Vorhees CV, Skelton MR, Grace CE, Schaefer TL, Graham DL, Braun AA et al. Effects of (+)-methamphetamine on path integration and spatial learning, but not locomotor activity or acoustic startle, align with the stress hyporesponsive period in rats. Int J Dev Neurosci 27: 289-298

Division of Neurology, Department of Pediatrics, Cincinnati Children's Research Foundation and University of Cincinnati College of Medicine, 3333 Burnet Avenue, Cincinnati, OH 45229, USA.
International journal of developmental neuroscience: the official journal of the International Society for Developmental Neuroscience (Impact Factor: 2.58). 05/2009; 27(3):289-98. DOI: 10.1016/j.ijdevneu.2008.12.003
Source: PubMed


Rats treated with (+)-methamphetamine (MA) on postnatal days (P) 11-20 exhibit long-term spatial and path integration (Morris water maze (MWM) and Cincinnati water maze (CWM)) learning deficits whereas those treated on P1-10 do not. MA treatment increases corticosterone release in an age-dependent U-shaped pattern that corresponds to the stress hyporesponsive period (SHRP; P4-15). Here we tested the hypothesis that the cognitive effects induced by MA are associated with treatment that begins within the SHRP. Three treatment regimens were compared, P1-10, P6-15, and P11-20. One male/female pair/litter received 0, 10, or 25mg/kg MA/dose (four doses/day at 2h intervals given s.c. with 19-21 litters/regimen). Locomotor activity and acoustic startle were tested as behaviors not predicted to be associated with the SHRP. Cincinnati and Morris water maze findings were consistent with the hypothesis in that MA-treated animals exposed from P6-15 or P11-20 showed impaired learning compared to those exposed from P1-10; however, on probe trials in the Morris water maze, MA-induced memory impairments were not regimen-specific and were contributed to by all treatment regimens. All MA treatment regimens induced reductions in locomotor activity and acoustic startle facilitation as expected. No differential effect on prepulse trials was seen suggesting no impairment in sensory gating. Cognitive deficits from neonatal MA treatment are associated with the SHRP and may be the product of hypothalamic-pituitary-adrenal (HPA) axis dysregulation during critical periods of brain development.

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    • "However to date, the current literature with regards to prenatal MA exposure has failed to reflect an accurate clinical experience in aspects such as route of administration, dose of MA and time and duration of MA exposure. For example, the most common route of administration in these animal studies is subcutaneous (s.c.) injection with 88% of the existing studies using this route (Vorhees et al., 2009; Grace et al., 2010; Slamberova et al., 2011). Intraperitoneal (i.p.) injection has also been used in some studies (Inoue et al., 2004; Wong et al., 2008; Siegel et al., 2010) and this shows the same advantages and disadvantages as the s.c. "
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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.
    International journal of developmental neuroscience: the official journal of the International Society for Developmental Neuroscience 06/2014; 35. DOI:10.1016/j.ijdevneu.2014.03.005 · 2.58 Impact Factor
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    • "Animal studies also found that acute low-dose amphetamine, METH or cocaine could facilitate memory performance (Kennedy et al., 2010; Wood et al., 2007), especially the consolidation of memory (Iñiguez et al., 2011; Wiig et al., 2009). Memory impairment was also detected in both humans and rodents which had been exposed to METH (Belcher et al., 2007; Kalechstein et al., 2003; Nordahl et al., 2003; Simon et al., 2000; Vorhees et al., 2009). "
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    ABSTRACT: Drugs of abuse modulated learning and memory in humans yet the underlying mechanism remained unclear. The extracellular signal-regulated kinase (ERK) and the transcription factor cAMP response element-binding protein (CREB) were involved in neuroplastic changes associated with learning and memory. In the current study, we used a Morris water maze to examine the effect of methamphetamine (METH) on different processes of spatial memory in mice. We then investigated the status of ERK and CREB in the hippocampus and prefrontal cortex (PFC). We found that 1.0 mg/kg dose of METH facilitated spatial memory consolidation when it was injected immediately after the last learning trial. In contrast, the same dose of METH had no effect on spatial memory retrieval when it was injected 30 min before the test. Furthermore, 1.0 mg/kg dose of METH injected immediately after retrieval had no effect on spatial memory reconsolidation. Activation of both ERK and CREB in the hippocampus was found following memory consolidation but not after retrieval or reconsolidation in METH-treated mouse groups. In contrast, activation of both ERK and CREB in the PFC was found following memory retrieval but not other processes in METH-treated mouse groups. These results suggested that METH facilitated spatial memory consolidation but not retrieval or reconsolidation. Moreover, activation of the ERK and CREB signaling pathway in the hippocampus might be involved in METH-induced spatial memory changes.
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    • "In addition, a large database on cross-species comparisons of brain development shows P11 in the rat corresponds with human in-utero brain development at 26 weeks for cortical and 19 weeks for limbic structures (Clancy et al., 2007b;Clancy et al., 2007a). We previously demonstrated that P11–15 and P11–20 MA exposure results in learning deficits in the Cincinnati (CWM) and Morris (MWM) water mazes (Williams et al., 2002;Williams et al., 2003c;Vorhees et al., 2009) and that the shorter interval (P11–15) induces effects smaller than those induced by the longer interval (P11–20) (Vorhees et al., 2008;Williams et al., 2003b). These exposure periods also produce morphological changes in the dentate gyrus and nucleus accumbens (Williams et al., 2004). "
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    ABSTRACT: In rats, neonatal (+)-methamphetamine (MA) exposure and maternal separation stress increase corticosterone during treatment and result in learning and memory impairments later in life. Early-life stress also changes later responses to acute stress. We tested the hypothesis that neonatal MA exposure would alter adult corticosterone after acute stress or MA challenge. Rats were treated with MA (10 mg/kg × 4/day), saline, or handling on postnatal (P) days 11-15 or 11-20 (days that lead to learning and memory impairments at this dose). As adults, corticosterone was measured before and after 15 min forced swim (FS) or 15 min forced confinement (FC), counterbalanced, and after an acute MA challenge (10 mg/kg) given last. FS increased corticosterone more than FC; order and stress type interacted but did not interact with treatment; treatment interacted with FS but not with FC. In the P11-15 regimen, MA-treated rats showed more rapid increases in corticosterone after FS than controls. In the P11-20 regimen, MA-treated rats showed a trend toward more rapid decrease in corticosterone after FS. No differences were found after MA challenge. The data do not support the hypothesis that neonatal MA causes changes in adult stress responsiveness to FS, FC, or an acute MA challenge.
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