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Humanized mouse models to study effects of anti-cocaine vaccine
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Abstracts / Drug and Alcohol Dependence 140 (2014) e169–e251
Longitudinal outcomes of MDMA (Ecstasy)-exposed infants in the United Kingdom Lynn Singer 1 , D.G. Moore 2 , Meeyoung O. Min 1 , J. Goodwin 2 , J.J. Turner 2 , S. Fulton 1 , A.C. Parrott 3 1 Case Western Reserve University, Cleveland, OH, United States 2 The University of East London, London, United Kingdom 3 Swansea University, Singleton Park, United Kingdom
Aims: The present study assessed longitudinal outcomes in mental and motor development through 2 years in infants whose mothers used MDMA (Ecstasy) during pregnancy. Methods: Pregnant women in the United Kingdom (28 MDMA uses; 68 non-MDMA users) were interviewed about recreational drug use and their infants followed from birth to 4, 12, 18, and 24 months of age. Assessments included the Bayley Mental and Motor Scales of Development (MDI, PDI) and mothers completed the HOME, the Brief Symptom Inventory (BSI) and the Drug Abuse Screening Test (DAST). Women were polydrug users, of middle socioeconomic status, average IQ, and in stable relationships. All but one MDMA user discontinued use after the first trimester and users were divided into heavier and lighter groups based on a median split. Infant birth parameters were not different except more MDMA infants were male. Effects of MDMA outcomes over time were assessed through a mixed model analysis, controlling for covariates of other drug use, HOME environment, and gender. Results: There was a significant main effect of first trimester MDMA exposure on motor outcomes from 4 months to 2 years (F = 11.3, p < .002) with more heavily MDMA-exposed children showing delays compared to lighter-exposed and non-exposed children (PDI = 90.8 (SE = 3.76) for MDMA vs.98.7 (SE = 1.39) for lighter and non-exposed at 2 years). Mental outcomes were not affected. Conclusions: Prenatal MDMA exposure predicts poorer motor outcomes from 4 months to 2 years of age. Given the widespread recreational use of MDMA (Ecstasy), pregnant women should be cautioned about possible developmental effects in offspring. Financial support: Supported by grant DA14910-05 NIH – National Institute on Drug Abuse. http://dx.doi.org/10.1016/j.drugalcdep.2014.02.583 Humanized mouse models to study effects of anti-cocaine vaccine Rana A. Singh 1,2 , B.M. Kinsey 1,2 , Z. Huang 3 , T.R. Kosten 1,2 , F.M. Orson 1,2 1
Medicine, BCM, Houston, TX, United States Immunology, VA Hospitals, Houston, TX, United States 3 Walvax Biotechnology Co., Ltd, Kunming, China 2
Aims: Initial vaccine formulation testing cannot be done in humans, and yet response characteristics in humans are often different than in lab animals. Therefore, human hematopoietic stem cells were transplanted into immunodeficient NOD – Rag1null IL2r␥null mice (Humanized-mice, Hu-mice). Hu-mice were vaccinated with conjugate vaccine against cocaine (tetanus toxiod-succinylnorcocaine; TT-SNC + Alhydrogel adjuvant) and were supplemented with plasmids expressing cytokines. The human specific cocaine antibody and locomotor responses to cocaine challenge were assessed at various time points.
Methods: Hu-mice were immunized with TT-SNC and received a booster dose 3 weeks later. Plasmids expressing GMCSF, IL-4 or IL12 were delivered by a Genegun alone or in various combinations. Serum was assessed for human-specific anticocaine antibodies by ELISA. At 7 weeks, locomotor activity after cocaine challenge (15 mg/kg) was assessed. Results: Anti-cocaine specific antibodies were detectable in the serum samples as early as 4 weeks, with a peak response at 6 weeks. In most cases, addition of cytokine expressing plasmids significantly increased antibody level over the group of mice immunized with TT-SNC alone that produced 848 g anti-cocaine IgG/ml of serum (=1×). Maximum antibody was observed in the presence of GMCSF expressing plasmid (2.16×) followed by GMCSF + IL-4 combination (2.15×). The lowest antibody was produced in the presence of IL-4 + IL-12 and GMCSF (1.12×) followed by IL-12 (1.35×). There was a marked effect on the locomotor response in immunized mice, with substantial inhibition in the TT-SNC vaccinated mice and complete blockade of the response in the GM-CSF supplemented vaccinated mice. Conclusions: Cocaine conjugate vaccine generated significantly high amount of human anti-cocaine IgG antibodies in this Hu-mice model, which was further increased in the presence of plasmids encoding various cytokines. Hu-mice showing maximum antibody level effectively blocked cocaine-induced locomotor responses. Financial support: DA023898, DA023898, DA030338, DP1DA033502. http://dx.doi.org/10.1016/j.drugalcdep.2014.02.584 A longitudinal study of marijuana use motives across emerging adulthood M. Sitney 1 , Kristen G. Anderson 1 , H. White 2 1 Psychology, Reed College, Portland, OR, United States 2 Center of Alcohol Studies, Rutgers University, New Brunswick, NJ, United States
Aims: We examined the reciprocal influence of marijuana use motives (MJM) and marijuana use status across emerging adulthood. Endorsement of enhancement and social motives is higher among marijuana users than their nonusing peers and has been shown to relate to increased use among young adults cross-sectionally (Zvolensky et al., 2007). We anticipated that endorsement of MJM at one point in time would prospectively predict marijuana use status (nonuser/user) at a later point in time, above and beyond their current use status. Methods: Using data from the Rutgers Health and Human Development Project (N = 419), use status and MJM were assessed at ages 18, 21, and 28 years. MJM were categorized as positive reinforcement (social/enhancement; SE), negative reinforcement (coping/conformity; CC), or Expansion (EXP) categories. A path analytic model tested longitudinal relations between use status and MJM across time. Results: The derived scales generally demonstrated a high level of reliability. As expected, MJM were positively associated with each other at each time point (rs = .14–.85, ps = <.001). Concurrently, all motive categories were related to use status at age 18 (rs = .23–.49, ps = <.0001) and age 21 (rs = .24–.41 ps = <.0001). However, only SE motives were associated cross-sectionally with use status at age 28 (b = .14, p = .004). 22% of the variance in use status at age 21 was predicted by greater endorsement of SE motives at age 18, b = .28, p < .0001, and past use status (age 18), b = .32, p < .0001. By age 28, 33.7% of the variance in use status was accounted for by the
Abstracts / Drug and Alcohol Dependence 140 (2014) e169–e251
Longitudinal outcomes of MDMA (Ecstasy)-exposed infants in the United Kingdom Lynn Singer 1 , D.G. Moore 2 , Meeyoung O. Min 1 , J. Goodwin 2 , J.J. Turner 2 , S. Fulton 1 , A.C. Parrott 3 1 Case Western Reserve University, Cleveland, OH, United States 2 The University of East London, London, United Kingdom 3 Swansea University, Singleton Park, United Kingdom
Aims: The present study assessed longitudinal outcomes in mental and motor development through 2 years in infants whose mothers used MDMA (Ecstasy) during pregnancy. Methods: Pregnant women in the United Kingdom (28 MDMA uses; 68 non-MDMA users) were interviewed about recreational drug use and their infants followed from birth to 4, 12, 18, and 24 months of age. Assessments included the Bayley Mental and Motor Scales of Development (MDI, PDI) and mothers completed the HOME, the Brief Symptom Inventory (BSI) and the Drug Abuse Screening Test (DAST). Women were polydrug users, of middle socioeconomic status, average IQ, and in stable relationships. All but one MDMA user discontinued use after the first trimester and users were divided into heavier and lighter groups based on a median split. Infant birth parameters were not different except more MDMA infants were male. Effects of MDMA outcomes over time were assessed through a mixed model analysis, controlling for covariates of other drug use, HOME environment, and gender. Results: There was a significant main effect of first trimester MDMA exposure on motor outcomes from 4 months to 2 years (F = 11.3, p < .002) with more heavily MDMA-exposed children showing delays compared to lighter-exposed and non-exposed children (PDI = 90.8 (SE = 3.76) for MDMA vs.98.7 (SE = 1.39) for lighter and non-exposed at 2 years). Mental outcomes were not affected. Conclusions: Prenatal MDMA exposure predicts poorer motor outcomes from 4 months to 2 years of age. Given the widespread recreational use of MDMA (Ecstasy), pregnant women should be cautioned about possible developmental effects in offspring. Financial support: Supported by grant DA14910-05 NIH – National Institute on Drug Abuse. http://dx.doi.org/10.1016/j.drugalcdep.2014.02.583 Humanized mouse models to study effects of anti-cocaine vaccine Rana A. Singh 1,2 , B.M. Kinsey 1,2 , Z. Huang 3 , T.R. Kosten 1,2 , F.M. Orson 1,2 1
Medicine, BCM, Houston, TX, United States Immunology, VA Hospitals, Houston, TX, United States 3 Walvax Biotechnology Co., Ltd, Kunming, China 2
Aims: Initial vaccine formulation testing cannot be done in humans, and yet response characteristics in humans are often different than in lab animals. Therefore, human hematopoietic stem cells were transplanted into immunodeficient NOD – Rag1null IL2r␥null mice (Humanized-mice, Hu-mice). Hu-mice were vaccinated with conjugate vaccine against cocaine (tetanus toxiod-succinylnorcocaine; TT-SNC + Alhydrogel adjuvant) and were supplemented with plasmids expressing cytokines. The human specific cocaine antibody and locomotor responses to cocaine challenge were assessed at various time points.
Methods: Hu-mice were immunized with TT-SNC and received a booster dose 3 weeks later. Plasmids expressing GMCSF, IL-4 or IL12 were delivered by a Genegun alone or in various combinations. Serum was assessed for human-specific anticocaine antibodies by ELISA. At 7 weeks, locomotor activity after cocaine challenge (15 mg/kg) was assessed. Results: Anti-cocaine specific antibodies were detectable in the serum samples as early as 4 weeks, with a peak response at 6 weeks. In most cases, addition of cytokine expressing plasmids significantly increased antibody level over the group of mice immunized with TT-SNC alone that produced 848 g anti-cocaine IgG/ml of serum (=1×). Maximum antibody was observed in the presence of GMCSF expressing plasmid (2.16×) followed by GMCSF + IL-4 combination (2.15×). The lowest antibody was produced in the presence of IL-4 + IL-12 and GMCSF (1.12×) followed by IL-12 (1.35×). There was a marked effect on the locomotor response in immunized mice, with substantial inhibition in the TT-SNC vaccinated mice and complete blockade of the response in the GM-CSF supplemented vaccinated mice. Conclusions: Cocaine conjugate vaccine generated significantly high amount of human anti-cocaine IgG antibodies in this Hu-mice model, which was further increased in the presence of plasmids encoding various cytokines. Hu-mice showing maximum antibody level effectively blocked cocaine-induced locomotor responses. Financial support: DA023898, DA023898, DA030338, DP1DA033502. http://dx.doi.org/10.1016/j.drugalcdep.2014.02.584 A longitudinal study of marijuana use motives across emerging adulthood M. Sitney 1 , Kristen G. Anderson 1 , H. White 2 1 Psychology, Reed College, Portland, OR, United States 2 Center of Alcohol Studies, Rutgers University, New Brunswick, NJ, United States
Aims: We examined the reciprocal influence of marijuana use motives (MJM) and marijuana use status across emerging adulthood. Endorsement of enhancement and social motives is higher among marijuana users than their nonusing peers and has been shown to relate to increased use among young adults cross-sectionally (Zvolensky et al., 2007). We anticipated that endorsement of MJM at one point in time would prospectively predict marijuana use status (nonuser/user) at a later point in time, above and beyond their current use status. Methods: Using data from the Rutgers Health and Human Development Project (N = 419), use status and MJM were assessed at ages 18, 21, and 28 years. MJM were categorized as positive reinforcement (social/enhancement; SE), negative reinforcement (coping/conformity; CC), or Expansion (EXP) categories. A path analytic model tested longitudinal relations between use status and MJM across time. Results: The derived scales generally demonstrated a high level of reliability. As expected, MJM were positively associated with each other at each time point (rs = .14–.85, ps = <.001). Concurrently, all motive categories were related to use status at age 18 (rs = .23–.49, ps = <.0001) and age 21 (rs = .24–.41 ps = <.0001). However, only SE motives were associated cross-sectionally with use status at age 28 (b = .14, p = .004). 22% of the variance in use status at age 21 was predicted by greater endorsement of SE motives at age 18, b = .28, p < .0001, and past use status (age 18), b = .32, p < .0001. By age 28, 33.7% of the variance in use status was accounted for by the