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PubMed2004

Brain-derived neurotrophic factor serum concentrations are increased in drug-naive schizophrenic patients with chronic cannabis abuse and multiple substance abuse.

Neurotrophins such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are critically implicated in development and maintenance of function of neurons. Neurodevelopment is reported to be impaired in schizophrenia and vulnerable schizophrenic brains may be more sensitive to toxic influences. Thus, cannabis as a neurotoxin, may be more harmful to schizophrenic brains than to non-schizophrenic brains when used chronically. And neurotoxic events may promote disease-onset and lead to exaggerated release of neurotrophins. We investigated 157 drug-naive first-episode schizophrenic patients and found significantly elevated BDNF serum concentrations (by up to 34%) in patients with chronic cannabis abuse (n = 35, p < 0.001) or multiple substance abuse (n = 20, p < 0.001) prior to disease onset. Drug-naive schizophrenic patients without cannabis consumption showed similar results to normal controls and cannabis controls without schizophrenia. Thus, raised BDNF serum levels are not related to schizophrenia and/or substance abuse itself but may reflect a cannabis-related idiosyncratic damage of the schizophrenic brain. In line with this hypothesis, disease onset was 5.2 years earlier in the cannabis-consuming group (p = 0.0111).

Adult↗

PubMed2005

Human p53 tumor suppressor gene (TP53) and schizophrenia: case-control and family studies.

The human p53 tumor suppressor gene (TP53) is considered as a candidate susceptibility gene for schizophrenia because of its functions in neurodevelopment. To test for an association between TP53 and schizophrenia, both the case-control study and the transmission disequilibrium test (TDT) were performed on genotype data from eight polymorphisms in TP53. Our samples included 286 Toronto schizophrenia cases and 264 controls, and 163 Portuguese nuclear families. In the Toronto case-control study significant differences of allele frequencies of the CAA Ins/Del (p=0.027) and the 16bp Ins/Del (p=0.022) were detected. In TDT analysis we found significant differences for transmission of the CAA Ins/Del (p=0.017) in Portuguese schizophrenia families. Haplotype analysis also showed a significant association between TP53 and schizophrenia. These results provide further evidence that TP53 may play a role in the pathogenesis of schizophrenia.

Brain Chemistry↗

PubMed2006

Adequate antipsychotic treatment normalizes serum nerve growth factor concentrations in schizophrenia with and without cannabis or additional substance abuse.

Neurotrophins such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are important for the development and maintenance of neuron function. Neurodevelopment is thought to be impaired in schizophrenia, and vulnerable schizophrenic brains may be more sensitive to toxic influences. Thus, cannabis as a neurotoxin (and other substances) may be more harmful to schizophrenic brains than to non-schizophrenic brains, when used chronically. In a previous study we demonstrated an earlier disease onset and significantly higher serum NGF concentrations in drug-naïve schizophrenic patients with previous long-term cannabis abuse than in schizophrenics without cannabis abuse or cannabis abusers without schizophrenia. We therefore investigated whether this difference is still observed after treatment. Serum NGF measured in 114 treated schizophrenic patients (schizophrenia alone, n=66; schizophrenia plus cannabis abuse, n=42; schizophrenia plus multiple substance abuse, n=6) no longer differed significantly among those groups and from the control groups (healthy controls, n=51; cannabis controls, n=24; multiple substance controls, n=6). These results were confirmed by an additional prospective study in 28 patients suffering from schizophrenia (S) or schizophrenia with cannabis abuse (SC). Previously elevated serum NGF levels in the drug-naïve state, also differing between the groups (S: 83.44+/-265.25 pg/ml; SC: 246.89+/-310.24 pg/ml, S versus SC: p=0.03) dropped to 10.72+/-14.13 pg/ml (S) and 34.19+/-38.96 pg/ml (SC) (S versus SC, p>0.05), respectively, after adequate antipsychotic treatment. We thus conclude that antipsychotic treatment leads to recovery of neural integrity, as indicated by renormalized NGF values.

Adolescent↗

PubMed2006

TAp73alpha induces tau phosphorylation in HEK293a cells via a transcription-dependent mechanism.

p73 and tau both play roles in neurodevelopment and neurodegeneration. In this pilot study we show by Western blotting that TAp73alpha induces phosphorylation of human 2N4R tau at threonine-205 and at the PHF-1 epitope (serine366/serine404) in HEK293a cells. Neither the dominant negative isoform, DeltaNp73, nor a transcriptionally inactive mutant TAp73alpha(R292H) altered tau phosphorylation indicating that tau phosphorylation is dependent on the transcriptional activity of TAp73alpha. Consistent with this, confocal microscopy revealed that tau and TAp73alpha were spatially separated within the cell; tau being located in the cytoskeletal compartment whilst TAp73alpha was found in the nucleus. These findings have ramifications for microtubule dynamics associated with axonal growth during development and for neuronal death associated with Alzheimer's disease and other tauopathies.

Alzheimer Disease↗

PubMed2005

Polymorphisms of heat shock protein 70 gene (HSPA1A, HSPA1B and HSPA1L) and schizophrenia.

The heat shock protein 70 (HSP70) is believed to be involved in the pathogenesis of schizophrenia with regards to neurodevelopment. An aberration in the HSP70 has been proposed in schizophrenia patients, suggesting that it is a candidate gene for schizophrenia. This study aimed to investigate the association between the three polymorphisms of HSP70-1 (HSPA1A), HSP70-hom (HSPA1L) and HSP70-2 (HSPA1B) and schizophrenia. One hundred and sixty-one patients with schizophrenia and 165 controls were enrolled in the study. A polymerase chain reaction (PCR) with a restriction fragment length enzyme (RFLP) was used to genotype the HSPA1A, HSPA1L and HSPA1B polymorphisms. There were no significant differences in the allelic or genotype frequencies of the HSPA1A and HSPA1L polymorphisms between the schizophrenia patients and the controls, while there was a marginal difference in the genotype frequency of the HSPA1B polymorphisms, and a significant difference in the allelic frequency of the HSPA1B polymorphisms between the schizophrenia patients and the controls. There was no evidence of an association between the clinical variables and schizophrenia across the genotypes among the three HSP70 gene polymorphisms. These results suggest that a HSPA1B polymorphism might be related to the pathogenesis of schizophrenia at least in the Korean population. Therefore, larger studies from different ethnic groups should be performed to confirm these results.

Adult↗

PubMed2006

Cavum septi pellucidi and intrusive recollections in cancer survivors.

A previous study reported abnormally large cavum septi pellucidi (CSP) in posttraumatic stress disorder (PTSD). We utilized magnetic resonance imaging to examine the frequency of large CSP, as defined by Nopoulos et al. (1997), in cancer survivors with and without intrusive recollections in a sample identical to that of our previous study. The frequency of large CSP did not differ between the two groups. The results suggest that alteration in midline structures during the course of neurodevelopment may lead to severe PTSD, while subthreshold PTSD, such as intrusive recollections, appear not to be associated with such alterations.

Adult↗

PubMed2006

Developmental switch in the effects of TNFalpha on ventral midbrain dopaminergic neurons.

The cytokine tumour necrosis factor-alpha (TNFalpha) has been implicated in the pathogenesis of neurodegenerative conditions as well as in the establishment of neural networks during development. This study investigated the in vitro effects of TNFalpha on embryonic dopaminergic neurons of the ventral mesencephalon. TNFalpha treatment enhanced the number of dopaminergic neurons in cultures derived from E12.5 mice embryos in a dose-dependent manner. In order to achieve this effect TNFalpha signalled via NF-kappaB. This enhancement in cell number was found to be due to TNFalpha promoting the differentiation of dopaminergic neurons rather than to an increase in cell survival. In contrast, TNFalpha-treated cultures derived from E14 or E16 mice demonstrated a decrease in dopaminergic neurons, and this loss was negated by pharmacological inhibition of caspases. The data presented demonstrate that during embryonic development, dopaminergic ventral mesencephalic neurons switch their in vitro response to TNFalpha from neurotrophic to neurotoxic. This is the first report of a population of neurons exhibiting this switch in TNFalpha responsiveness during neurodevelopment.

Animals↗

PubMed2005

Concentrations of environmental chemicals associated with neurodevelopmental effects in U.S. population.

Humans are exposed to many environmental chemicals, some of which can potentially affect neurodevelopment. Fetuses, infants, and young children are the most susceptible to the effects of these chemicals. As part of the National Health and Examination Survey, 1999-2000, the Centers for Disease Control and Prevention analyzed biological samples for many of these chemicals in a representative sampling of the U.S. population. Concentration data of selected metals, persistent organic pollutants, organophosphorus and carbamate insecticides, and cotinine are presented. For example, the 95th percentile estimates for serum total PCBs (whole weight) in the population aged 20 years and older is about 2.7 ng/g. The 95th percentile estimates for serum dioxin total toxic equivalence in the U.S. population aged 20 years and older is between 40 and 50 pg/g lipid basis. In general, human levels of these chemicals are decreasing over time in the U.S. population. This reflects the effects of legislation, industry efforts, and changes in lifestyle/activity patterns in the U.S. population. These data will continue to be collected in 2-year cycles and thus allow changes in human levels to be followed.

Adolescent↗

PubMed2005

Association between in utero organophosphate pesticide exposure and abnormal reflexes in neonates.

The detrimental effects of organophosphate pesticide (OP) exposure on neurodevelopment have been shown in animals. The present study aimed to assess the relationship between in utero and early postnatal OP exposure and neonatal neurobehavior in humans, as measured by seven clusters (habituation, orientation, motor performance, range of state, regulation of state, autonomic stability, and reflex) on the Brazelton Neonatal Behavioral Assessment Scale (BNBAS). We assessed 381 infants < or = 2 months old and born to women participating in the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS) study, a longitudinal, birth cohort study of low-income, Latina women living in the agricultural community of the Salinas Valley, California. Exposure to OP pesticides was determined by urinary levels of dialkylphosphate (DAP) metabolites, including dimethyl and diethylphosphate metabolites, measured twice during pregnancy (M = 14 and 26 weeks gestation) and once post-delivery (M = 7 days postpartum). The relationship between exposure and BNBAS performance was examined for the entire sample and stratified by the median age at assessment, 3 days. We observed a significant association between exposure and the reflex cluster for the entire sample and for infants >3 days old (n = 184). Among the >3 day old infants, increasing average prenatal urinary metabolite levels were associated with both an increase in number of abnormal reflexes (total DAP: adjusted beta = 0.53, 95% CI = 0.23, 0.82; dimethyls: adjusted beta = 0.41, 95% CI = 0.12, 0.69; diethyls: adjusted beta = 0.37, 95% CI = 0.09, 0.64), and the proportion of infants with more than three abnormal reflexes (total DAP: adjusted OR = 4.9, 95% CI = 1.5, 16.1; dimethyls: adjusted OR = 3.2, 95% CI = 1.1, 9.8; diethyls: adjusted OR = 3.4, 95% CI = 1.2, 9.9). No detrimental associations were found between postnatal urinary metabolite levels and any of the BNBAS clusters for infants < or = 3 or >3 days old at assessment. Whether neonatal reflex functioning is predictive of neuropsychological functioning as the child matures will continue to be evaluated in this birth cohort.

Adult↗

PubMed2006

Developing methods for assessing neurotoxic effects in Hispanic non-English speaking children.

Many factors affect the growth and development of children, including chemicals in the environment. Children have greater exposure to toxicants than adults due to both behavior and their increased food: body-mass ratio. Furthermore, the developing brain and organ systems of infants and children and their immature metabolism also make them more vulnerable to environmental toxins. Children from all cultures and backgrounds are at risk. However, minorities may be at greatest risk. In order to evaluate the impact of environmental exposures on neurodevelopment it is necessary to have effective methods that will allow accurate conclusions to be drawn. We have developed a battery to assess neurobehavioral performance in non-English speaking Hispanic children ages 4 years and older. This paper will examine the associations between age and performance and present test-retest correlations. Two hundred and forty one Hispanic children between the ages of 4 and 9 years completed a neurobehavioral test battery twice, approximately 1 month apart. The battery consists of computerized tests from the Behavioral Assessment and Research System, tests selected from the Pediatric Environmental Neurobehavioral Test Battery, and the Object Memory Test. Multiple regression was used to examine the association between age, gender and mother's education on performance. All of the tests, except for Continuous Performance, showed that performance improved as the child gets older. Gender differences were found on several tests with females generally performing worse than males. Correlation coefficients on performance retest measures ranged from .51 to .88. This study has demonstrated the utility of using this test battery to assess cognitive and motor performance in non-English speaking Hispanic children. Tests in the battery assess a range of functions and the measures are sensitive to differences in ages. Test-retest correlations show the reliability of the battery. These support the use of this battery in both cross-sectional and longitudinal studies.

Child↗

PubMed2005

Taking an "intentional stance" on eye-gaze shifts: a functional neuroimaging study of social perception in children.

During middle childhood, children develop an increasing understanding of intentions and other social information conveyed through dynamic facial cues such as changes in eye-gaze direction. Recent work in our laboratory has focused on using functional magnetic resonance imaging (fMRI) in adults to map the neural circuitry subserving the visual analysis of others' actions and the intentions underlying these actions. In these studies, the superior temporal sulcus (STS) region has been continually implicated in processing shifts in eye gaze. Further, these studies have indicated that STS activity is modulated by the context within which eye-gaze shifts occur, suggesting that this region is involved in social perception via its role in the analysis of the intentions of observed actions. Still, no studies have investigated the neural circuitry supporting eye-gaze processing in children. We used event-related fMRI to examine brain activity in 7- to 10-year-old healthy children observing an animated virtual actor who shifted her eyes towards either a target object or empty space. Consistent with prior studies in adults, the STS, middle temporal gyrus, and inferior parietal lobule were sensitive to the intentions underlying the stimulus character's eye movements. These findings suggest that the neural circuitry underlying the processing of eye gaze and the detection of intentions conveyed through shifts in eye gaze in children are similar to that found previously in adults. We discuss these findings and potential implications for mapping the neurodevelopment of the social cognition and social perception abnormalities characteristic of autism.

Aging↗

PubMed2005

Ventricular enlargement in schizophrenia is associated with a genetic polymorphism at the interleukin-1 receptor antagonist gene.

Magnetic resonance imaging (MRI) studies have shown some morphological and volumetric peculiarities in brains of schizophrenic patients. The authors explored the influence of genetic polymorphisms at interleukin-1beta (IL-1B) and interleukin-1 receptor antagonist (IL-1RN) genes on these abnormalities. Hippocampus, lateral ventricles, and dorsolateral prefrontal cortex gray matter volumes were measured in a sample of 23 DSM-IV diagnosed schizophrenic patients of Spanish origin using MRI scans; MRI data were adjusted for age and brain volume using regression parameters from a healthy control group (n = 45). IL-1B and IL-1RN genes, involved in neurodevelopment and neurodegenerative processes, were analyzed in the patient sample. Patients carrying VNTR-allele*2 of IL-1RN gene showed a significant enlargement of both left (P = 0.002) and right (P = 0.01) ventricles. Sex and illness duration were controlled for in the analyses. Our results, though preliminary, suggest that IL-1RN gene might contribute to the ventricular volumetric changes observed in schizophrenic patients.

Adult↗

PubMed2006

Thalamo-cortical connectivity in children born preterm mapped using probabilistic magnetic resonance tractography.

Our aim was to investigate the feasibility of studying white matter tracts and connections between the thalamus and the cortex in 2-year-old infants who were born preterm by probabilistic magnetic resonance (MR) tractography. Using this approach, we were able to visualize and quantify connectivity distributions in a number of white matter tracts, including the corticospinal tracts, optic radiations, fibers of the genu and splenium of the corpus callosum, superior longitudinal fasciculus and inferior fronto-occipital fasciculus, and to map the distribution within thalamus of fibers connecting to specific cortical regions. In eleven infants with no MR evidence of focal cerebral lesions and appropriate neurodevelopment as shown by general quotient (GQ) scores above 100, we mapped cortical connections to the thalamus that appeared similar to those reported in adults. However, in a proof-of-principle experiment, we examined one further child with marked white matter abnormalities and found that the volume and pattern of thalamo-cortical connections were severely disrupted. This technique promises to be a useful tool for assessing connectivity in the developing brain and in infants with lesions.

Cerebral Cortex↗

PubMed2005

Increased temporal lobe gyrification in preterm children.

Preterm birth often results in significant learning disability, and previous magnetic resonance imaging (MRI) studies of preterm children have demonstrated reduction in overall cortical tissue with particular vulnerability in the temporal lobe. We measured cortical gyrification in 73 preterm and 33 term control children at 8 years of age and correlated these findings with tests of language ability to determine the associations among preterm birth, neurodevelopment and functional outcome. Preterm children demonstrated significantly increased bilateral temporal lobe gyrification index compared to term controls. Left temporal gyrification index was significantly negatively correlated with left temporal lobe gray matter volume as well as reading recognition scores in the preterm group. Cortical development in the temporal lobe appears to be differentially vulnerable to preterm birth.

Cerebral Cortex↗

PubMed2005

A possible role for dopamine D3 receptor stimulation in the induction of neurogenesis in the adult rat substantia nigra.

Small molecule neurotransmitters, such as dopamine, have been shown to regulate cell cycles in the developing brain [Spencer GE, Klumperman J, Syed NI (1998) Neurotransmitters and neurodevelopment: Role of dopamine in neurite outgrowth, target selection and specific synapse formation. Perspect Dev Neurobiol 5:451-467; Ohtani N, Goto T, Waeber C, Bhide PG (2003) Dopamine modulates cell cycle in the lateral ganglionic eminence. J Neurosci 23:2840-2850] and may provide an alternative to traditional growth factors for the regulation of neurogenesis. Specifically, the dopamine D3 receptor appears to play an important role in neural development, and shows a persistent expression through adulthood in the proliferative subventricular zone [Diaz J, Ridray S, Mignon V, Griffon N, Schwartz JC, Sokoloff P (1997) Selective expression of dopamine D3 receptor mRNA in proliferative zones during embryonic development of the rat brain. J Neurosci 17:4282-4292]. Furthermore, pharmacological stimulation of D3 receptors promotes proliferation of adult subventricular zone cells, both in vitro [Coronas V, Bantubungi K, Fombonne J, Krantic S, Schiffmann SN, Roger M (2004) Dopamine D3 receptor stimulation promotes the proliferation of cells derived from the post-natal subventricular zone. J Neurochem 91:1292-1301] and in vivo [Van Kampen JM, Hagg T, Robertson HA (2004) Induction of neurogenesis in the adult rat subventricular zone and neostriatum following dopamine D3 receptor stimulation. Eur J Neurosci 19:2377-2387]. In earlier work, we have demonstrated the induction of cell proliferation in the subventricular zone of the adult rat brain accompanied by a dramatic 10-fold induction of neurogenesis in the neighboring neostriatum, following administration of the preferential D3 receptor agonist, 7-hydroxy-N,N-di-n-propyl-2-aminotetralin [Van Kampen JM, Hagg T, Robertson HA (2004) Induction of neurogenesis in the adult rat subventricular zone and neostriatum following dopamine D3 receptor stimulation. Eur J Neurosci 19:2377-2387]. Dopamine D3 receptors have also been found in the substantia nigra [Diaz J, Pilon C, Le Foll B, Gross C, Triller A, Schwartz JC, Sokoloff P (2000) Dopamine D3 receptors expressed by all mesencephalic dopamine neurons. J Neurosci 20:8677-8684], a region of the adult brain shown to exhibit ongoing cytogenesis and neurogenic potential [Lie DC, Dziewczapolski G, Willhoite AR, Kaspar BK, Shults CW, Gage FH (2002) The adult substantia nigra contains progenitor cells with neurogenic potential. J Neurosci 22:6639-6649; Zhao M, Momma S, Delfani K, Carlen M, Cassidy RM, Johansson CB, Brismar H, Shupliakov O, Frisen J, Janson AM (2003) Evidence for neurogenesis in the adult mammalian substantia nigra. Proc Natl Acad Sci U S A 100:7925-7930]. We have found that chronic intraventricular administration of 7-hydroxy-N,N-di-n-propyl-2-aminotetralin triggers a profound induction of cell proliferation in the rat substantia nigra and promotes the adoption of a neuronal phenotype in a proportion of these newly generated cells.

Animals↗

PubMed2006

Perinatal allopregnanolone influences prefrontal cortex structure, connectivity and behavior in adult rats.

Cortical neurosteroid levels vary dramatically across development; during the second week of life elevated levels of allopregnanolone are associated with decreased GABA(A) receptor function. Since GABA(A) receptor modulation plays a role in proliferative regulation in developing neocortex, it is possible that endogenous neurosteroids such as allopregnanolone, acting through GABA(A) receptors, modulate cortical development. We augmented normally low levels with exogenous administration of allopregnanolone (10 mg/kg) during the first week of rodent life. The localization of parvalbumin-labeled cells was markedly altered; the ratio of cell number in the deep (layers V-VI) vs. superficial (layers I-III) layers of adult prefrontal cortex increased two-fold in rats administered allopregnanolone on postnatal day 1 or 5. The mechanism underlying these anatomical changes likely involves GABA(A) receptors because similar changes in interneuron placement were observed after neonatal benzodiazepine administration. Measures of mature cortical function were also altered after neonatal neurosteroid administration, including [(3)H]MK-801 binding, prepulse inhibition and amphetamine-induced locomotor activity. Moreover, neonatal allopregnanolone administration increases the number of parvalbumin-expressing neurons in medial dorsal nucleus of the thalamus while the total neuron number is decreased. These findings suggest that connectivity between the medial dorsal nucleus of the thalamus and prefrontal cortex is likely altered by neonatal neurosteroid administration and may result in a disinhibited frontal cortex. Disinhibition in the prefrontal cortex is associated with behavioral changes relevant to human psychosis and developmental disorders. If neurosteroids play a role in normal development of prefrontal/medial dorsal patency as suggested by these studies, then alterations in neurosteroid levels may contribute to abnormal neurodevelopment.

Animals↗

PubMed2006

Peri-pubertal maturation after developmental disturbance: a model for psychosis onset in the rat.

Schizophrenia is thought to be associated with abnormalities during neurodevelopment although those disturbances usually remain silent until puberty; suggesting that postnatal brain maturation precipitates the emergence of psychosis. In an attempt to model neurodevelopmental defects in the rat, brain cellular proliferation was briefly interrupted with methylazoxymethanol (MAM) during late gestation at embryonic day 17 (E17). The litters were explored at pre- and post-puberty and compared with E17 saline-injected rats. We measured spontaneous and provoked locomotion, working memory test, social interaction, and prepulse inhibition (PPI). As compared with the saline-exposed rats, the E17 MAM-exposed rats exhibited spontaneous hyperactivity that emerged only after puberty. At adulthood, they also exhibited hypersensitivity to the locomotor activating effects of a mild stress and a glutamatergic N-methyl-D-aspartate receptor antagonist (MK-801), as well as PPI deficits whereas before puberty no perturbations were observed. In addition, spatial working memory did not undergo the normal peri-pubertal maturation seen in the sham rats. Social interaction deficits were observed in MAM rats, at both pre- and post-puberty. Our study further confirms that transient prenatal disruption of neurogenesis by MAM at E17 is a valid behavioral model for schizophrenia as it is able to reproduce some fundamental features of schizophrenia with respect to both phenomenology and temporal pattern of the onset of symptoms and deficits.

Age Factors↗

PubMedDate not supplied

Neurobehavioral assessment of mice after developmental AZT exposure.

Azidothymidine (AZT) is administered to pregnant women with HIV to prevent the spread of infection to their fetuses. Since gestation is a period of critical neurodevelopment, it is important to determine the risk AZT exposure may pose to neurobehavioral function of the offspring. The current study focused on teratological risks of developmental AZT exposure to neurocognitive function. Male and female Swiss mice were administered AZT or vehicle (0, 100, or 200 mg/kg/day po given twice daily in equal amounts for 32 weeks before and during gestation). Adult male and female offspring (n = 10/sex/treatment group) underwent neurobehavioral testing focused on determining learning and memory capabilities in the radial-arm maze. AZT exposure did not cause significant deficits during radial-arm maze acquisition. No impairment was seen in asymptotic levels of choice accuracy indicative of working memory function. Attempts to unmask subtle learning impairments following developmental AZT by the introduction of behavioral challenges such as reduction of motivational state (food restriction either 4-6 h or 22-24 h) or imposition of intrasession delays of 1.5 min to 2.5 h were unsuccessful. With a 4-week intersession delay, a significant AZT Treatment x Delay effect was seen with a significantly greater decline seen in the controls as compared to the 100 mg/kg/day AZT group. Locomotor activity on the radial-arm maze was significantly affected by AZT treatment (100 mg/kg/day) during the acquisition phase, but not during the other test phases. No behavioral alterations were seen related to stress as measured by the elevated plus maze. Vestibulomotor functioning on the balance beam remained unaltered. Using an extended dosing regimen including dosing of both sires and dams, as well as placing a greater demand on reproductive system performance with three continuous breedings, this study detected only subtle neurobehavioral impairments in mice after prenatal AZT exposure at clinically relevant doses.

Age Factors↗