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NTP-CERHR Expert Panel Report on the reproductive and developmental toxicity of amphetamine and methamphetamine

Carleton University, Ottawa, Ontario, Canada
Birth Defects Research Part B Developmental and Reproductive Toxicology (Impact Factor: 0.77). 12/2005; 74(6):471-584. DOI: 10.1002/bdrb.20048
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    • "Rats were assigned randomly to control or MAtreated groups based on body weights and likelihood of pregnancy (n = 13 for controls, n = 18 for MA treatments). MA abusers generally use a dose starting at 20 mg with a common MA dose being 30 mg (Golub et al., 2005). When extrapolating this dose back to a preclinical model, the use of an allometric scale (Reagan-Shaw et al., 2008) takes into account the body weight and the body surface area of the human and the animal. "
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    ABSTRACT: Many preclinical studies have aimed to elucidate the effects of methamphetamine (MA) exposure during pregnancy on the offspring in recent years. However, the severity of effects on the neonate may be related to the subcutaneous (sc) route of administration of the drug that is often employed (88% of preclinical studies) and consequently the delivered dose that the foetus is exposed to. To date there is a paucity of comparative studies investigating different routes of administration for MA during pregnancy and it is not known how these different routes compare when it comes to neonatal outcome. Thus, the aim of this study was to determine if the route of administration of MA (oral gavage or sc injection) during pregnancy at a pharmacological dose affects the magnitude of neurodevelopmental and behavioural effects in the resultant rat offspring. Pregnant Sprague-Dawley dams (n = 10 dams/group) received MA (3.75 mg/kg) or control (distilled water) via oral gavage or sc injection from gestation day 7–21. A range of well-recognised neurodevelopmental parameters were examined in the offspring. When administered sc, MA significantly reduced maternal weight gain and altered maternal behaviour; mothers spent less time in the nest with pups and spent less time nursing compared to controls. Significant impairments in neurodevelopmental parameters were evident in both MA treatment groups. Somatic development such as pinna unfolding, fur appearance and eye opening were all delayed after MA exposure but these impairments were more pronounced in the MA sc group. Other somatic parameters such as ano-genital distance and body length were only impeded by sc MA. Behavioural development in the surface righting, inclined plane and forelimb grip tests were also altered for both MA treatment groups. This study demonstrates that prenatal MA can have a profound effect on neonatal outcome, but this can be exacerbated if given via the subcutaneous route, as well as producing additional effects not seen with the oral gavage route. Consequently, the route of administration should be considered when interpreting preclinical studies investigating prenatal MA exposure.
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    • "However, in the clinical situation we know that the offspring are exposed indirectly to the drug through breast milk and not by direct exposure via injection and so, the same should be performed in preclinical studies. Methamphetamine abusers generally use a dose starting at 20 mg with a common MA dose being 30 mg (Golub et al., 2005). When extrapolating this dose back to a preclinical model, the use of an allometric scale (Reagan-Shaw et al., 2008) takes into account the body weight and the body surface area of the human and the animal. "
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    ABSTRACT: In recent years methamphetamine (MA) use has become more prevalent, and of particular concern is its growing popularity of MA among women of childbearing age. However, to date, studies examining MA effects on the developing offspring in laboratory animals are limited. Thus, the aim of this study was to determine if in utero MA exposure in rats at pharmacological doses can have a negative impact on neonatal neurodevelopment and behaviour. Pregnant Sprague-Dawley dams (n = 10 dams/group) received MA (0, 0.625, 1.25, 2.5) once daily via oral gavage from gestational day 7-21. Maternal body weight, food and water consumption were recorded daily. A range of standard neurodevelopment parameters were examined in the offspring during the neonatal period. There were no neurodevelopmental deficits observed with offspring exposed to 0.625 mg/kg MA, in fact, there were enhancements of neurodevelopment in some parameters at this low dose. However, exposure to the 1.25 mg/kg MA dose resulted in significant impairments in surface righting reflex and forelimb grip in both sexes. Exposure to the 2.5 mg/kg MA dose resulted in a significant reduction in ano-genital distance in males, and in both sexes resulted in delayed fur appearance and eye opening, impairments in surface righting reflex and negative geotaxis, and a reduction in body length. In conclusion, this study demonstrates that pharmacologically relevant doses of MA can have profound dose-related effects on neonatal outcome. If extrapolated to the clinical scenario this will give cause for concern regarding the risks associated with this drug of abuse at relatively low doses.
    Full-text · Article · Jun 2014 · International journal of developmental neuroscience: the official journal of the International Society for Developmental Neuroscience
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    • "Previous MRS studies of normally developing children (Kreis et al. 1993), and of healthy mice (Weiss et al. 2009), found agedependent increases in tCR, NA, and GLX, similar to the levels observed in the MRS studies discussed above. Alternatively, it is possible that the known vasoconstrictive effects of PME could result in an alteration in cell energy metabolism in children with PME (Won et al. 2001; Golub et al. 2005). "
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    ABSTRACT: Prenatal methamphetamine exposure (PME) is a significant problem in several parts of the world and poses important health risks for the developing fetus. Research on the short- and long-term outcomes of PME is scarce, however. Here, we summarize present knowledge on the cognitive and behavioral outcomes of PME, based on a review of the neuroimaging, neuropsychology, and neuroscience literature published in the past 15 years. Several studies have reported that the behavioral and cognitive sequelae of PME include broad deficits in the domains of attention, memory, and visual-motor integration. Knowledge regarding brain-behavior relationships is poor, however, in large part because imaging studies are rare. Hence, the effects of PME on developing neurocircuitry and brain architecture remain speculative, and are largely deductive. Some studies have implicated the dopamine-rich fronto-striatal pathways; however, cognitive deficits (e.g., impaired visual-motor integration) that should be associated with damage to those pathways are not manifested consistently across studies. We conclude by discussing challenges endemic to research on prenatal drug exposure, and argue that they may account for some of the inconsistencies in the extant research on PME. Studies confirming predicted brain-behavior relationships in PME, and exploring possible mechanisms underlying those relationships, are needed if neuroscience is to address the urgency of this growing public health problem.
    Full-text · Article · Dec 2013 · Metabolic Brain Disease
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