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Developmental stress, including low socioeconomic status (SES), can induce dysregulation of the hypothalamic-pituitary-adrenal axis and result in long-term changes in stress reactivity. Children in lower SES conditions often experience more stress than those in other SES groups. There are multiple model systems of early environmental stress (EES), one of which is reduced cage bedding. Here we tested the effects of both prenatal and lactational EES in rats on a range of long-term behavioral and cognitive outcomes. There were persistent reductions in body weight in the EES rats in both sexes. The behavioral results showed no effects on learning and memory using tests of spatial learning or cognitive flexibility in the Morris water maze, egocentric learning in the Cincinnati water maze, or working memory in the radial-arm maze. There were no effects on basic open-field activity, elevated zero-maze, or forced swim test, but EES rats had reduced time in the dark side of the light/dark test. When rats were drug challenged in the open-field with d-amphetamine or MK-801, there were no differential responses to d-amphetamine, but the EES group under responded compared with the drug-induced hyperactivity in the control group in both males and females. The objective was to establish a developmental stress model that induced cognitive deficits and to the extent that this method did not cause such effects it was not the model we sought. However, the data showed several long-term effects of EES, including the reduced response to the irreversible NMDA antagonist MK-801. This effect merits further investigation. • Developmental stress can cause long-term neurobehavioral effects. • Some developmental stressors cause long-term cognitive deficits. • Early Environmental Stress (EES) is reported to cause cognitive deficits in mice. • We tested whether EES in rats causes cognitive and behavioral deficits. • We did not find cognitive deficits in the EES group but found other effects. • The major finding was an under-response to the glutamatergic antagonist MK-801. [ABSTRACT FROM AUTHOR]

Summary The RASopathy neurofibromatosis type 1 (NF1) is one of the most common autosomal dominant genetic disorders. In NF1 patients, neurological issues may result from damaged myelin, and mice with a neurofibromin gene ( Nf1 ) mutation show white matter (WM) defects including myelin decompaction. Using mouse genetics, we find that altered Nf1 gene-dose in mature oligodendrocytes results in progressive myelin defects and behavioral abnormalities mediated by aberrant Notch activation. Blocking Notch, upstream mitogen-activated protein kinase (MAPK), or nitric oxide signaling rescues myelin defects in hemizygous Nf1 mutants, and pharmacological gamma secretase inhibition rescues aberrant behavior with no effects in wild-type (WT) mice. Concomitant pathway inhibition rescues myelin abnormalities in homozygous mutants. Notch activation is also observed in Nf1 +/− mouse brains, and cells containing active Notch are increased in NF1 patient WM. We thus identify Notch as an Nf1 effector regulating myelin structure and behavior in a RASopathy and suggest that inhibition of Notch signaling may be a therapeutic strategy for NF1. [ABSTRACT FROM AUTHOR]

Advantageous maneuvering through the environment to find food and avoid or escape danger is central to survival of most animal species. The ability to do so depends on learning and remembering different locations, especially home-base. This capacity is encoded in the brain by two systems: one using cues outside the organism (distal cues), allocentric navigation, and one using self-movement, internal cues (proximal cues), for egocentric navigation. Whereas allocentric navigation involves the hippocampus, entorhinal cortex, and surrounding structures, egocentric navigation involves the dorsal striatum and connected structures; in humans this system encodes routes and integrated paths and when over-learned, becomes procedural memory. Allocentric assessment methods have been extensively reviewed elsewhere. The purpose of this paper is to review one specific method for assessing egocentric, route-based navigation in rats: the Cincinnati water maze (CWM). The test is an asymmetric multiple-T maze arranged in such a way that rats must learn to find path openings along walls rather at ends in order to reach the goal. Failing to do this leads to cul-de-sacs and repeated errors. The task may be learned in the light or dark, but in the dark, wherein distal cues are eliminated, provides the best assessment of egocentric navigation. When used in conjunction with tests of other types of learning, such as allocentric navigation, the CWM provides a balanced approach to assessing the two major forms of navigational learning and memory found in mammals. [ABSTRACT FROM AUTHOR]

Cognitive tests of learning and memory (L&M) have been required by U.S. Environmental Protection Agency (EPA) developmental neurotoxicity test (DNT) guidelines for more than two decades. To evaluate the utility of these guidelines, the EPA reviewed 69 pesticide DNT studies. This review found that the DNT provided or could provide the point-of-departure for risk assessment by showing the Lowest Observable Adverse Effect Level (LOAEL) in 28 of these studies in relation to other reported end points. Among the behavioral tests, locomotor activity and auditory/acoustic startle provided the most LOAELs, and tests of cognitive function and the Functional Observational Battery (FOB) the fewest. Two issues arose from the review: (1) what is the relative utility of cognitive tests versus tests of unconditioned behavior, and (2) how might cognitive tests be improved? The EPA sponsored a symposium to address this. Bushnell reviewed studies in which both screening (locomotor activity, FOB, reflex ontogeny, etc.) and complex tests (those requiring training) were used within the same study; he found relatively little evidence that complex tests provided a LOAEL lower than screening tests (with exceptions). Levin reviewed reasons for including cognitive tests in regulatory studies and methods and evidence for the radial arm maze and its place in developmental neurotoxicity assessments. Driscoll and Strupp reviewed the value of serial reaction time operant methods for assessing executive function in developmental neurotoxicity studies. Vorhees and Williams reviewed the value of allocentric (spatial) and egocentric cognitive tests and presented methods for using the Morris water maze for spatial and the Cincinnati water maze for egocentric cognitive assessment. They also reviewed the possible use of water radial mazes. The relatively lower impact of cognitive tests in previous DNT studies in the face of the frequency of human complaints of chemical-induced cognitive dysfunction indicates that animal cognitive tests need improvement. The contributors to this symposium suggest that if the guidelines are updated, they be made more specific by recommending preferred tests and providing greater detail on key characteristics of such tests. Additionally, it is recommended that guidance be developed to address important issues with cognitive tests and to provide the information needed to improve the design, conduct, and interpretation of tests of higher function within a regulatory context. These steps will maximize the value of cognitive tests for use in hazard evaluation and risk assessment. [ABSTRACT FROM AUTHOR]

There are a variety of chemicals, including pharmaceuticals, that alter neurobehavior following developmental exposure and guidelines for the conduct of studies to detect such effects by statute in the United States and Europe. Guidelines for Developmental Neurotoxicity Testing (DNT) studies issued by the U.S. Environmental Protection Agency (EPA) under prevailing law and European Organization for Economic Cooperation and Development (OECD) recommendations to member countries provide that such studies include a series of neurobehavioral and neuropathological assessments. Among these are assessment of cognitive function, specifically learning and memory. After reviewing 69 DNT studies submitted to the EPA, tests of learning and memory were noted to have detected the lowest observed adverse effect level (LOAELs) less frequently than behavioral tests of locomotor activity and acoustic/auditory startle, but slightly more than for the developmental Functional Observational Battery (devFOB; which is less extensive than the full FOB), but the reasons for the lower LOAEL detection rate for learning and memory assessment could not be determined. A major concern identified in the review, however, was the adequacy of the methods employed in these studies rather than on the importance of learning and memory to the proper assessment of brain function. Accordingly, a symposium was conducted to consider how the guidelines for tests of learning and memory might be improved. Four laboratories with established histories investigating the effects of chemical exposures during development on learning, memory, and attention, were invited to review the topic and offer recommendations, both theoretical and practical, on approaches to improve the assessment of these vital CNS functions. Reviewers were asked to recommend methods that are grounded in functional importance to CNS integrity, well-validated, reliable, and amenable to the context of regulatory studies as well as to basic research on the underlying processes they measure. This Introduction sets the stage for the reviews by providing the background and regulatory context for improved tests for learning and memory in DNT and other regulatory studies, such as single- or multi-generational studies where similar methods are incorporated. [ABSTRACT FROM AUTHOR]

Maneuvering safely through the environment is central to survival of all animals. The ability to do this depends on learning and remembering locations. This capacity is encoded in the brain by two systems: one using cues outside the organism (distal cues), allocentric navigation, and one using self-movement, internal cues and sometimes proximal cues, egocentric navigation. Allocentric navigation involves the hippocampus, entorhinal cortex, and surrounding structures (e.g., subiculum); in humans this system encodes declarative memory (allocentric, semantic, and episodic, i.e., memory for people, places, things, and events). This form of memory is assessed in laboratory animals by many methods, but predominantly the Morris water maze (MWM). Egocentric navigation involves the dorsal striatum and connected structures; in humans this system encodes routes and integrated paths and when over-learned becomes implicit or procedural memory. Several allocentric methods for rodents are reviewed and compared with the MWM with particular focus on the Cincinnati water maze (CWM). MWM advantages include minimal training, no food deprivation, ease of testing, reliable learning, insensitivity to differences in body weight and appetite, absence of non-performers, control methods for performance effects, repeated testing capability and other factors that make this test well-suited for regulatory studies. MWM limitations are also reviewed. Evidence-based MWM design and testing methods are presented. On balance, the MWM is arguably the preferred test for assessing learning and memory in basic research and regulatory studies and the CWM is recommended if two tests can be accommodated so that both allocentric (MWM) and egocentric (CWM) learning and memory can be effectively and efficiently assessed. [ABSTRACT FROM AUTHOR]

Prenatal maternal immune activation increases risk for schizophrenia and/or autism. Previous data suggest that maternal weight change in response to the immune activator polyinosinic–polycytidylic (Poly IC) in rats influences the severity of effect in the offspring as does the exposure period. We treated gravid Sprague–Dawley rats from E14 to 18 with 8 mg/kg/day Poly IC or saline. The Poly IC group was divided into those that gained the least weight or lost (Poly IC (L)) and those that gained the most (Poly IC (H)) weight. There were no effects of Poly IC on anxiety (elevated zero-maze, open-field, object burying), or Morris water maze cued learning or working memory or Cincinnati water maze egocentric learning. The Poly IC (H) group males had decreased acoustic startle whereas Poly IC (L) females had reduced startle and increased PPI. Poly IC offspring showed exaggerated hyperactivity in response to amphetamine (primarily in the Poly IC (H) group) and attenuated hyperactivity in response to MK-801 challenge (primarily in the Poly IC (L) group). Poly IC (L) males showed reduced cued conditioned freezing; both sexes showed less time in the dark in a light–dark test, and the Poly IC groups showed impaired Morris water maze hidden platform acquisition and probe performance. The data demonstrate that offspring from the most affected dams were more affected than those from less reactive dams indicating that degree of maternal immune activation predicts severity of effects on offspring behavior. [ABSTRACT FROM AUTHOR]

This commentary is in response to the remarks of Drs. Christina Sobin, Mari Golub, and David Herr on the Special Issue of this Journal entitled “Assessment of Learning, Memory, and Attention in Developmental Neurotoxicology Regulatory Testing.” I endorse the views expressed by Drs. Sobin, Golub, and Herr and add some discussion on a recent Organization for Economic Cooperation and Development (OECD) guideline, the Extended One Generation Reproductive Toxicology Guideline (OECD 446), in which testing for higher cognitive function (learning and memory) has been eliminated. The case against this decision is offered. It is noted that deficits in higher cognitive function are one of the hallmarks of human studies that find neurobehavioral toxicity in children after exposure to environmental agents such as lead, methylmercury, PCB, pesticides, and other environmental agents. It is noted that the OECD decision is at variance with the views of the scientific community in this field, including those of Drs. Sobin, Golub, and Herr. Why OECD took such action without the advice and consent of the field of developmental neurotoxicology is deeply concerning and potentially hazardous to children. I also endorse Dr. Herr's recommendation that in the future the Environmental Protection Agency negotiate study designs in advance with submitters as the Food and Drug Administration does to improve data quality for all neurobehavioral methods, and especially for tests of learning and memory that have not been adequately conducted in many past studies. [ABSTRACT FROM AUTHOR]

Maneuvering safely through the environment is central to survival of all animals. The ability to do this depends on learning and remembering locations. This capacity is encoded in the brain by two systems: one using cues outside the organism (distal cues), allocentric navigation, and one using self-movement, internal cues and sometimes proximal cues, egocentric navigation. Allocentric navigation involves the hippocampus, entorhinal cortex, and surrounding structures (e.g., subiculum); in humans this system encodes declarative memory (allocentric, semantic, and episodic, i.e., memory for people, places, things, and events). This form of memory is assessed in laboratory animals by many methods, but predominantly the Morris water maze (MWM). Egocentric navigation involves the dorsal striatum and connected structures; in humans this system encodes routes and integrated paths and when over-learned becomes implicit or procedural memory. Several allocentric methods for rodents are reviewed and compared with the MWM with particular focus on the Cincinnati water maze (CWM). MWM advantages include minimal training, no food deprivation, ease of testing, reliable learning, insensitivity to differences in body weight and appetite, absence of non-performers, control methods for performance effects, repeated testing capability and other factors that make this test well-suited for regulatory studies. MWM limitations are also reviewed. Evidence-based MWM design and testing methods are presented. On balance, the MWM is arguably the preferred test for assessing learning and memory in basic research and regulatory studies and the CWM is recommended if two tests can be accommodated so that both allocentric (MWM) and egocentric (CWM) learning and memory can be effectively and efficiently assessed. [ABSTRACT FROM AUTHOR]

Summary: Patients with neurofibromatosis type 1 (NF1) and Costello syndrome Rasopathy have behavioral deficits. In NF1 patients, these may correlate with white matter enlargement and aberrant myelin. To model these features, we induced Nf1 loss or HRas hyperactivation in mouse oligodendrocytes. Enlarged brain white matter tracts correlated with myelin decompaction, downregulation of claudin-11, and mislocalization of connexin-32. Surprisingly, non-cell-autonomous defects in perivascular astrocytes and the blood-brain barrier (BBB) developed, implicating a soluble mediator. Nitric oxide (NO) can disrupt tight junctions and gap junctions, and NO and NO synthases (NOS1–NOS3) were upregulated in mutant white matter. Treating mice with the NOS inhibitor NG-nitro-L-arginine methyl ester or the antioxidant N-acetyl cysteine corrected cellular phenotypes. CNP-HRasG12V mice also displayed locomotor hyperactivity, which could be rescued by antioxidant treatment. We conclude that Nf1/Ras regulates oligodendrocyte NOS and that dysregulated NO signaling in oligodendrocytes can alter the surrounding vasculature. The data suggest that antioxidants may improve some behavioral deficits in Rasopathy patients. [Copyright &y& Elsevier]

Abstract: Developmental exposure to the dopamine D2/3 receptor agonist quinpirole is reported to induce D2 priming, impair Morris water maze performance, reduce acoustic startle prepulse inhibition (PPI), and alter locomotor activity. We treated rats from postnatal days 1–21 with the dose reported to induce these effects, 1.0 mg/kg/day, and two higher doses, 2.0 and 4.0 mg/kg/day, or saline. Offspring were tested in the Morris water maze, PPI, exploratory locomotor activity, activity after quinpirole and (+)-methamphetamine challenge, elevated zero maze, light-dark box, marble burying, straight channel swimming, and Cincinnati water maze. In the Morris water maze, all quinpirole groups had longer latencies on test days 3–5 of acquisition, but no effects on reversal or shifted-reduced platform trials. The quinpirole 4.0 mg/kg group had significantly reduced mean search distances on probe trials when combined across the 3 phases of testing but not separately. The male 4.0 mg/kg quinpirole group showed a greater increase in methamphetamine-stimulated activity during the first 10 min after drug challenge but not in the remainder of the 2 h test. No quinpirole effects were found for light-dark box, marble burying, exploratory locomotor activity, straight channel, Cincinnati water maze, or locomotor activity after quinpirole challenge. No effects were found on most measures in the elevated zero maze however the quinpirole 4.0 mg/kg females had longer latencies to enter an open quadrant. The results partially support prior Morris maze deficits induced by developmental quinpirole treatment but little evidence of dopamine D2/3 priming was found using locomotor activity with quinpirole or methamphetamine challenge or acoustic startle/PPI. The limited comparability to published data using developmental quinpirole exposure may be attributable to differences in experimental procedures or may be the result of quinpirole having limited effects. The data suggest that caution is warranted concerning the developmental efficacy of quinpirole. [Copyright &y& Elsevier]

Abstract: We have previously shown that P11–20 treatment with d-methamphetamine (MA) induces impaired spatial navigation in the Morris water maze (MWM), whereas P1–10 treatment does not. Little is known about the long-term behavioral consequences of MA during juvenile, adolescent, and early adult brain development. In dose–response experiments, we tested successive 10-day intervals of exposure to MA in rats (P21–30, P31–40, P41–50, and P51–60; four doses per day). MA dosing prior to P21 produces little or no toxicity; however, we observed an increased toxicity with advancing age. Across-age comparisons revealed no MWM acquisition or Cincinnati water maze (CWM) effects after MA treatment on P21–30 (2.5–10 mg/kg/dose), P31–40 (1.25–7.5 mg/kg/dose), or P51–60 (1.25–5.0 mg/kg/dose); however, significantly impaired MWM acquisition was observed after P41–50 MA treatment at the highest dose (6.25 mg/kg/dose). Learning in the CWM was also impaired in this group. No effects were seen at 1.25, 2.5, or 5 mg/kg/dose following P41–50 MA treatment. MWM reversal learning trials after P41–50 treatment showed a trend towards longer latency in all MA dose groups, but no effect on double-reversal trials. Reversal and double-reversal also showed no effects at the other exposure ages. No differences in straight channel swimming or cued learning in the MWM were seen after MA treatment at any exposure age. P41–50 is the periadolescent stage of brain development in rodents. The effects observed at this age may suggest a previously unrecognized period of susceptibility for MA-induced cognitive deficits. [Copyright &y& Elsevier]

Spatial learning and memory deficits in a water maze have been observed in adult animals exposed to a regimen of 4 daily doses of d-methamphetamine (MA) at 2 h intervals from postnatal day 11 to 20. An interpretational issue for these long-term effects of MA is whether they are truly spatial deficits or are secondary to alterations in sensorimotor systems. In this experiment, we evaluated the effects of a pretraining procedure shown to minimize the influence of drug-induced sensorimotor deficits. Animals within a litter were treated with MA or saline. Animals were either pretrained for nonspatial task requirements in the water maze (i.e., swimming and platform climbing) or were naı¨ve to the task. Animals that received the pretraining did better than the naı¨ve animals. The naı¨ve MA animals performed worse than the naı¨ve control animals as previously observed. By contrast, no difference in search time was noted between pretrained MA- and SAL-treated animals during the acquisition phase of testing. When the platform was relocated in a novel position, spatial learning was impaired for MA animals, regardless of pretraining. No increase in the number of platform nonrecognition events (swimovers, deflections, or jump-offs) occurred among pretrained or naı¨ve groups compared to controls. These data suggest that sensorimotor deficits do not account for the spatial learning and memory deficits in animals exposed neonatally to MA. [Copyright &y& Elsevier]

Apoptosis is an important process in the development and function of the central nervous system (CNS). To study the role of DNA fragmentation factor 45 (DFF45/ICAD) in CNS function, we previously generated DFF45 knockout mice. We found that whereas they exhibit apparently normal CNS development, DFF45 knockout mice exhibit an increased number of granule cells in the dentate gyrus and enhanced spatial learning and memory compared to wild-type mice in a Morris water maze test. In this study, we examined the performance of the DFF45 knockout mice in a novel object recognition task to measure short-term nonspatial memory that is believed to depend on the hippocampal formation. Both wild-type and DFF45 knockout mice exhibited novel object recognition 1 h posttraining. However, whereas wild-type mice no longer did so, DFF45 knockout mice were still able to differentiate the novel versus the familiar object 3 h posttraining. The longer memory retention in DFF45 knockout mice did not last up to 24 h as neither wild-type nor DFF45 knockout mice demonstrated novel object recognition 24 h posttraining. These results suggest that a lack of DFF45 facilitates hippocampus-dependent nonspatial memory, as well as hippocampus-dependent spatial memory. [Copyright &y& Elsevier]

Developmental neurotoxicity (DNT) studies could benefit from revisions to study design, data analysis, and some behavioral test methods to enhance reproducibility. The Environmental Protection Agency (EPA) reviewed 69 studies submitted to the Office of Pesticide Programs. Two of the behavioral tests identified the lowest observable adverse effect level (LOAEL) 20 and 13 times, respectively, while the other two tests identified the LOAEL only 3 and 4 times, respectively. The EPA review showed that the functional observational battery (FOB) was least effective at detecting the LOAEL, whereas tests of learning and memory (L&M) had methodological shortcomings. Human neurodevelopmental toxicity studies over the past 30 years show that most of the adverse effects are on higher cognitive functions such as L&M. The results of human studies together with structure-function relationships from neuroscience, suggest that tests of working memory, spatial navigation/memory, and egocentric navigation/memory should be added to guideline studies. Collectively, the above suggest that EPA and EU DNT studies would better reflect human findings and be more relevant to children by aligning L&M tests to the same domains that are affected in children, removing less useful methods (FOB), and using newer statistical models to better account for random factors of litter and litter × sex. Common issues in study design and data analyses are discussed: sample size, random group assignment, blinding, elimination of subjective rating methods, avoiding confirmation bias, more complete reporting of species, housing, test protocols, age, test order, and litter effects. Litter in DNT studies should at least be included as a random factor in ANOVA models and may benefit from inclusion of litter × sex as random factors. • Developmental neurotoxicity (DNT) studies need to improve rigor and reproducibility. • Regulatory DNT study guidelines need revision based on data in children. • Small N, lack of litter control, and correlated variables compromise DNT studies. • Litter and litter x sex should be random factors in ANOVA models. • Randomization, blinding, confirmation bias, and "helping" animals remain issues. [ABSTRACT FROM AUTHOR]

Two developmental stressors were compared in preweaning rats exposed to either one stressor or both. Stressors were barren cage rearing or maternal separation (pup isolation). 40 gravid Sprague-Dawley CD/IGS rats were randomly assigned to two cage conditions: standard (Std) cage or barren cage (Bar), 20 litters/condition throughout gestation and lactation. After delivery, litters were randomly culled to 4 males and 4 females. The second stressor was maternal separation: Two male/female pairs per litter were isolated from their dam 4 h/day (Iso) and two pairs were not (Norm). Hence, there were 4 conditions: Std-Norm, Std-Iso, Bar-Norm, and Bar-Iso. One pair/litter/stress condition received the following: elevated zero-maze (EZM), open-field, swim channel, Cincinnati water maze, conditioned fear, and open-field with methamphetamine challenge. The second pair/litter/condition received the light-dark test, swim channel, Morris water maze, forced swim, and EZM with diazepam challenge. Barren rearing reduced EZM time-in-open, whereas isolation rearing reduced open-field activity in males and increased it in females. Effects on straight channel swimming were minor. In the Cincinnati water maze test of egocentric learning, isolation rearing increased errors whereas barren cage housing reduced errors in combination with normal rearing. Barren cage with maternal separation (pup isolation) increased Cincinnati water maze escape latency but not errors. Barren cage housing reduced hyperactivity in response to methamphetamine. Isolation rearing increased time in open in the EZM after diazepam challenge. Trends were seen in the Morris water maze. These suggested that barren cage and isolation rearing in combination reduced latency on acquisition on days 1 and 2 in males, whereas females had increased latency on days 2 and 3. Combined exposure to two developmental stressors did not induce additive or synergistic effects, however the data show that these stressors had long-term effects with some evidence that the combination of both caused effects when either stressor alone did not, but synergism was not observed. • Compare barren cage rearing to maternal separation (pup isolation) on behavior. • Barren cage rearing increased anxiety-like behavior in the elevated zero maze. • Isolation reduced open-field activity in males and increased it in females. • Isolation increased Cincinnati water maze (CWM) errors, barren cage reduced them. • Barren + isolation increased anxiety-like behavior and decreased CWM performance. [ABSTRACT FROM AUTHOR]

The importance of litter effects (clustering of variance among offspring in rodents) has been known for decades. The standard approach was to treat the entire litter as a unit or to select one male and one female from each litter to prevent oversampling. These methods work but are imperfect. Treating the litter as a whole fails to use valuable interindividual differences among offspring, and selecting representative pups fails to use all the data available. Golub and Sobin [ https://doi.org/10.1016/j.ntt.2019.106841 ] address this using a better method. They show that using litter as a random factor in mixed linear models resolves this conundrum. As they demonstrate, such models control for litter clustering by partitioning litter variance from error variance. This reduces error variance and increases the power of F-tests of the independent variable(s). In our experience, this is the optimal solution. But as good as mixed linear models are when used with litter as a random factor, if other aspects of the experimental design are not appropriate, this cannot compensate for threats to validity from small sample sizes, dams not strictly randomly assigned to groups, repeated measure covariance structures not appropriately modeled, interactions not properly sliced, or a posteriori group comparisons not controlled for multiple comparisons. Appropriate handling of litter is only one consideration of experimental design and statistical analysis that when used in combination lead to valid, reproducible data. • In prenatal and many preweaning studies dam/litter is the unit of analysis. • It is known that within litter variance is less than between litter variance. • Golub and Sobin show the optimal statistical method to account for litter effects. • Litter should be a random factor in mixed linear ANOVA models. • Failure to control litter effects is a serious flaw found in many studies. [ABSTRACT FROM AUTHOR]

• ADHD is polygenic with multiple small effect gene variants contributing. • ADHD is associated with some environmental chemical or drug exposures. • Selectively bred and gene knockout models are reviewed. • Genetic and environmental models have been studied separately. • No two or three combination knockout/knockdown models have been described. Attention deficit hyperactivity disorder (ADHD) is a polygenic neurodevelopmental disorder that affects 8–12 % of children and >4 % of adults. Environmental factors are believed to interact with genetic predispositions to increase susceptibility to ADHD. No existing rodent model captures all aspects of ADHD, but several show promise. The main genetic models are the spontaneous hypertensive rat, dopamine transporter knock-out (KO) mice, dopamine receptor subtype KO mice, Snap-25 KO mice, guanylyl cyclase-c KO mice, and latrophilin-3 KO mice and rats. Environmental factors thought to contribute to ADHD include ethanol, nicotine, PCBs, lead (Pb), ionizing irradiation, 6-hydroxydopamine, neonatal hypoxia, some pesticides, and organic pollutants. Model validation criteria are outlined, and current genetic models evaluated against these criteria. Future research should explore induced multiple gene KOs given that ADHD is polygenic and epigenetic contributions. Furthermore, genetic models should be combined with environmental agents to test for interactions. [ABSTRACT FROM AUTHOR]

• Latrophilins are adhesion G-protein-coupled receptors. • Latrophilin-3 (Lphn3) is a trans-synaptic regulator of synaptic function. • 21 gene variants of LPHN3 are linked to ADHD. • Lphn3 disruption in Drosophila , zebrafish, mice, and rats result in hyperactivity. • Lphn3 KO rats show selective cognitive deficits and dopamine abnormalities. Latrophilin-3 (LPHN3), a G-protein-coupled receptor belonging to the adhesion subfamily, is a regulator of synaptic function and maintenance in brain regions that mediate locomotor activity, attention, and memory for location and path. Variants of LPHN3 are associated with increased risk for attention deficit hyperactivity disorder (ADHD) in some patients. Here we review the role of LPHN3 in the central nervous system (CNS). We describe synaptic localization of LPHN3, its trans-synaptic binding partners, links to neurodevelopmental disorders, animal models of Lphn3 disruption in different species, and evidence that LPHN3 is involved in cognition as well as activity and attention. The evidence shows that LPHN3 plays a more significant role in neuroplasticity than previously appreciated. [ABSTRACT FROM AUTHOR]

Abstract: Methylphenidate (MPD) is the most prescribed drug for attention deficit hyperactivity disorder. Licit and illicit use also occurs during pregnancy, however the effects from this use on offspring development are unknown. To model late gestational exposure, Sprague–Dawley litters were treated with 0, 5, 10, 20, or 30mg/kg×4/day every 2h with MPD on postnatal days 11–20 (within-litter design; days chosen to be comparable to human third trimester brain development). During treatment, body weights were decreased in MPD-treated groups; weight recovery occurred in all but the MPD-30 group by start of testing. MPD-treated rats showed no changes in anxiety (elevated zero maze), swimming ability (straight channel swimming), or spatial learning/reference memory (Morris water maze). MPD does not appear to pose a risk to these CNS functions after exposure during a stage of rat development analogous to third trimester human brain development. [Copyright &y& Elsevier]

Abstract: The elevated plus and zero mazes (Plus and Zero, respectively) are used to assess behavior related to anxiety in rodents but direct comparisons of the two tests are lacking for rats. We compared the two methods in adult male Sprague–Dawley rats. Untreated rats in the Zero spent more time in open zones and exhibited more head dips than in the Plus whereas start latency and closed area entries were lower in the Zero than in the Plus. Diazepam (1mg/kg) exposure increased time in the open in both mazes. Restraint (60min prior to testing), yohimbine (2.5mg/kg), and caffeine (100mg/kg) had the opposite effect, significantly decreasing time spent in open zones in both mazes. No sexual dimorphism in behavior was seen in either maze in untreated rats. Although more open area time was evident in untreated animals in the Zero, after drug challenge both mazes detected anxiolytic and anxiogenic effects equally. Zero maze data can be analyzed directly because no center region exists; otherwise the two methods appear comparable following challenge. [ABSTRACT FROM AUTHOR]

Abstract: Mucopolysaccharidosis type I (MPS I) is one of the most common lysosomal storage diseases with progressive neurological dysfunction. To characterize the chronological behavioral profiles and identify the onset of functional deficits in a MPS I mouse model (IDUA−/−), we evaluated anxiety, locomotor behavior, startle, spatial learning and memory with mice at 2, 4, 6 and 8 months of age. In automated open-field test, IDUA−/− mice showed hypoactivity as early as 2 months of age and altered anxiety starting from 6 months of age during the initial exploratory phase, even though normal habituation was observed at all ages. In the marble-burying task, the anxiety-like compulsive behavior was normal in IDUA−/− mice at almost all tested ages, but significantly reduced in 8-month old male IDUA−/− mice which coincided with the rapid death of IDUA−/− males starting from 7 months of age. In the Morris water maze, IDUA−/− mice exhibited impaired proficient learning only at 4 months of age during the acquisition phase. Spatial memory deficits were observed in IDUA−/− mice during both 1 and 7 days probe trials at 4 and 8 months of age. The IDUA−/− mice performed normally in a novel object recognition task at younger ages until 8 months old when reduced visual cognitive memory retention was noted in the IDUA−/− mice. In addition, 8-month-old IDUA−/− mice failed to habituate to repeated open-field exposure, suggesting deficits in non-aversive and non-associative memory. In acoustic startle assessment, significantly more non-responders were found in IDUA−/− mice, but normal performance was seen in those that did show a response. These results presented a temporal evaluation of phenotypic behavioral dysfunctions in IDUA−/− mice from adolescence to maturity, indicating the impairments, with different ages of onset, in locomotor and anxiety-like compulsive behaviors, spatial learning and memory, visual recognition and short-term non-associative memory retention. This study would also provide guidelines for the experimental designs of behavioral evaluation on innovative therapies for the treatment of MPS type I. [Copyright &y& Elsevier]

Abstract: Background and purpose: Hypoxic–ischemic injury in term neonates remains a significant cause of long-term neurological morbidity. The post-natal day 10 (P10) mouse is accepted as a model for the term human. This study was designed to assess the relationships between the duration of hypoxia–ischemia (HI) on P10 and the structural and functional neurological deficits that appear in the adult mouse as a consequence. Methods: Post-natal day 10 129T2×C57Bl/6 F1 hybrid mice were subjected to 0, 45, 60 or 75 min of hypoxia–ischemia using the Rice–Vannucci model. Beginning on P50 these mice were tested over the next 8 weeks using zero maze, locomotor activity, novel object recognition, cued, hidden and reduced Morris water mazes, delayed probe trials and response to apomorphine injection. Brain weights and histology were obtained at the end of testing. Results: The degree of structural and behavioral abnormalities in adult mice correlated with the duration of hypoxia–ischemia on P10. Useful behavioral tests for separating adult mice according to duration of hypoxia–ischemia on P10 include locomotor activity, the Morris water mazes and response to apomorphine. We found cued “learning” persisted, although latencies increased, with increasing HI time while spatial learning decayed as a function of HI time. Severe HI injury involving the ventral hippocampus resulted in excessive locomotor activity. Conclusions: After correcting for motor deficits, there is evidence for persistence of “cued” learning but not spatial learning with increasing hypoxia–ischemia time on P10 in this model system. [Copyright &y& Elsevier]

Background: ±3,4-Methylenedioxymethamphetamine (MDMA) is a recreational drug that causes cognitive deficits in humans. A rat model for learning and memory deficits has not been established, although some cognitive deficits have been reported. Methods: Male Sprague-Dawley rats were treated with MDMA (15 mg/kg x 4 doses) or saline (SAL) (n = 20/treatment group) and tested in different learning paradigms: 1) path integration in the Cincinnati water maze (CWM), 2) spatial learning in the Morris water maze (MWM), and 3) novel object recognition (NOR). One week after drug administration, testing began in the CWM, then four phases of MWM, and finally NOR. Following behavioral testing, monoamine levels were assessed. Results: ±3,4-Methylenedioxymethamphetamine-treated rats committed more CWM errors than did SAL-treated rats. ±3,4-Methylenedioxymethamphetamine-treated animals were further from the former platform position during each 30-second MWM probe trial but showed no differences during learning trials with the platform present. There were no group differences in NOR. ±3,4-Methylenedioxymethamphetamine depleted serotonin in all brain regions and dopamine in the striatum. Conclusions: ±3,4-Methylenedioxymethamphetamine produced MWM reference memory deficits even after complex learning in the CWM, where deficits in path integration learning occurred. Assessment of path integration may provide a sensitive index of MDMA-induced learning deficits. [Copyright &y& Elsevier]

Deltamethrin (DLM) is a Type II pyrethroid pesticide widely used in agriculture, homes, public spaces, and medicine. Epidemiological studies report that increased pyrethroid exposure during development is associated with neurobehavioral disorders. This raises concern about the safety of these chemicals for children. Few animal studies have explored the long-term effects of developmental exposure to DLM on the brain. Here we review the CNS effects of pyrethroids, with emphasis on DLM. Current data on behavioral and cognitive effects after developmental exposure are emphasized. Although, the acute mechanisms of action of DLM are known, how these translate to long-term effects is only beginning to be understood. But existing data clearly show there are lasting effects on locomotor activity, acoustic startle, learning and memory, apoptosis, and dopamine in mice and rats after early exposure. The most consistent neurochemical findings are reductions in the dopamine transporter and the dopamine D1 receptor. The data show that DLM is developmentally neurotoxic but more research on its mechanisms of long-term effects is needed. • Pyrethroid insecticides are used worldwide may adversely affect children. • Pyrethroids mechanisms and effects are reviewed with emphasis on deltamethrin. • Deltamethrin can cause acute and chronic effects on brain and behavior. • Deltamethrin is developmentally neurotoxic to dopamine systems. • Developmental deltamethrin causes cognitive impairments in rats and mice. [ABSTRACT FROM AUTHOR]

Developmental stress, including low socioeconomic status (SES), can induce dysregulation of the hypothalamic-pituitary-adrenal axis and result in long-term changes in stress reactivity. Children in lower SES households experience more stress and are more likely to be exposed to environmental neurotoxins such as lead (Pb) and manganese (Mn) than children in higher SES households. Co-exposure to stress, Pb, and Mn during early development may increase the risk of central nervous system dysfunction compared with unexposed children. To investigate the potential interaction of these factors, Sprague-Dawley rats were bred, and litters born in-house were culled on postnatal day (P)1 to 6 males and 6 females. One male and female within each litter were assigned to one of the following groups: 0 (vehicle), 10 mg/kg Pb, 100 mg/kg Mn, or 10 mg/kg Pb + 100 mg/kg Mn (Pb Mn), water gavage, and handled only from P4–28 with half the litters reared in cages with standard bedding (29 litters) and half with no bedding (Barren; 27 litters). Mn and Pb Mn groups had decreased anxiety, reduced acoustic startle, initial open-field hypoactivity, increased activity following (+)-methamphetamine, deficits in egocentric learning in the Cincinnati water maze (CWM), and deficits in latent inhibition conditioning. Pb increased anxiety and reduced open-field activity. Barren-reared rats had decreased anxiety, CWM deficits, increased startle, and initial open-field hyperactivity. Mn, Pb Mn, Pb Barren-reared groups had impaired Morris water maze performance. Pb altered neostriatal serotonin and norepinephrine, Mn increased hippocampal serotonin in males, Mn + Barren-rearing increased neostriatal serotonin, and Barren-rearing decreased neostriatal dopamine in males. At the doses used here, most effects were in the Mn and Pb Mn groups. Few interactions between Mn, Pb, and rearing stress were found, indicating that the interaction of these three variables is not as impactful as hypothesized. [ABSTRACT FROM AUTHOR]

Manganese (Mn) is an essential element but neurotoxic at higher exposure levels. The effects of Mn overexposure (MnOE) on hippocampal and striatal-dependent learning and memory in rats were tested in combination with iron deficiency (FeD) and developmental stress that often co-occur with MnOE. Moderate FeD affects up to 15% of U.S. children and developmental stress is common in lower socio-economic areas where MnOE occurs. Pregnant Sprague-Dawley rats and their litters were housed in cages with or without (barren cage (BAR)) standard bedding from embryonic day (E)7 to postnatal day (P)28. Dams were fed a 90% FeD or iron sufficient (FeS) diet from E15-P28. Within each litter, separate offspring were treated with 100 mg/kg Mn (MnOE) or vehicle (VEH) by gavage on alternate days from P4-28. Offspring were tested as adults in the Morris and Cincinnati water mazes. FeD and developmental stress interactively impaired spatial learning in the Morris water maze. Developmental stress and MnOE impaired learning and memory in both mazes. MnOE resulted in reduced CA1 hippocampal long-term potentiation (LTP) and increased levels of α-synuclein. Preweaning MnOE resulted in cognitive deficits on multiple domains of learning and memory accompanied by impaired LTP and α-synuclein changes, effects worsened by developmental stress. [ABSTRACT FROM AUTHOR]

Manganese (Mn) is an essential element but neurotoxic at higher exposures, however, Mn exposure seldom occurs in isolation. It often co-occurs in populations with inadequate dietary iron (Fe) and limited resources that result in stress. Subclinical FeD affects up to 15% of U.S. children and exacerbates Mn toxicity by increasing Mn bioavailability. Therefore, we investigated Mn overexposure (MnOE) in rats in combination with Fe deficiency (FeD) and developmental stress, for which we used barren cage rearing. For barren cage rearing (BAR), rats were housed in cages with a wire grid floor or standard bedding material (STD) from embryonic day (E)7 through postnatal day (P)28. For FeD, dams were fed a 90% Fe-deficient NIH-07 diet from E15 through P28. Within each litter, different offspring were treated with 100 mg/kg Mn (MnOE) or vehicle (VEH) by gavage every other day from P4-28. Behavior was assessed at two ages and consisted of: open-field, anxiety tests, acoustic startle response (ASR) with prepulse inhibition (PPI), sociability, sucrose preference, tapered beam crossing, and the Porsolt's forced swim test. MnOE had main effects of decreasing activity, ASR, social preference, and social novelty. BAR and FeD transiently modified MnOE effects. BAR groups weighed less and showed decreased anxiety in the elevated zero maze, had increased ASR and decreased PPI, and exhibited reduced sucrose preference compared with the STD groups. FeD animals also weighed less and had increased slips on the tapered beam. Most of the monoamine effects were dopaminergic and occurred in the MnOE groups. The results showed that Mn is a pervasive developmental neurotoxin, the effects of which are modulated by FeD and/or BAR cage rearing. [ABSTRACT FROM AUTHOR]

Background Voiding disorders in humans, particularly in children are associated with increased incidence of behavioral issues as well as past history of childhood abuse. We hypothesized that creating stress in mice, utilizing either a chronic social defeat model (SD) or restraint stress in shallow water model (RSSW) would engender changes in bladder function, morphology, and behavior, thereby enabling us to study the resultant voiding dysfunction. Methods For SD stress (14 days), C57BL/6 male mice were exposed daily to a larger aggressive CD-1 male for 10 min, followed by sensory exposure in a barrier cage for 24 h. Control mice were similarly housed with no exposure. For RSSW (21 days), C57BL/6 mice were put in a perforated conical tube with feet immersed in water daily for 4 h, then returned to single housing cages. Control mice were also in single housing. After the stress period, voiding patterns were obtained on filter paper, followed by behavioral tests. At necropsy, blood was taken for corticosterone analysis, and bladder and body weights measured. Bladder cryosections were stained with hematoxylin and eosin (H&E) for morphological assessment. Sequential sections were immunostained with antibodies to Ki-67 as a proliferation marker, CD31 (endothelial cell marker), and uroplakin-II. ImageJ software was used to measure bladder wall thickness on blinded H&E photomicrographs as well as quantitate CD31 staining. Both Ki-67-positive and -negative nuclei were counted with Imaris software to obtain a proliferation index. Results Only SD mice had a single large void pattern. Bladder-to-body weight ratios increased in SD mice (p ≤ 0.02) but not in RSSW mice. Plasma corticosterone levels were elevated in all stressed mice. SD mice exhibited lower levels of locomotor activity compared with controls; RSSW mice were hyperactive. In SD mice, bladder wall thickness was increased (p ≤ 0.003) but no change was seen in Ki-67 proliferation index, consistent with hypertrophy. No difference with control mice was seen in vascularity as visualized by CD31 staining. Uniform uroplakin-II staining lined the urothelium of both SD and control mice. Conclusions Mice exposed to repeated SD (14 days) respond with altered voiding indicative of urine retention, and exhibit bladder wall changes consistent with hypertrophy while the urothelial barrier is maintained. These changes were not observed with repeated RSSW. SD, in contrast to RSSW, provides a model of psychological stress to further study the interplay of behavior and bladder dysfunction, enabling an improved understanding of voiding dysfunction, and the ability to create innovative and more effective management pathways for children who present with voiding dysfunction. [ABSTRACT FROM AUTHOR]

Use of silver nanoparticles (AgNPs) for their antimicrobial properties is widespread. Much of the previous work on the toxicity of AgNPs has been conducted in vitro or following oral or intravenous administration in vivo. Intranasal (IN) instillation of AgNPs mimics inhalation exposure and allows further exploration of the toxicity of these particles via respiratory tract exposure. The present study involved 1) single-dose exposures to assess tissue distribution and toxicity and 2) repeated exposures to assess behavioral effects of IN AgNP exposure (nominally uncoated 25 nm AgNP). AgNP deposition was localized in the liver, gut-associated lymphoid tissue, and brain. Decrease cellularity in spleen follicles was observed in treated mice, along with changes in cell number and populations in the spleen. The splenic GSH:GSSG ratio was also reduced following AgNP exposure. Expression of the oxidative stress-responsive gene Hmox1 was elevated in the hippocampus, but not cortex of treated mice, as was the level of HMOX1 protein. Mice receiving 7 days of IN exposure to 50 mg/kg AgNPs exhibited similar learning- and memory-related behaviors to control mice, except that treated mice spent significantly less time in the target quadrant of the Morris Water Maze during the acquisition phase probe trial. These findings indicate systemic distribution and toxicity following IN administration of AgNPs. [ABSTRACT FROM AUTHOR]

Abstract: Although maternal cigarette smoking during pregnancy is a well-documented risk factor for a variety of adverse pregnancy outcomes, how prenatal cigarette smoke exposure affects postnatal neurobehavioral/cognitive development remains poorly defined. In order to investigate the cause of an altered behavioral phenotype, mice developmentally exposed to a paradigm of ‘active’ maternal cigarette smoke is needed. Accordingly, cigarette smoke exposed (CSE) and air-exposed C57BL/6J mice were treated for 6h per day in paired inhalation chambers throughout gestation and lactation and were tested for neurobehavioral effects while controlling for litter effects. CSE mice exhibited less than normal anxiety in the elevated zero maze, transient hypoactivity during a 1h locomotor activity test, had longer latencies on the last day of cued Morris water maze testing, impaired hidden platform learning in the Morris water maze during acquisition, reversal, and shift trials, and impaired retention for platform location on probe trials after reversal but not after acquisition or shift. CSE mice also showed a sexually dimorphic response in central zone locomotion to a methamphetamine challenge (males under-responded and females over-responded), and showed reduced anxiety in the light–dark test by spending more time on the light side. No differences on tests of marble burying, acoustic startle response with prepulse inhibition, Cincinnati water maze, matching-to-sample Morris water maze, conditioned fear, forced swim, or MK-801-induced locomotor activation were found. Collectively, the data indicate that developmental cigarette smoke exposure induces subnormal anxiety in a novel environment, impairs spatial learning and reference memory while sparing other behaviors (route-based learning, fear conditioning, and forced swim immobility). The findings add support to mounting evidence that developmental cigarette smoke exposure has long-term adverse effects on brain function. [Copyright &y& Elsevier]

Abstract: Enhanced oxidative stress or deficient oxidative stress response in the brain is associated with neurodegenerative disorders and behavioral abnormalities. Previously we generated a knockout mouse line lacking the gene encoding glutamate-cysteine ligase modifier subunit (GCLM). Gclm(−/−) knockout (KO) mice are viable and fertile, yet exhibit only 9–35% of wild-type levels of reduced glutathione (GSH) in tissues, making them a useful model for chronic GSH depletion. Having the global absence of this gene, KO mice – from the time of conception and throughout postnatal life – experience chronic oxidative stress in all tissues, including brain. Between postnatal day (P) 60 and P100, we carried out behavioral phenotyping tests in adults, comparing male and female Gclm(−/−) with Gclm(+/+) wild-type (WT) littermates. Compared with WT, KO mice exhibited: subnormal anxiety in the elevated zero maze; normal overall exploratory open-field activity, but slightly more activity in the peripheral zones; normal acoustic startle and prepulse inhibition reactions; normal novel object recognition with increased time attending to the stimulus objects; slightly reduced latencies to reach a random marked platform in the Morris water maze; normal spatial learning and memory in multiple phases of the Morris water maze; and significantly greater hyperactivity in response to methamphetamine in the open field. These findings are generally in agreement with two prior studies on these mice and suggest that the brain is remarkably resilient to lowered GSH levels, implying significant reserve capacity to regulate reactive oxygen species—but with regional differences such that anxiety and stimulated locomotor control brain regions might be more vulnerable. [Copyright &y& Elsevier]

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 (10mg/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 15min forced swim (FS) or 15min forced confinement (FC), counterbalanced, and after an acute MA challenge (10mg/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. [Copyright &y& Elsevier]

Summary: NPSR1 is a G protein coupled receptor expressed in multiple brain regions involved in modulation of stress. Central administration of NPS, the putative endogenous ligand of NPSR1, can induce hyperlocomotion, anxiolytic effects and activation of the HPA axis. The role of NPSR1 in the brain remains unsettled. Here we used NPSR1 gene-targeted mice to define the functional role of NPSR1 under basal conditions on locomotion, anxiety- and/or depression-like behavior, corticosterone levels, acoustic startle with prepulse inhibition, learning and memory, and under NPS-induced locomotor activation, anxiolysis, and corticosterone release. Male, but not female, NPSR1-deficient mice exhibited enhanced depression-like behavior in a forced swim test, reduced acoustic startle response, and minor changes in the Morris water maze. Neither male nor female NPSR1-deficient mice showed alterations of baseline locomotion, anxiety-like behavior, or corticosterone release after exposure to a forced swim test or methamphetamine challenge in an open-field. After intracerebroventricular (ICV) administration of NPS, NPSR1-deficient mice failed to show normal NPS-induced increases in locomotion, anxiolysis, or corticosterone release compared with WT NPS-treated mice. These findings demonstrate that NPSR1 is essential in mediating NPS effects on behavior. [ABSTRACT FROM AUTHOR]

Abstract: Rat neonatal methamphetamine exposure results in corticosterone release and learning and memory impairments in later life; effects also observed after neonatal stress. Previous attempts to test the role of corticosterone release after methamphetamine using corticosterone inhibitors were unsuccessful and adrenalectomy caused reductions in hippocampal serotonin greater than those caused by methamphetamine alone. Here we tested whether adrenal autotransplantation could be used to attenuate methamphetamine-induced corticosterone release without also altering the effects of the drug on serotonin. Adrenal autotransplantation surgery occurred on postnatal day 9 followed by methamphetamine or saline treatment from postnatal day 11–20 (10mg/kg/dose×4/day). Plasma corticosterone and hippocampal serotonin and 5-hydroxyindoleacetic acid were determined 30min following the first treatment on each day between postnatal days 11–20. Adrenal autotransplantation attenuated neonatal methamphetamine-induced corticosterone release by ∼70% initially, ∼55% midway through treatment, and ∼25% by the end of treatment. Methamphetamine reduced serotonin and 5-hydroxyindoleacetic acid in the hippocampus in the ADXA rats to the same degree as in SHAM rats. The data show that neonatal adrenal autotransplantation is an effective method for partially reducing treatment-induced corticosterone release while providing sufficient corticosterone to sustain normal growth and development. The method should be applicable to other models of developmental stress/corticosterone release. [Copyright &y& Elsevier]

Abstract: Rationale: In rats, neurotoxic doses of methamphetamine (MA) induce astrogliosis, long lasting monoamine reductions, reuptake transporter down-regulation, and learning impairments. Objective: We tested whether comparable effects occur in C57BL/6 mice. Method: C57BL/6 mice were treated with 10mg/kgs.c.×4 MA on a single day and evaluated at various intervals thereafter. Results: The neurotoxic dose regimen of MA caused the predicted acute hyperthermia and increased striatal glial fibrillary acidic protein and reduced neostriatal dopamine. The MA-treated mice were hypoactive 24h later but not 48h later. MA-treated mice also showed exaggerated initial hyperactivity after a pharmacological dose of MA used to stimulate locomotion followed by a later phase of hypoactivity compared to saline-treated mice. No differences were observed on learning or memory tests (novel object recognition, egocentric, or spatial learning/memory). MA-treated mice showed a trend toward increased prepulse inhibition but not baseline acoustic startle reactivity. After testing, MA-treated mice showed reduced neostriatal dopamine and increased basal plasma corticosterone. Conclusions: A neurotoxic/binge regimen of MA in mice that produces the typical pattern of neurotoxic changes to those seen in rats, results in few behavioral changes. This may limit the utility of C57BL/6 mice for modeling the cognitive and behavioral effects described in human MA users who show such changes even after prolonged abstinence. [Copyright &y& Elsevier]

Abstract: The use of the club drugs 3,4-methylenedioxymethamphetamine (MDMA) and 5-methoxy-n,n-diisopropyltryptamine (Foxy) is of growing concern, especially as many of the effects, particularly during development, are unknown. The effects of these drugs upon homeostasis may be important since both are known to stimulate the hypothalamic–pituitary–adrenal axis. The purpose of this experiment was to examine alterations in rats in corticosterone and glucose following an acute exposure to these drugs at different stages of development: preweaning, juvenile, and adulthood. Both MDMA and Foxy increased corticosterone levels significantly at all ages examined, while glucose was elevated at all stages except at the juvenile time point (postnatal day 28). For both measures, there were no differences between the sexes with either drug. The data indicate that an acute exposure to these drugs alters CORT and glucose levels, raising the possibility that these changes may have effects on behavioral and cognitive function, as we and others have previously demonstrated. [Copyright &y& Elsevier]