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HIV-1 Tat-protein elevates forebrain glutathione levels and increases morphine drug-seeking and depression-like behaviors in mice
Abstracts / Drug and Alcohol Dependence 171 (2017) e2–e226
Development and pilot test of integrated cognitive behavioral therapy for anxiety and opioid use disorder Kathryn McHugh ∗ , Shelly F. Greenfield, Roger Weiss McLean Hospital/Harvard Medical School, Belmont, MA, United States Aims: Anxiety disorders are common among those with opioid use disorder and are associated with a more severe course and poor treatment outcome. The aim of this study was to develop and pilot test the feasibility and initial clinical outcomes of a novel cognitive behavioral therapy for this population. Methods: This Stage 1A behavioral treatment development trial enrolled a sample of 5 adults with opioid use disorder and a DSM-5 anxiety disorder in an open trial of 12 weeks of cognitive behavioral therapy. Feasibility was evaluated using participant ratings of satisfaction. Urine-confirmed self-report of opioid use, opioid craving and anxiety symptom severity were collected weekly. Results: Treatment satisfaction was very high at mid-treatment; all participants reported being at least mostly satisfied with the treatment. Three participants completed all treatment sessions, one participant dropped out at mid-treatment, and one participant died of an accidental opioid overdose. Opioid use decreased for all participants who completed treatment, with 2 participants remaining abstinent for the last 4 weeks and 1 decreasing use by 50%. Anxiety also decreased throughout treatment, with 3 of the 5 participants reporting anxiety below the cut-off for clinical anxiety by their final session. Conclusions: Initial results from this pilot test indicate that this novel approach is feasible and associated with high satisfaction and improvement in both opioid use and anxiety symptoms. Efficacy testing in a randomized clinical trial is ongoing. Financial support: This study was supported by NIDA grant K23DA035297. http://dx.doi.org/10.1016/j.drugalcdep.2016.08.384 Polydrug use among a cohort of adolescent light smokers Karma McKelvey ∗ , Danielle Ramo, Kevin Delucchi, Mark Rubinstein UCSF, San Francisco, CA, United States Aims: Classify distinct subgroups of polydrug users among ALS & identify associated personal characteristics and 3-year outcomes. Methods: Participants were 176 teens (age ∼16; 35% male; 27% white) who reported smoking at least 1 cigarette in the past month and no more than 10 per day. Latent class analysis was used to identify subgroups of polydrug users based on past month use of other tobacco (pipe, cigar, spit) alcohol, marijuana, and other drugs (e.g., ecstasy, hallucinogens, prescriptions) (y/n); classes were compared on drug use and psychometrics over 3 years. Results: Most (96%) reported using, on average, 2 (SD = .97) drugs (alcohol, tobacco, or other drugs (ATOD)) in addition to cigarettes. A two-class model fit the data best (LMR p < .05). Subgroups were Divergent Users (DU) (16%), with high likelihood of ATOD use; and Typical Users, with likelihood of alcohol, tobacco, and marijuana use. Subgroups did not differ on age, gender, race, mother’s education level, or proportion reporting marijuana or alcohol use. At baseline, DU were more likely to report smoking the entire cigarette (RR = 1.24; 95% CI 1.08,1.42); using a pipe (2.76; 1.11, 6.88); using more drugs (t(174) = 9.33, p < .001); more depressive symptoms (t(164) = 2.12, p < .04); and feeling nervous, restless,
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or anxious when they could not smoke (x2 = 21; p < .01); at baseline and 12 months DU were more likely to report other drug use. Mean depression scores at 24 (t(150) = 2.32; p < .03) and 36 months (t(26) = 2.18; p < .04) were higher for DU and higher than baseline. Conclusions: ALS should be targeted for polydrug use interventions as they are a group at risk for early drug use, primarily alcohol and marijuana. Screening for depressive symptoms among ALS could identify those at increased risk to use additional illicit drugs (e.g. prescription drugs, hallucinogens). Financial support: Study: R01 CA140216 (Rubinstein); abstract & analysis: K23 DA032578 (Ramo) & R25 CA113710 (McKelvey). http://dx.doi.org/10.1016/j.drugalcdep.2016.08.385 HIV-1 Tat-protein elevates forebrain glutathione levels and increases morphine drug-seeking and depression-like behaviors in mice Jay P. McLaughlin 2,∗ , Shainnel Eans 2 , Jessica Medina 2 , Kristen Hymel 2 , Anna Rock 3 , Dionyssios Mintzopoulos 3 , Marc J. Kaufman 1 1
Brain Imaging Center, McLean Hospital, Belmont, MA, United States 2 Pharmacodynamics, University of Florida, Gainesville, FL, United States 3 McLean Imaging Center, McLean Hospital, Belmont, MA, United States Aims: As HIV-1 Tat protein induces oxidative stress, and oxidative stress is associated with morphine dependence and behavioral depression, we hypothesized that HIV-1 Tat expressed in brain would elevate intracellular levels of glutathione (GSH) in forebrain and increase the rewarding effects of morphine and depression-like behavior. Methods: Using the GT-tg bigenic mouse model, in which brainselective Tat expression can be induced by doxycycline (Dox), magnetic resonance spectroscopy (MRS) was used to determine whether exposure to Tat protein alters medial frontal cortex intracellular GSH levels. In behavioral tests, we characterized effects of Tat protein on the rewarding effects of morphine with the conditioned place preference (CPP) assay and on depression-like behavior with the tail-suspension test (TST). We also assessed effects of treatments that modulate GSH levels. Results: MRS studies of medial frontal cortex GSH found significant increases in GT-tg mice administered Dox (100 mg/kg/d, i.p.) for 7 days. In a separate GT-tg mouse cohort given Dox for 7 days, morphine-CPP doubled in a manner dependent on the magnitude of exposure to Tat protein. GT-tg bigenic mice induced with Dox for 1 or 7 d also demonstrated significant increases in time spent immobile during the TST. Notably, daily co-treatment with the antioxidant methyl sulfonyl methane reversed behavioral effects of Tat protein. By contrast, GSH depletion with diethyl maleate increased depression-like behavior in a dose-related manner in saline-treated GT-tg mice not exposed to Tat protein. Conclusions: Overall, these data suggest that behavioral effects of HIV-1 Tat protein could be a consequence of oxidative stress, and that treatments mitigating oxidative stress could be beneficial for alleviating maladaptive behavioral responses. Financial support: NIH grants R01-MH085607, R01-DA039044, and S10-RR019356. http://dx.doi.org/10.1016/j.drugalcdep.2016.08.386
Development and pilot test of integrated cognitive behavioral therapy for anxiety and opioid use disorder Kathryn McHugh ∗ , Shelly F. Greenfield, Roger Weiss McLean Hospital/Harvard Medical School, Belmont, MA, United States Aims: Anxiety disorders are common among those with opioid use disorder and are associated with a more severe course and poor treatment outcome. The aim of this study was to develop and pilot test the feasibility and initial clinical outcomes of a novel cognitive behavioral therapy for this population. Methods: This Stage 1A behavioral treatment development trial enrolled a sample of 5 adults with opioid use disorder and a DSM-5 anxiety disorder in an open trial of 12 weeks of cognitive behavioral therapy. Feasibility was evaluated using participant ratings of satisfaction. Urine-confirmed self-report of opioid use, opioid craving and anxiety symptom severity were collected weekly. Results: Treatment satisfaction was very high at mid-treatment; all participants reported being at least mostly satisfied with the treatment. Three participants completed all treatment sessions, one participant dropped out at mid-treatment, and one participant died of an accidental opioid overdose. Opioid use decreased for all participants who completed treatment, with 2 participants remaining abstinent for the last 4 weeks and 1 decreasing use by 50%. Anxiety also decreased throughout treatment, with 3 of the 5 participants reporting anxiety below the cut-off for clinical anxiety by their final session. Conclusions: Initial results from this pilot test indicate that this novel approach is feasible and associated with high satisfaction and improvement in both opioid use and anxiety symptoms. Efficacy testing in a randomized clinical trial is ongoing. Financial support: This study was supported by NIDA grant K23DA035297. http://dx.doi.org/10.1016/j.drugalcdep.2016.08.384 Polydrug use among a cohort of adolescent light smokers Karma McKelvey ∗ , Danielle Ramo, Kevin Delucchi, Mark Rubinstein UCSF, San Francisco, CA, United States Aims: Classify distinct subgroups of polydrug users among ALS & identify associated personal characteristics and 3-year outcomes. Methods: Participants were 176 teens (age ∼16; 35% male; 27% white) who reported smoking at least 1 cigarette in the past month and no more than 10 per day. Latent class analysis was used to identify subgroups of polydrug users based on past month use of other tobacco (pipe, cigar, spit) alcohol, marijuana, and other drugs (e.g., ecstasy, hallucinogens, prescriptions) (y/n); classes were compared on drug use and psychometrics over 3 years. Results: Most (96%) reported using, on average, 2 (SD = .97) drugs (alcohol, tobacco, or other drugs (ATOD)) in addition to cigarettes. A two-class model fit the data best (LMR p < .05). Subgroups were Divergent Users (DU) (16%), with high likelihood of ATOD use; and Typical Users, with likelihood of alcohol, tobacco, and marijuana use. Subgroups did not differ on age, gender, race, mother’s education level, or proportion reporting marijuana or alcohol use. At baseline, DU were more likely to report smoking the entire cigarette (RR = 1.24; 95% CI 1.08,1.42); using a pipe (2.76; 1.11, 6.88); using more drugs (t(174) = 9.33, p < .001); more depressive symptoms (t(164) = 2.12, p < .04); and feeling nervous, restless,
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or anxious when they could not smoke (x2 = 21; p < .01); at baseline and 12 months DU were more likely to report other drug use. Mean depression scores at 24 (t(150) = 2.32; p < .03) and 36 months (t(26) = 2.18; p < .04) were higher for DU and higher than baseline. Conclusions: ALS should be targeted for polydrug use interventions as they are a group at risk for early drug use, primarily alcohol and marijuana. Screening for depressive symptoms among ALS could identify those at increased risk to use additional illicit drugs (e.g. prescription drugs, hallucinogens). Financial support: Study: R01 CA140216 (Rubinstein); abstract & analysis: K23 DA032578 (Ramo) & R25 CA113710 (McKelvey). http://dx.doi.org/10.1016/j.drugalcdep.2016.08.385 HIV-1 Tat-protein elevates forebrain glutathione levels and increases morphine drug-seeking and depression-like behaviors in mice Jay P. McLaughlin 2,∗ , Shainnel Eans 2 , Jessica Medina 2 , Kristen Hymel 2 , Anna Rock 3 , Dionyssios Mintzopoulos 3 , Marc J. Kaufman 1 1
Brain Imaging Center, McLean Hospital, Belmont, MA, United States 2 Pharmacodynamics, University of Florida, Gainesville, FL, United States 3 McLean Imaging Center, McLean Hospital, Belmont, MA, United States Aims: As HIV-1 Tat protein induces oxidative stress, and oxidative stress is associated with morphine dependence and behavioral depression, we hypothesized that HIV-1 Tat expressed in brain would elevate intracellular levels of glutathione (GSH) in forebrain and increase the rewarding effects of morphine and depression-like behavior. Methods: Using the GT-tg bigenic mouse model, in which brainselective Tat expression can be induced by doxycycline (Dox), magnetic resonance spectroscopy (MRS) was used to determine whether exposure to Tat protein alters medial frontal cortex intracellular GSH levels. In behavioral tests, we characterized effects of Tat protein on the rewarding effects of morphine with the conditioned place preference (CPP) assay and on depression-like behavior with the tail-suspension test (TST). We also assessed effects of treatments that modulate GSH levels. Results: MRS studies of medial frontal cortex GSH found significant increases in GT-tg mice administered Dox (100 mg/kg/d, i.p.) for 7 days. In a separate GT-tg mouse cohort given Dox for 7 days, morphine-CPP doubled in a manner dependent on the magnitude of exposure to Tat protein. GT-tg bigenic mice induced with Dox for 1 or 7 d also demonstrated significant increases in time spent immobile during the TST. Notably, daily co-treatment with the antioxidant methyl sulfonyl methane reversed behavioral effects of Tat protein. By contrast, GSH depletion with diethyl maleate increased depression-like behavior in a dose-related manner in saline-treated GT-tg mice not exposed to Tat protein. Conclusions: Overall, these data suggest that behavioral effects of HIV-1 Tat protein could be a consequence of oxidative stress, and that treatments mitigating oxidative stress could be beneficial for alleviating maladaptive behavioral responses. Financial support: NIH grants R01-MH085607, R01-DA039044, and S10-RR019356. http://dx.doi.org/10.1016/j.drugalcdep.2016.08.386