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Wheel running dose dependently attenuates cocaine-seeking and associated neuroadaptations in the prefrontal cortex
Abstracts / Drug and Alcohol Dependence 140 (2014) e169–e251
Financial support: Funding for this study was provided by NIDA grants R01 DA024104 and DA027748.
Impact of race and age on treatment completion among adult marijuana users
http://dx.doi.org/10.1016/j.drugalcdep.2014.02.490
Erica N. Peters 1,2 , P.S. Hendricks 3 , C.B. Clark 3 , Karen L. Cropsey 3 , F. Vocci 1
Rats that self-administer methamphetamine show parkinson’s disease-like inflammation and ␣-synuclein neuropathology Amanda Persons, Sharanya Kousik, L.P. Kelly, S.M. Graves, T.C. Napier Department of Pharmacology and Center for Compulsive Behavior and Addiction, Rush University Medical Center, Chicago, IL, United States Aims: Abuse of methamphetamine (meth), a potent psychostimulant, appears to increase the risk for developing Parkinson’s disease (PD) (Callaghan et al. Drug Alcohol Depend 120, 2012). This enhanced vulnerability may relate to the known neurotoxic effects of meth via oxidative stress, mitochondrial dysfunction and inflammation (Yamamoto et al. Ann NY Acad Sci 1187, 2010), factors also implicated in PD pathology. However, in vivo studies assessing meth-induced toxicity are largely based on acute, high doses of non-contingently administered meth. It is unknown if similar outcomes occur with meth administration protocols that better emulate human drug-taking, e.g., self-administration. The current study determined if meth self-administering rats exhibited markers of inflammation, i.e., glial fibrillary acidic protein (GFAP; marker of glial cell activation) and tumor necrosis factor-␣ (TNF␣; pro-inflammatory cytokine). To substantiate the concept that meth abuse enhances vulnerability for PD, we assayed the SN for ␣-synuclein, a neuropathological hallmark for PD. Methods: Male Sprague-Dawley rats self-administered meth for 14 days; rats were sacrificed and tissue harvested on day 15. Saline-yoked rats served as controls. Western blotting was used for harvested rostral striatum (rSTR) and substantia nigra (SN), the terminal and cell body regions (respectively) of dopamine neurons most severely affected in PD. Results: Meth self-administration increased GFAP and TNF-␣ levels in the rSTR and SN (p < 0.01). In the SN, ␣-synuclein was also increased in METH-treated rats compared to saline controls (p < 0.0001). Conclusions: These brain changes occur in the absence of any detectable degradation in motor function. These results provide the first evidence for PD-like pathology in meth self-administering rats, and therefore offer insight into mechanisms underlying the enhanced vulnerability of meth abusers to develop PD. Financial support: Daniel F. and Ada L. Rice Fdn and the CCBA at Rush University Medical Center. http://dx.doi.org/10.1016/j.drugalcdep.2014.02.491
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1 Friends Research Institute, Baltimore, MD, United States 2 Yale School of Medicine, New Haven, CT, United States 3 University of Alabama at Birmingham, Birmingham, AL, United States
Aims: The prevalence of marijuana use disorders has increased significantly among African American (A-A) adults in recent years. A-A young adults (aged 18–25) are less likely to complete marijuana treatment than their White counterparts, but it is not clear if these trends extend beyond the young adult years. Methods: This study examines 2 samples of adults receiving community-based outpatient substance abuse treatment and reporting primary marijuana use. Sample #1 (N = 160) was composed of adults in the southeastern US, 70.6% of whom were A-A, with a mean age of 27.9 years. Sample #2 (N = 324) was composed of adults in the US mid-Atlantic region, 38.3% of whom were A-A, with a mean age of 25.0 years. In both samples, treatment completion was defined as regular treatment attendance, sustained negative urine drug screens, participation in 12-step groups, and achievement of individualized treatment goals. Results: In Sample #1, treatment completion was significantly associated with the interaction of race and age (odds ratio [OR] = 1.18, p < .01) such that older age was significantly correlated with completing treatment for A-A (r = .23, p = .02) but not for White adults (p = .28). In Sample #2, treatment completion was significantly associated with age (OR = 0.95, p < .01) such that older adults were less likely to complete treatment, but was not associated with race or the interaction of race and age. Conclusions: In contrast to prior results, completion of substance abuse treatment in “real-world” community settings was not poorer for A-A vs. White adults with primary marijuana use; in fact, some older A-As may show higher rates of treatment completion. In spite of treatment completion, older vs. younger adults may not derive the same benefit from treatment, regardless of race. Future studies should explore the relationship between age and marijuana treatment outcome given the mixed findings of the current research. Financial support: Supported by FRI and UAB internal funds, R01CA141663, R34 DA031936 and U01 DA031515-03S1. http://dx.doi.org/10.1016/j.drugalcdep.2014.02.492 Wheel running dose dependently attenuates cocaine-seeking and associated neuroadaptations in the prefrontal cortex Alexis B. Peterson 1 , J.L. Abel 2 , W.J. Lynch 1 1
Psychiatry and Neurobehavioral Sciences, University of Virginia, Charlottesville, VA, United States 2 Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA, United States Aims: Aerobic exercise has been suggested as a potential treatment for cocaine addiction. We recently showed that 2 h/day of wheel running, an animal model of aerobic exercise, was sufficient to attenuate subsequent cocaine-seeking and associated neuroadaptations in the prefrontal cortex (PFC). The goal of the current study was to identify the running wheeling conditions that produce
e176
Abstracts / Drug and Alcohol Dependence 140 (2014) e169–e251
the most efficacious response, and given recent findings implicating the promotor IV region of BDNF in cocaine-seeking, an additional goal was to determine whether wheel running dose-dependently modified this region of the BDNF gene in the PFC. Methods: Once male rats (N = 45) acquired cocaine selfadministration, they were given extended access (ExA) to cocaine (1.5 mg/kg/infusion) under a discrete trial procedure (4 infusions/h, 24 h/day) for a total of 10 days. Following ExA self-administration rats began a 14 day abstinence period wherein they had 1, 2, or 6 h/day access to a locked or unlocked running wheel. Cocaine-seeking, as assessed under a cued-induced reinstatement paradigm, was then examined after the 14th day of abstinence. PFC punches were removed and BDNF promoter IV mRNA expression was examined by qPCR. Results: Prior to abstinence and wheel assignment all rats had similar cocaine intake over the 10 day ExA period. Rats given longer wheel running access ran significantly more than rats given shorter access. Levels of cocaine-seeking progressively decreased with increasing levels of access to an unlocked running wheel. ExA cocaine self-administration induced a significant increase in BDNF-IV expression in the PFC when compared to saline controls, and this increase was attenuated by wheel running, particularly in the 6 h group. Conclusions: Taken together, these data suggest that wheel running dose-dependently attenuates cocaine-seeking by blocking changes in BDNF promoter IV mRNA expression in the PFC. Financial support: NIDA grant R01DA024716 (Wendy J. Lynch). http://dx.doi.org/10.1016/j.drugalcdep.2014.02.493 Variation of serum BDND levels in adolescent crack-cocaine abusers after 20 days’ abstinence Thiago G. Pianca 1 , Claudia Szobot 1,2 , R.L. Rosa 3 , P.B. Ferronatto 1 , M.C. Jensen 2 , R.C. Abrahão 2 , P.M. Lazzari 2 , A.P. Begnis 2 , R. Halpern 2 , B.W. de Aguiar 1 , K.M. Cereser 1 , F.H. Kessler 1 , F. Kapczinsky 1 , F. Pechansky 1 , L.A. Rohde 1 1 Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil 2 Universidade Luterana do Brasil, Canoas, Brazil 3 Hospital Psiquiátrico São Pedro, Canoas, Brazil
Aims: Our aim was to evaluate if there is a change in periferic blood Briain – Derived-Neurotrophic Factor (BDNF) levels after a period of abstinence in adolescent crack cocaine abusers. Methods: A consecutive sample of Adolescents (12–17 years and 11 months) was collected in two inpatient wards in the city of Porto Alegre, in the south of Brazil. All patients and either one of the parents or legal guardian gave informed written consent for participation. A blood sample was collected at baseline (up to 72 h after admission) and right before discharge, 20 days later. BDNF levels were measured through Enzyme Linked Immuno Sorbent Assay (ELISA), according to the instructions provided by the kit’s manufacturer. Patients were evaluated by administration of the Kiddie-Schedule for Affective Disorders and Schizophrenia, Present-Lifetime version (K-SADS-PL) and later clinical evaluation by a child psychiatrist. Statistical analyses where made using Student’s t test for paired samples, since the distribution was normal, and a level of significance of 5% was used for all the analyses. All analyses were made in SPSS program version 17.0. Results: A total of 62 subjects were included in the study. There was a significant difference on BDNF levels between the baseline and the 20-day abstinence sample (means = 26.929 ng/ml vs. 31.763 ng/ml, p = 0.007).
Conclusions: A period of abstinence of crack use in a closed ward seem to increase BDNF levels in adolescent crack users. That might be an indicator of neuroadaptation during that period. Further studies are needed to asses whether this implies in better prognosis for recovery, or is a predictor of relapse. Financial support: The authors have no financial relationships that related to the topic of this presentation. http://dx.doi.org/10.1016/j.drugalcdep.2014.02.494 Emotion regulation predicts drug use among college binge drinkers Alison Pickover 1 , A.M. Yurasek 1 , C.W. Lejuez 2 , J.G. Murphy 1 1 Department of Psychology, University of Memphis, Memphis, TN, United States 2 CAPER, University of Maryland, College Park, MD, United States
Aims: Binge drinking among college students represents an important public health concern, and illicit drug use is significantly elevated in this population and accounts for incremental risk. Consistent with the Affective Motivational Model (Baker et al., 2004), in which negative affect is central to motivating drug use, difficulties regulating one’s emotions may be a risk factor for engaging in illicit drug use and developing subsequent drug-related problems among this vulnerable population. The present research examined the hypothesis that difficulty regulating one’s emotions would account for drug use after controlling for other established risk factors (i.e., gender, ethnicity, and impulsivity). Methods: Participants were 207 college students who reported one or more binge episodes (defined as having 4/5 drinks or more on one occasion for women/men) in the past month. Participants reported on illicit drug use in the past six months, days of marijuana use in the past 30 days, and drug-related problems. They also completed a delay discounting measure and the Difficulties in Emotion Regulation Scale (DERS). Results: Hierarchical multiple regression was used to assess the ability of the DERS to predict number of illicit drugs used in the past six months. After controlling for the influence of gender, ethnicity, and delay discounting, poorer emotion regulation (ER) significantly predicted greater number of illicit drugs used, R2 = .033, F(4, 194) = 3.32, p = .01. A separate hierarchical multiple regression was used to assess the ability of the DERS to predict drug-related problem severity. After controlling for the influence of gender, ethnicity, and days of marijuana use in the past month, poorer ER significantly predicted greater drug-related problems, R2 = .10, F(4, 112) = 13.13, p < .001. Conclusions: Difficulty regulating one’s emotions represents a significant risk factor for illicit drug-related problems among college binge drinkers and may be an important target for interventions aiming to decrease college student drug use. Financial support: Alcohol Research Foundation (ABMRF). http://dx.doi.org/10.1016/j.drugalcdep.2014.02.495
Financial support: Funding for this study was provided by NIDA grants R01 DA024104 and DA027748.
Impact of race and age on treatment completion among adult marijuana users
http://dx.doi.org/10.1016/j.drugalcdep.2014.02.490
Erica N. Peters 1,2 , P.S. Hendricks 3 , C.B. Clark 3 , Karen L. Cropsey 3 , F. Vocci 1
Rats that self-administer methamphetamine show parkinson’s disease-like inflammation and ␣-synuclein neuropathology Amanda Persons, Sharanya Kousik, L.P. Kelly, S.M. Graves, T.C. Napier Department of Pharmacology and Center for Compulsive Behavior and Addiction, Rush University Medical Center, Chicago, IL, United States Aims: Abuse of methamphetamine (meth), a potent psychostimulant, appears to increase the risk for developing Parkinson’s disease (PD) (Callaghan et al. Drug Alcohol Depend 120, 2012). This enhanced vulnerability may relate to the known neurotoxic effects of meth via oxidative stress, mitochondrial dysfunction and inflammation (Yamamoto et al. Ann NY Acad Sci 1187, 2010), factors also implicated in PD pathology. However, in vivo studies assessing meth-induced toxicity are largely based on acute, high doses of non-contingently administered meth. It is unknown if similar outcomes occur with meth administration protocols that better emulate human drug-taking, e.g., self-administration. The current study determined if meth self-administering rats exhibited markers of inflammation, i.e., glial fibrillary acidic protein (GFAP; marker of glial cell activation) and tumor necrosis factor-␣ (TNF␣; pro-inflammatory cytokine). To substantiate the concept that meth abuse enhances vulnerability for PD, we assayed the SN for ␣-synuclein, a neuropathological hallmark for PD. Methods: Male Sprague-Dawley rats self-administered meth for 14 days; rats were sacrificed and tissue harvested on day 15. Saline-yoked rats served as controls. Western blotting was used for harvested rostral striatum (rSTR) and substantia nigra (SN), the terminal and cell body regions (respectively) of dopamine neurons most severely affected in PD. Results: Meth self-administration increased GFAP and TNF-␣ levels in the rSTR and SN (p < 0.01). In the SN, ␣-synuclein was also increased in METH-treated rats compared to saline controls (p < 0.0001). Conclusions: These brain changes occur in the absence of any detectable degradation in motor function. These results provide the first evidence for PD-like pathology in meth self-administering rats, and therefore offer insight into mechanisms underlying the enhanced vulnerability of meth abusers to develop PD. Financial support: Daniel F. and Ada L. Rice Fdn and the CCBA at Rush University Medical Center. http://dx.doi.org/10.1016/j.drugalcdep.2014.02.491
e175
1 Friends Research Institute, Baltimore, MD, United States 2 Yale School of Medicine, New Haven, CT, United States 3 University of Alabama at Birmingham, Birmingham, AL, United States
Aims: The prevalence of marijuana use disorders has increased significantly among African American (A-A) adults in recent years. A-A young adults (aged 18–25) are less likely to complete marijuana treatment than their White counterparts, but it is not clear if these trends extend beyond the young adult years. Methods: This study examines 2 samples of adults receiving community-based outpatient substance abuse treatment and reporting primary marijuana use. Sample #1 (N = 160) was composed of adults in the southeastern US, 70.6% of whom were A-A, with a mean age of 27.9 years. Sample #2 (N = 324) was composed of adults in the US mid-Atlantic region, 38.3% of whom were A-A, with a mean age of 25.0 years. In both samples, treatment completion was defined as regular treatment attendance, sustained negative urine drug screens, participation in 12-step groups, and achievement of individualized treatment goals. Results: In Sample #1, treatment completion was significantly associated with the interaction of race and age (odds ratio [OR] = 1.18, p < .01) such that older age was significantly correlated with completing treatment for A-A (r = .23, p = .02) but not for White adults (p = .28). In Sample #2, treatment completion was significantly associated with age (OR = 0.95, p < .01) such that older adults were less likely to complete treatment, but was not associated with race or the interaction of race and age. Conclusions: In contrast to prior results, completion of substance abuse treatment in “real-world” community settings was not poorer for A-A vs. White adults with primary marijuana use; in fact, some older A-As may show higher rates of treatment completion. In spite of treatment completion, older vs. younger adults may not derive the same benefit from treatment, regardless of race. Future studies should explore the relationship between age and marijuana treatment outcome given the mixed findings of the current research. Financial support: Supported by FRI and UAB internal funds, R01CA141663, R34 DA031936 and U01 DA031515-03S1. http://dx.doi.org/10.1016/j.drugalcdep.2014.02.492 Wheel running dose dependently attenuates cocaine-seeking and associated neuroadaptations in the prefrontal cortex Alexis B. Peterson 1 , J.L. Abel 2 , W.J. Lynch 1 1
Psychiatry and Neurobehavioral Sciences, University of Virginia, Charlottesville, VA, United States 2 Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA, United States Aims: Aerobic exercise has been suggested as a potential treatment for cocaine addiction. We recently showed that 2 h/day of wheel running, an animal model of aerobic exercise, was sufficient to attenuate subsequent cocaine-seeking and associated neuroadaptations in the prefrontal cortex (PFC). The goal of the current study was to identify the running wheeling conditions that produce
e176
Abstracts / Drug and Alcohol Dependence 140 (2014) e169–e251
the most efficacious response, and given recent findings implicating the promotor IV region of BDNF in cocaine-seeking, an additional goal was to determine whether wheel running dose-dependently modified this region of the BDNF gene in the PFC. Methods: Once male rats (N = 45) acquired cocaine selfadministration, they were given extended access (ExA) to cocaine (1.5 mg/kg/infusion) under a discrete trial procedure (4 infusions/h, 24 h/day) for a total of 10 days. Following ExA self-administration rats began a 14 day abstinence period wherein they had 1, 2, or 6 h/day access to a locked or unlocked running wheel. Cocaine-seeking, as assessed under a cued-induced reinstatement paradigm, was then examined after the 14th day of abstinence. PFC punches were removed and BDNF promoter IV mRNA expression was examined by qPCR. Results: Prior to abstinence and wheel assignment all rats had similar cocaine intake over the 10 day ExA period. Rats given longer wheel running access ran significantly more than rats given shorter access. Levels of cocaine-seeking progressively decreased with increasing levels of access to an unlocked running wheel. ExA cocaine self-administration induced a significant increase in BDNF-IV expression in the PFC when compared to saline controls, and this increase was attenuated by wheel running, particularly in the 6 h group. Conclusions: Taken together, these data suggest that wheel running dose-dependently attenuates cocaine-seeking by blocking changes in BDNF promoter IV mRNA expression in the PFC. Financial support: NIDA grant R01DA024716 (Wendy J. Lynch). http://dx.doi.org/10.1016/j.drugalcdep.2014.02.493 Variation of serum BDND levels in adolescent crack-cocaine abusers after 20 days’ abstinence Thiago G. Pianca 1 , Claudia Szobot 1,2 , R.L. Rosa 3 , P.B. Ferronatto 1 , M.C. Jensen 2 , R.C. Abrahão 2 , P.M. Lazzari 2 , A.P. Begnis 2 , R. Halpern 2 , B.W. de Aguiar 1 , K.M. Cereser 1 , F.H. Kessler 1 , F. Kapczinsky 1 , F. Pechansky 1 , L.A. Rohde 1 1 Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil 2 Universidade Luterana do Brasil, Canoas, Brazil 3 Hospital Psiquiátrico São Pedro, Canoas, Brazil
Aims: Our aim was to evaluate if there is a change in periferic blood Briain – Derived-Neurotrophic Factor (BDNF) levels after a period of abstinence in adolescent crack cocaine abusers. Methods: A consecutive sample of Adolescents (12–17 years and 11 months) was collected in two inpatient wards in the city of Porto Alegre, in the south of Brazil. All patients and either one of the parents or legal guardian gave informed written consent for participation. A blood sample was collected at baseline (up to 72 h after admission) and right before discharge, 20 days later. BDNF levels were measured through Enzyme Linked Immuno Sorbent Assay (ELISA), according to the instructions provided by the kit’s manufacturer. Patients were evaluated by administration of the Kiddie-Schedule for Affective Disorders and Schizophrenia, Present-Lifetime version (K-SADS-PL) and later clinical evaluation by a child psychiatrist. Statistical analyses where made using Student’s t test for paired samples, since the distribution was normal, and a level of significance of 5% was used for all the analyses. All analyses were made in SPSS program version 17.0. Results: A total of 62 subjects were included in the study. There was a significant difference on BDNF levels between the baseline and the 20-day abstinence sample (means = 26.929 ng/ml vs. 31.763 ng/ml, p = 0.007).
Conclusions: A period of abstinence of crack use in a closed ward seem to increase BDNF levels in adolescent crack users. That might be an indicator of neuroadaptation during that period. Further studies are needed to asses whether this implies in better prognosis for recovery, or is a predictor of relapse. Financial support: The authors have no financial relationships that related to the topic of this presentation. http://dx.doi.org/10.1016/j.drugalcdep.2014.02.494 Emotion regulation predicts drug use among college binge drinkers Alison Pickover 1 , A.M. Yurasek 1 , C.W. Lejuez 2 , J.G. Murphy 1 1 Department of Psychology, University of Memphis, Memphis, TN, United States 2 CAPER, University of Maryland, College Park, MD, United States
Aims: Binge drinking among college students represents an important public health concern, and illicit drug use is significantly elevated in this population and accounts for incremental risk. Consistent with the Affective Motivational Model (Baker et al., 2004), in which negative affect is central to motivating drug use, difficulties regulating one’s emotions may be a risk factor for engaging in illicit drug use and developing subsequent drug-related problems among this vulnerable population. The present research examined the hypothesis that difficulty regulating one’s emotions would account for drug use after controlling for other established risk factors (i.e., gender, ethnicity, and impulsivity). Methods: Participants were 207 college students who reported one or more binge episodes (defined as having 4/5 drinks or more on one occasion for women/men) in the past month. Participants reported on illicit drug use in the past six months, days of marijuana use in the past 30 days, and drug-related problems. They also completed a delay discounting measure and the Difficulties in Emotion Regulation Scale (DERS). Results: Hierarchical multiple regression was used to assess the ability of the DERS to predict number of illicit drugs used in the past six months. After controlling for the influence of gender, ethnicity, and delay discounting, poorer emotion regulation (ER) significantly predicted greater number of illicit drugs used, R2 = .033, F(4, 194) = 3.32, p = .01. A separate hierarchical multiple regression was used to assess the ability of the DERS to predict drug-related problem severity. After controlling for the influence of gender, ethnicity, and days of marijuana use in the past month, poorer ER significantly predicted greater drug-related problems, R2 = .10, F(4, 112) = 13.13, p < .001. Conclusions: Difficulty regulating one’s emotions represents a significant risk factor for illicit drug-related problems among college binge drinkers and may be an important target for interventions aiming to decrease college student drug use. Financial support: Alcohol Research Foundation (ABMRF). http://dx.doi.org/10.1016/j.drugalcdep.2014.02.495