- Email: [email protected]
Endocannabinoid-CB1R signaling: A link between early life stress and changes in limbic system function?
NBTS 2012 Abstracts
tested during drug administration and during drug abstinence. THC altered activity, anxiety, and cocaine reward differently in male and female rats. Possible mechanisms for these sex differences will also be presented. In summary, the role of endocannabinoids in brain development and the effects of THC administration during the prenatal or adolescent period will be presented. THC produces long-term effects on cognition, affect, and drug reward. Therefore, smoking marijuana during pregnancy or adolescence has long-term effects on brain function. (Supported by NIH grants DA 019348 and P50 DA 025484-0001) doi:10.1016/j.ntt.2012.05.016
NBTS 16 Developmental cannabis exposure and its epigenetic consequences Yasmin Hurd Mount Sinai School of Medicine, New York, NY, United States Marijuana (Cannabis sativa) continues to be the most used illicit drug in the USA with recent years showing a disconcerting increased use among teens and reduced perceived risk of harm associated with the use of this drug. Such perception also fuels the debates as to whether there are any significant developmental effects of cannabis exposure. To address these questions and to obtain insights into the potential relationship of developmental cannabis exposure to psychiatric vulnerability, we have studied molecular mechanisms in the brains of human subjects with in utero cannabis exposure, as well as animal models in which drug history could be controlled and causal effects on behavior could be better established. Our results have revealed specific long-term molecular disturbances of prenatal and adolescent cannabis/D9-tetrahydrocannabinol (THC; psychoactive component of cannabis) exposure of genes associated with mesolimbic striatopallidal circuit (e.g., proenkephalin and D2). The fact that these striatopallidal genes are critical to reward and impulsivity suggests the potential of early cannabis exposure to disturb neurobiological systems significantly associated with addiction vulnerability in line with altered heroin self-administration behavior seen in our developmental THC rodent models. Moreover, our studies have begun to characterize specific THC-induced epigenetic histone modifications that appear to maintain the protracted discrete gene expression disturbances after exposure to the drug. In addition, new experiments have begun to reveal cross-generational effects associated with adolescent THC exposure. Overall, these and other ongoing studies emphasize the significant contribution of developmental cannabis to epigenetic disturbances that may relate to psychiatric vulnerability. doi:10.1016/j.ntt.2012.05.017
NBTS 17 Endocannabinoid-CB1R signaling: A link between early life stress and changes in limbic system function? Cecilia Hillard, Dylan Coss Medical College of Wisconsin, Milwaukee, WI, United States Considerable evidence has accumulated suggesting that endogenous CB1R signaling (ECS) is stress responsive. Recent studies in hypothalamus, hippocampus and prefrontal cortex demonstrate that glucocorticoids mobilize ECS. Endocrine and behavioral effects of stress are altered by ECS. For example, ECS in the medial prefrontal cortex is required for appropriate recovery of the hypothalamic–pituitary–adrenal axis following stress and inhibition of ECS potentiates anxiety-like behaviors in several models. ECS exhibits plasticity; it is down-regulated in several
373
models of chronic stress. Taken together, considerable experimental evidence supports the hypotheses that ECS functions as a stress buffer in the brain and can be modified by previous experience. Human epidemiological and preclinical evidence demonstrate that exposure to stress in early life results in life-long alterations in behavioral and endocrine responses to stress. Therefore, we hypothesized that stress in early life results in long-lasting alterations in ECS that contribute to changes in endocrine and behavioral responses to stress exposure in later life. Sprague Dawley dams and litters were exposed to limited bedding stress using the model of Baram and colleagues. From days 1–9 of age, bedding was reduced to one-third of normal (0.5 liters in a standard rat cage) in the stress cohort. Pups were sacrificed on day 10 and CB1R mRNA was quantified in prefrontal cortex (PFC) and amygdala using qPCR. In the PFC, significant main effects of both sex and stress exposure, as well as a significant interaction, occurred. Post hoc tests revealed that female pups had significantly greater CB1R mRNA expression than males. Stress exposure significantly reduced mRNA expression in both sexes; the effect was greater in females (75% reduction) than males. In amygdala, significant main effects of both sex and stress exposure were observed; post hoc tests revealed that stress produced a significant reduction in CB1R mRNA expression only in females. These data suggest that early life stress alters the expression of the CB1R in brain regions critical for stress responsivity in a sex-specific manner and support the hypothesis that early life stress can modulate ECS, particularly in female offspring. doi:10.1016/j.ntt.2012.05.018
NBTS 18 Developmental effects of marijuana exposure: Gestation and early adolescence Nancy L. Day University of Pittsburgh School of Medicine, Pittsburgh, PA, United States There are two points in human development that are known to be critical times for marijuana exposure. The first, exposure during gestation, has been shown to have long-term effects on the development of the offspring. These are CNS deficits expressed as behavioral and cognitive problems. There have been few reports of prenatal marijuana exposure (PME) affecting growth or morphology. The second vulnerable period is during early adolescence. Adolescents who begin to use marijuana before age 16, defined as early age of onset (EAO), have more behavioral problems, and a higher rate of mental disorders, including the development of psychotic symptoms and psychotic disorders. It has also been shown that PME predicts the age of onset of marijuana use. This presentation will use the findings from the Maternal Health Practices and Child Development Study, which is a longitudinal study of the long-term effects of PME. In this study, mothers were recruited during their fourth prenatal month and the mothers and offspring have been followed through the offspring age of 22 years. The cohort size at birth was 519 mother/ child pairs. This presentation will discuss these two critical exposure periods and the effects of exposure to PME and EAO on subsequent behaviors and psychiatric symptomatology and disorders. doi:10.1016/j.ntt.2012.05.019
NBTS 19 Illicit and prescription drugs targeting the developing serotonergic system have deleterious effects on cognition Tori Schaefera, Curtis Graceb, Devon Grahamc, Matthew Skeltona, Michael Williamsa, Charles Vorheesa
tested during drug administration and during drug abstinence. THC altered activity, anxiety, and cocaine reward differently in male and female rats. Possible mechanisms for these sex differences will also be presented. In summary, the role of endocannabinoids in brain development and the effects of THC administration during the prenatal or adolescent period will be presented. THC produces long-term effects on cognition, affect, and drug reward. Therefore, smoking marijuana during pregnancy or adolescence has long-term effects on brain function. (Supported by NIH grants DA 019348 and P50 DA 025484-0001) doi:10.1016/j.ntt.2012.05.016
NBTS 16 Developmental cannabis exposure and its epigenetic consequences Yasmin Hurd Mount Sinai School of Medicine, New York, NY, United States Marijuana (Cannabis sativa) continues to be the most used illicit drug in the USA with recent years showing a disconcerting increased use among teens and reduced perceived risk of harm associated with the use of this drug. Such perception also fuels the debates as to whether there are any significant developmental effects of cannabis exposure. To address these questions and to obtain insights into the potential relationship of developmental cannabis exposure to psychiatric vulnerability, we have studied molecular mechanisms in the brains of human subjects with in utero cannabis exposure, as well as animal models in which drug history could be controlled and causal effects on behavior could be better established. Our results have revealed specific long-term molecular disturbances of prenatal and adolescent cannabis/D9-tetrahydrocannabinol (THC; psychoactive component of cannabis) exposure of genes associated with mesolimbic striatopallidal circuit (e.g., proenkephalin and D2). The fact that these striatopallidal genes are critical to reward and impulsivity suggests the potential of early cannabis exposure to disturb neurobiological systems significantly associated with addiction vulnerability in line with altered heroin self-administration behavior seen in our developmental THC rodent models. Moreover, our studies have begun to characterize specific THC-induced epigenetic histone modifications that appear to maintain the protracted discrete gene expression disturbances after exposure to the drug. In addition, new experiments have begun to reveal cross-generational effects associated with adolescent THC exposure. Overall, these and other ongoing studies emphasize the significant contribution of developmental cannabis to epigenetic disturbances that may relate to psychiatric vulnerability. doi:10.1016/j.ntt.2012.05.017
NBTS 17 Endocannabinoid-CB1R signaling: A link between early life stress and changes in limbic system function? Cecilia Hillard, Dylan Coss Medical College of Wisconsin, Milwaukee, WI, United States Considerable evidence has accumulated suggesting that endogenous CB1R signaling (ECS) is stress responsive. Recent studies in hypothalamus, hippocampus and prefrontal cortex demonstrate that glucocorticoids mobilize ECS. Endocrine and behavioral effects of stress are altered by ECS. For example, ECS in the medial prefrontal cortex is required for appropriate recovery of the hypothalamic–pituitary–adrenal axis following stress and inhibition of ECS potentiates anxiety-like behaviors in several models. ECS exhibits plasticity; it is down-regulated in several
373
models of chronic stress. Taken together, considerable experimental evidence supports the hypotheses that ECS functions as a stress buffer in the brain and can be modified by previous experience. Human epidemiological and preclinical evidence demonstrate that exposure to stress in early life results in life-long alterations in behavioral and endocrine responses to stress. Therefore, we hypothesized that stress in early life results in long-lasting alterations in ECS that contribute to changes in endocrine and behavioral responses to stress exposure in later life. Sprague Dawley dams and litters were exposed to limited bedding stress using the model of Baram and colleagues. From days 1–9 of age, bedding was reduced to one-third of normal (0.5 liters in a standard rat cage) in the stress cohort. Pups were sacrificed on day 10 and CB1R mRNA was quantified in prefrontal cortex (PFC) and amygdala using qPCR. In the PFC, significant main effects of both sex and stress exposure, as well as a significant interaction, occurred. Post hoc tests revealed that female pups had significantly greater CB1R mRNA expression than males. Stress exposure significantly reduced mRNA expression in both sexes; the effect was greater in females (75% reduction) than males. In amygdala, significant main effects of both sex and stress exposure were observed; post hoc tests revealed that stress produced a significant reduction in CB1R mRNA expression only in females. These data suggest that early life stress alters the expression of the CB1R in brain regions critical for stress responsivity in a sex-specific manner and support the hypothesis that early life stress can modulate ECS, particularly in female offspring. doi:10.1016/j.ntt.2012.05.018
NBTS 18 Developmental effects of marijuana exposure: Gestation and early adolescence Nancy L. Day University of Pittsburgh School of Medicine, Pittsburgh, PA, United States There are two points in human development that are known to be critical times for marijuana exposure. The first, exposure during gestation, has been shown to have long-term effects on the development of the offspring. These are CNS deficits expressed as behavioral and cognitive problems. There have been few reports of prenatal marijuana exposure (PME) affecting growth or morphology. The second vulnerable period is during early adolescence. Adolescents who begin to use marijuana before age 16, defined as early age of onset (EAO), have more behavioral problems, and a higher rate of mental disorders, including the development of psychotic symptoms and psychotic disorders. It has also been shown that PME predicts the age of onset of marijuana use. This presentation will use the findings from the Maternal Health Practices and Child Development Study, which is a longitudinal study of the long-term effects of PME. In this study, mothers were recruited during their fourth prenatal month and the mothers and offspring have been followed through the offspring age of 22 years. The cohort size at birth was 519 mother/ child pairs. This presentation will discuss these two critical exposure periods and the effects of exposure to PME and EAO on subsequent behaviors and psychiatric symptomatology and disorders. doi:10.1016/j.ntt.2012.05.019
NBTS 19 Illicit and prescription drugs targeting the developing serotonergic system have deleterious effects on cognition Tori Schaefera, Curtis Graceb, Devon Grahamc, Matthew Skeltona, Michael Williamsa, Charles Vorheesa