 1.3 more cigarettes on cocaine-using days when compared to non-cocaine using days. There was a significant interaction between treatment and placebo groups for
Abstract / Drug and Alcohol Dependence 156 (2015) e183–e245
the amount spent on cocaine as a predictor of smoking (p = 0.01). Specifically, patients receiving MAS-XR spent $43 more on cocaine to increase their smoking by 1 cigarette, while patients receiving placebo spent $56 more on cocaine for the same result. Conclusions: Cocaine use correlates with smoking habits in both MAS-XR and placebo treated patients. For those who continue to use cocaine, MAS-XR with concurrent cocaine use may trigger greater smoking among ADHD/cocaine dependent smokers when compared to the placebo group. Financial Support: NIDA:1R25DA03516101 RFMH:1RO1DA23652/RO1DA23651. http://dx.doi.org/10.1016/j.drugalcdep.2015.07.562 Modulation of reinstated polydrug (cocaine/heroin) seeking by noradrenergic ␣2 agonists Roger D. Spealman 1,∗ , Jack Bergman 2 1
New England Primate Research Center, Harvard Medical School, Southborough, MA, United States 2 McLean Hospital, Harvard Medical School, Belmont, MA, United States Aims: Noradrenergic ␣2 agonists can alleviate opioid withdrawal and have been proposed for prevention of relapse to stimulant abuse. We investigated the potential of these drugs for attenuating relapse to polydrug (cocaine/heroin) abuse using a nonhuman primate model of reinstated drug seeking. Methods: Squirrel monkeys were trained to respond under concurrent second-order FR10 (FR5:S) schedules of i.v. cocaine/heroin (10:1) self-administration and milk delivery. Responding on the drug-associated lever subsequently was reduced to <10% of baseline by discontinuing drug injections and presentations of the drug-paired stimulus, while keeping the concurrent schedule of milk delivery intact. We next determined the degree to which drug seeking could be reinstated by: (1) restoring the drug-paired stimulus, (2) priming with a 10:1 cocaine/heroin mixture, or (3) priming + restoration of the drug-paired stimulus. Each condition was studied after pretreatment with vehicle or doses of ␣2 agonists that had no significant effects on an inventory of unconditioned behaviors: 0.1 mg/kg clonidine, 0.1 mg/kg lofexidine, 1.0 mg/kg guanfacine, and 0.03 mg/kg brimonidine. Results: Pretreatment with each ␣2 agonist attenuated reinstatement of drug-seeking induced by cocaine/heroin priming and had less effect on reinstatement induced by the drug-paired stimulus. Clonidine, lofexidine, and guanfacine also attenuated the more pronounced reinstatement induced by priming + restoration of the drug-paired stimulus. Additionally, clonidine and lofexidine reduced % responding on the drug-associated lever when reinstatement was induced by priming alone and/or priming + restoration of the drug-paired stimulus. Conclusions: The profile of effects seen with clonidine and lofexidine (attenuation of reinstated responding with a reduction in % responding on drug lever) suggests a selective effect of these ␣2 agonists on reinstated drug seeking and encourages further evaluation of their potential for polydrug relapse prevention. Financial Support: NIH grants DA031299, RR00168 and OD011103. http://dx.doi.org/10.1016/j.drugalcdep.2015.07.563
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Applying SBIRT to new settings: Preliminary findings of substance use disorder risk in community mental health settings Suzanne E. Spear 2,∗ , Mitch Karno 3 , Suzette Glasner-Edwards 3 , R. Rawson 3 , Richard Saitz 1 , Blanca Dominguez 3 1 Community Health Sciences, Boston University and Boston Medical Center, Boston, MA, United States 2 Health Sciences, California State University, Northridge, Northridge, CA, United States 3 Psychiatry, UCLA Integrated Substance Abuse Programs, Los Angeles, CA, United States
Aims: Screening, Brief Intervention, and Referral to Treatment (SBIRT) has not yet been tested in community mental health treatment settings despite the elevated risk of substance use disorders (SUD) among individuals with mental health disorders. This presentation reports on preliminary findings of SUD risk among 334 adult participants treated in community mental health clinics in Southern California. SUD risk was calculated from the AUDIT and DAST-10 screening tools. Methods: All participants are currently enrolled in a randomized controlled trial of SBIRT. Participants were recruited from four outpatient clinics and one inpatient clinic. High risk for SUDs was defined by scores on the AUDIT (≥13 for women and ≥15 for men) and the DAST-10 (≥3 for women and men). Associations between SUD risk and presence of mood disorders, anxiety disorders, and psychotic disorders were examined using chi-square tests. Results: Results showed that 37% of participants were at high risk for alcohol disorders and 66% of participants were at high risk for illicit drug use disorders. Alcohol disorder risk was significantly associated with mood disorders (2 = 13.25, p < .01) and anxiety disorders (2 = 8.6, p < .05). Illicit drug use disorder risk was significantly associated with anxiety disorders (2 = 25.96, p < .001). Presence of psychotic disorders was not associated with SUD risk. Conclusions: High rates of SUD risk in this community mental health sample were found. Participants with mood and/or anxiety disorders were found to be at high risk of SUDs. Subsequent research will test the efficacy of SBIRT for reducing SUD risk and linking participants with possible SUDs to treatment. Financial Support: Supported by NIDA grant R01DA032733. http://dx.doi.org/10.1016/j.drugalcdep.2015.07.564 Prescription monitoring programs: Best practice and Canadian program review Beth Sproule 1,2 1
Centre for Addiction and Mental Health, Toronto, ON, Canada 2 University of Toronto, Toronto, ON, Canada Aims: Prescription monitoring programs (PMPs) are one important component of an overall strategy in addressing prescription drug abuse. The objectives of this review were to examine research evidence to support best practices in PMPs and to review PMPs in Canada. Methods: As an update to a previous review, a search from 2012 to May 2014 was conducted using PubMed, PsycINFO, Project Cork and Google Scholar to identify articles about the effectiveness of PMPs. Search terms included: prescription drug monitoring, prescription monitoring, doctor shopping, multiple prescribers, unsolicited reporting, proactive reporting and controlled substance monitoring. Grey literature sources included individual PMP websites, PMP organization websites and Google. Information on the
Abstract / Drug and Alcohol Dependence 156 (2015) e183–e245
Scientific writing seminar to help early-stage investigators publish research James Sorensen ∗ , Carmen L. Masson, Annesa Flentje, Michael Shopshire, Joseph Guydish Department of Psychiatry, University of California, San Francisco, San Francisco, CA, United States Aims: In the addictions field there is insufficient information on how to increase the writing productivity of early-stage investigators. Possible ways to increase productivity range from brief “check ins” (Edwards, 2002) to classes and formal writing groups (Gianaros, 2006). We found no published studies addressing this issue; thus we aimed to fill a knowledge gap by reporting outcomes of a scientific writing seminar for postdoctoral fellows offered over 14 years. Methods: 113 postdoctoral trainees participated in 14 cohorts of the writing workshop conducted from 1999 to 2012. Ongoing records of submission and publication rates were analyzed. The writing seminar, called the Writers’ Task Force, occurred annually in 10 sessions over five months. Offered through NIDA training and center grants, the focus was on drug abuse treatment and services research. The initial meeting framed expectations, modeled the review process used in the seminar, and had fellows commit to writing and reviewing their work in future sessions. Remaining meetings focused on fellows’ manuscripts, with copies distributed a week before, author presentation of issues, three critiques by colleagues, and discussion. The seminar sometimes included presentations on writing/publishing topics but emphasized the active processes of writing and review. Results: Of the 113 participants, 98 (87%) submitted a manuscript for publication, and 88 participants (78%) published their manuscript. Mean time to publication after the end of the writing seminar was 2.68 years (SD = 1.49), and the median time to publication was 2 years. Conclusions: In this evaluation there was no control group, and the submission and publication rates of these papers without the seminar is unknown. A scientific writing seminar may benefit writing productivity; more research is needed to compare this training model to other approaches. Financial Support: NIH P50DA09253, T32DA07250, U10DA015815, P50DA09253, R25DA035163. http://dx.doi.org/10.1016/j.drugalcdep.2015.07.560 Disruption of serotonin 5-HT2c receptor (5-HT2c R) interaction with protein phosphatase and tensin homologue (PTEN) results in distinct patterns of cortical phosphorylated extracellular-signal regulated kinase1/2 (pERK1/2 ) Claudia Soto 1,∗ , Noelle C. Anastasio 1 , Sarah E. Swinford-Jackson 1 , Robert G. Fox 1 , Huang C. Du 2 , Scott Gilbertson 2 , Kathryn A. Cunningham 1 1 Ctr Addiction Res, University of Texas Medical Branch, Galveston, TX, United States 2 Dep Chem, University of Houston, Houston, TX, United States
Aims: The 5-HT2C R in the medial prefrontal cortex (mPFC) mediates relapse vulnerability in preclinical studies of cocaine use disorder. The mechanisms through which the 5-HT2C R modulates mPFC signaling are understudied. The 5-HT2C R interacts with Gaq/11 leading to nuclear pERK1/2 translocation and also directly associates with -arrestin2 resulting in cytoplasmic pERK1/2 sequestration.
pERK1/2 subcellular localization dictates its functional impact on signal transduction. Protein:protein interactions emerge as a mechanism to shift 5-HT2C R signal transduction towards a given pathway and thereby regulate pERK1/2 subcellular distribution. Disruption of 5-HT2C R:PTEN by TAT-3L4F potentiates 5-HT2C R agonist-induced pERK1/2 in vitro. We tested the hypothesis that 5HT2C R stimulation and/or disruption of 5-HT2C R:PTEN results in distinct mPFC pERK1/2 subcellular distribution. Methods: Male Sprague-Dawley rats received saline, 5-HT2C R agonist WAY163909 (1 mg/kg), TAT-3L4F (10 mol/kg), or the combination of WAY163909 plus TAT-3L4F. The mPFC tissue was harvested (20 min post-treatment) and nuclear and cytoplasmic pERK1/2 levels evaluated by immunoblotting. Results: WAY163909 increased nuclear and cytoplasmic pERK1/2 vs saline (p < 0.05). TAT-3L4F increased cytoplasmic (p < 0.05), but not nuclear pERK1/2 . WAY163909 plus TAT-3L4F increased cytoplasmic (p < 0.05), but not nuclear, pERK1/2 . Conclusions: TAT-3L4F may sequester pERK1/2 in the cytoplasm through a ® arrestin2 -dependent mechanism while WAY163909 induces a distinct mPFC pERK1/2 subcellular distribution. These data also suggest that disruption of 5-HT2C R:PTEN may alter WAY163909-induced intracellular signaling pathways (i.e., shift in pERK1/2 from the nuclear to soluble fraction). Taken together, these data provide novel insight into the mechanisms through which 5-HT2C R modulates signaling in the mPFC. Financial Support: DA030977, DA020087, DA033374, DA0728. http://dx.doi.org/10.1016/j.drugalcdep.2015.07.561 Cigarette smoking trajectories among comorbid cocaine-dependent and attention deficit/hyperactivity-disorder individuals treated with extended-release mixed amphetamine salts Brian Sou 1,∗ , Andrew Glass 2 , Daniel J. Brooks 3 , Amy Mahony 3 , John J. Mariani 3 , John Grabowski 4 , Frances R. Levin 3 1 The Sophie Davis School of Biomedical Education, New York, NY, United States 2 Biostatistics, New York State Psychiatric Institute, New York, NY, United States 3 New York State Psychiatric Institute, New York, NY, United States 4 Psychiatry, University of Minnesota, New York, NY, United States
Aims: To determine whether cocaine use correlates with nicotine use in ADHD/cocaine dependent individuals, and to examine the effects of MAS-XR on smoking in this population. Methods: The original randomized, double-blind, 14-week placebo controlled trial was conducted at Columbia University and at the University of Minnesota. This secondary analysis targeted treatment seeking adults who met DSM-IV criteria for ADHD, used cocaine ≥4 times in the past month at consent, and were cigarette smokers (≥1 cigarette per day; ≥4 days per week). Participants were randomly assigned to MAS-XR (80 mg), MAS-XR (60 mg), or placebo (n = 37). This analysis combined the two active treatment arms (n = 61). Cigarette smoking was assessed via self-report. Linear mixed effects models were used to model cigarette smoking as a function of cocaine use and treatment interaction. Results: The correlation between cocaine use and smoking was significant for both the MAS-XR group and the placebo group (p < 0.0001). Patients smoked 1.3 more cigarettes on cocaine-using days when compared to non-cocaine using days. There was a significant interaction between treatment and placebo groups for
Abstract / Drug and Alcohol Dependence 156 (2015) e183–e245
the amount spent on cocaine as a predictor of smoking (p = 0.01). Specifically, patients receiving MAS-XR spent $43 more on cocaine to increase their smoking by 1 cigarette, while patients receiving placebo spent $56 more on cocaine for the same result. Conclusions: Cocaine use correlates with smoking habits in both MAS-XR and placebo treated patients. For those who continue to use cocaine, MAS-XR with concurrent cocaine use may trigger greater smoking among ADHD/cocaine dependent smokers when compared to the placebo group. Financial Support: NIDA:1R25DA03516101 RFMH:1RO1DA23652/RO1DA23651. http://dx.doi.org/10.1016/j.drugalcdep.2015.07.562 Modulation of reinstated polydrug (cocaine/heroin) seeking by noradrenergic ␣2 agonists Roger D. Spealman 1,∗ , Jack Bergman 2 1
New England Primate Research Center, Harvard Medical School, Southborough, MA, United States 2 McLean Hospital, Harvard Medical School, Belmont, MA, United States Aims: Noradrenergic ␣2 agonists can alleviate opioid withdrawal and have been proposed for prevention of relapse to stimulant abuse. We investigated the potential of these drugs for attenuating relapse to polydrug (cocaine/heroin) abuse using a nonhuman primate model of reinstated drug seeking. Methods: Squirrel monkeys were trained to respond under concurrent second-order FR10 (FR5:S) schedules of i.v. cocaine/heroin (10:1) self-administration and milk delivery. Responding on the drug-associated lever subsequently was reduced to <10% of baseline by discontinuing drug injections and presentations of the drug-paired stimulus, while keeping the concurrent schedule of milk delivery intact. We next determined the degree to which drug seeking could be reinstated by: (1) restoring the drug-paired stimulus, (2) priming with a 10:1 cocaine/heroin mixture, or (3) priming + restoration of the drug-paired stimulus. Each condition was studied after pretreatment with vehicle or doses of ␣2 agonists that had no significant effects on an inventory of unconditioned behaviors: 0.1 mg/kg clonidine, 0.1 mg/kg lofexidine, 1.0 mg/kg guanfacine, and 0.03 mg/kg brimonidine. Results: Pretreatment with each ␣2 agonist attenuated reinstatement of drug-seeking induced by cocaine/heroin priming and had less effect on reinstatement induced by the drug-paired stimulus. Clonidine, lofexidine, and guanfacine also attenuated the more pronounced reinstatement induced by priming + restoration of the drug-paired stimulus. Additionally, clonidine and lofexidine reduced % responding on the drug-associated lever when reinstatement was induced by priming alone and/or priming + restoration of the drug-paired stimulus. Conclusions: The profile of effects seen with clonidine and lofexidine (attenuation of reinstated responding with a reduction in % responding on drug lever) suggests a selective effect of these ␣2 agonists on reinstated drug seeking and encourages further evaluation of their potential for polydrug relapse prevention. Financial Support: NIH grants DA031299, RR00168 and OD011103. http://dx.doi.org/10.1016/j.drugalcdep.2015.07.563
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Applying SBIRT to new settings: Preliminary findings of substance use disorder risk in community mental health settings Suzanne E. Spear 2,∗ , Mitch Karno 3 , Suzette Glasner-Edwards 3 , R. Rawson 3 , Richard Saitz 1 , Blanca Dominguez 3 1 Community Health Sciences, Boston University and Boston Medical Center, Boston, MA, United States 2 Health Sciences, California State University, Northridge, Northridge, CA, United States 3 Psychiatry, UCLA Integrated Substance Abuse Programs, Los Angeles, CA, United States
Aims: Screening, Brief Intervention, and Referral to Treatment (SBIRT) has not yet been tested in community mental health treatment settings despite the elevated risk of substance use disorders (SUD) among individuals with mental health disorders. This presentation reports on preliminary findings of SUD risk among 334 adult participants treated in community mental health clinics in Southern California. SUD risk was calculated from the AUDIT and DAST-10 screening tools. Methods: All participants are currently enrolled in a randomized controlled trial of SBIRT. Participants were recruited from four outpatient clinics and one inpatient clinic. High risk for SUDs was defined by scores on the AUDIT (≥13 for women and ≥15 for men) and the DAST-10 (≥3 for women and men). Associations between SUD risk and presence of mood disorders, anxiety disorders, and psychotic disorders were examined using chi-square tests. Results: Results showed that 37% of participants were at high risk for alcohol disorders and 66% of participants were at high risk for illicit drug use disorders. Alcohol disorder risk was significantly associated with mood disorders (2 = 13.25, p < .01) and anxiety disorders (2 = 8.6, p < .05). Illicit drug use disorder risk was significantly associated with anxiety disorders (2 = 25.96, p < .001). Presence of psychotic disorders was not associated with SUD risk. Conclusions: High rates of SUD risk in this community mental health sample were found. Participants with mood and/or anxiety disorders were found to be at high risk of SUDs. Subsequent research will test the efficacy of SBIRT for reducing SUD risk and linking participants with possible SUDs to treatment. Financial Support: Supported by NIDA grant R01DA032733. http://dx.doi.org/10.1016/j.drugalcdep.2015.07.564 Prescription monitoring programs: Best practice and Canadian program review Beth Sproule 1,2 1
Centre for Addiction and Mental Health, Toronto, ON, Canada 2 University of Toronto, Toronto, ON, Canada Aims: Prescription monitoring programs (PMPs) are one important component of an overall strategy in addressing prescription drug abuse. The objectives of this review were to examine research evidence to support best practices in PMPs and to review PMPs in Canada. Methods: As an update to a previous review, a search from 2012 to May 2014 was conducted using PubMed, PsycINFO, Project Cork and Google Scholar to identify articles about the effectiveness of PMPs. Search terms included: prescription drug monitoring, prescription monitoring, doctor shopping, multiple prescribers, unsolicited reporting, proactive reporting and controlled substance monitoring. Grey literature sources included individual PMP websites, PMP organization websites and Google. Information on the