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Juvenile male rhesus macaques received therapeutic doses of fluoxetine daily from one to three years of age and were compared to vehicle-treated controls (N=16/group). Genotyping for monoamine oxidase A (MAOA) polymorphisms was used to form subgroups (N=8) with high and low expression of the gene. Behavioral responses were scored during 30-second exposures to pictures differing in affective content. As expected from its therapeutic effect, fluoxetine decreased the behavioral response to emotionally evocative pictures. A 44% reduction in number of expressive behaviors was seen, but only in subjects with low expression MAOA polymorphisms. In general, this effect occurred for pictures of varying affective content and was not due to altered occurrence of one specific behavior or type of behavior. The drug*genotype interaction was seen after one and two years of treatment and did not reverse one year after discontinuation of dosing. Two potential translational implications are suggested: (1) MAOA genetic polymorphisms may be the source of some of the variability in response to fluoxetine treatment in children; (2) extended fluoxetine treatment during juvenile brain development may result in persistent effects on emotional regulation., (Copyright © 2016 Elsevier B.V. and ECNP. All rights reserved.)

The oxytocin receptor antagonist barusiban, currently being developed for treatment of preterm labour, was investigated in pregnant cynomolgus monkeys with a 9-month postnatal follow-up of their offspring. The nature of barusiban, its indication, and the potential exposure of pre- and postnatal infants entailed the design of a unique protocol to investigate all aspects of maternal and offspring well-being. Barusiban was administered to the mothers from gestation day 85 until delivery with daily subcutaneous dosages up to 2.5mg/kg body weight/day. There were no test article-related effects seen in the mothers at any time during the study. The postnatal examination of offspring included routine toxicological parameters, as well as specialised investigation of the immune, cardiovascular, renal and central nervous systems, including a full behavioural assessment. A full pathology examination of offspring was performed at the end of the 9-month postnatal period. No adverse infant findings occurred.

Proteins of the Homer1 immediate early gene family have been associated with synaptogenesis and synaptic plasticity suggesting broad behavioral consequences of loss of function. This study examined the behavior of male Homer1 knockout (KO) mice compared with wild-type (WT) and heterozygous mice using a battery of 10 behavioral tests probing sensory, motor, social, emotional and learning/memory functions. KO mice showed mild somatic growth retardation, poor motor coordination, enhanced sensory reactivity and learning deficits. Heterozygous mice showed increased aggression in social interactions with conspecifics. The distribution of mGluR5 and N-methyl-D-aspartate receptors (NMDA) receptors appeared to be unaltered in the hippocampus (HIP) of Homer1 KO mice. The results indicate an extensive range of disrupted behaviors that should contribute to the understanding of the Homer1 gene in brain development and behavior.

The objective of this study was to investigate the behavioral and cognitive outcomes associated with chronic marginal iron (Fe) intakes during early development. Offspring (3 males and 3 females/litter) of Swiss-Webster female mice who had been fed a control Fe diet (75 microg Fe/g diet) or marginal Fe diet (14 microg Fe/g diet) for 9 wk before mating were weaned on postnatal (PND) 21. Offspring of marginal Fe dams were fed either the marginal Fe diet (marginal group) or a control diet (replete group) from PND 21 throughout the duration of the study, whereas offspring of control dams consumed the control diet ad libitum (control group). On PND 30, 45 and 60, one male and female per litter underwent grip strength and auditory startle testing. A Morris maze was used to assess cognitive function in males starting at PND 50. Marginal Fe mice consistently demonstrated significantly lower grip strength, which was independent of differences in body weight. In addition, marginal Fe males demonstrated attenuated startle responsiveness, as well as altered performance in the Morris water maze. These differences in performance were found in association with lower brain Fe concentrations. Postnatal Fe supplementation did not reverse all of these disturbances because differences in brain Fe concentrations and maze learning persisted. This study demonstrates that chronic marginal Fe intakes during early development can result in persistent biochemical and behavioral changes in mice.

Primate species demonstrate a prolonged period of development before reproductive maturity that includes distinctive periods of rapid growth in the late fetal, late infancy and early adolescent stages. Rhesus monkeys resemble humans in this discontinuous pattern of growth and also in its relationship to brain development. Studies of zinc deprivation in rhesus monkeys have suggested an important relationship among growth rate, nutrient status and behavioral performance in infancy as well as adolescence. Recently, moderate combined zinc and iron deprivation (intake 0.2 mg Zn and 0.8 mg Fe/d, compared with control intake of 2.9 mg Zn and 1.7 mg Fe/d) during the adolescent growth spurt (29-32 mo. of age) of female rhesus monkeys (n = 8/group) was shown to influence behavior without affecting growth. Behavioral assessments included the Continuous Performance Test, the Delayed Nonmatch to Sample Test and activity (measured with an actimeter). The behavioral syndrome was characterized by reduced activity, reduced participation in behavioral testing and slower response. These changes could be reversed or prevented to some extent by altering the diet to include tablets of powdered beef (adding approximately 1.7 mg Zn and 0.7 mg Fe to daily intake). The study suggests that behavior may be sensitive to the quality of the diet available during the period of rapid adolescent growth and development.

Background: The adolescent growth spurt and menarche increase iron and zinc needs and could precipitate functional deficiencies if dietary sources are inadequate., Objective: The effects of mild, combined zinc and iron deprivation during the growth spurt and the ability of meat as a common dietary source of zinc and iron to reverse these effects was studied., Design: Pubertal female rhesus monkeys were fed control diets (n = 8) or diets marginally deficient in zinc (2 microg/g diet; n = 8) and iron (10 microg/g diet; n = 8) for 3 mo. A powdered beef supplement (104 microg Zn/g and 43 microg Fe/g, 11 +/- 2 g/d) was then fed daily to half of the deprived group for 3 additional months., Results: Growth and hematology were not affected significantly by iron-zinc deprivation, but plasma zinc and iron were somewhat lower in the deprived group than in the control group after 3 mo. The deprived monkeys reduced their participation in behavioral testing, responded more slowly and less frequently to test stimuli, and were less active. The beef supplement increased participation in testing and stabilized activity levels, but response times remained depressed. Plasma ferritin was lower in the nonsupplemented deprived monkeys than in the controls by the end of the experiment. Four of 8 of the deprived monkeys had iron deficiency anemia compared with none of the controls and 1 of 8 who received the beef supplement., Conclusions: Marginal zinc and iron deprivation in early adolescence can lead to behavioral and hematologic dysfunction in nonhuman primates and dietary beef supplements can prevent and reverse some of these effects.

To assess the effect of perinatal epidural bupivacaine analgesia on infant behavioral development, bupivacaine (1.2 mg/kg) was administered to term-pregnant rhesus monkeys (treated, n = 11, procedural controls, n = 8) and infant behavior was evaluated for 1 year using a test battery including infant neurobehavioral tests, observation of spontaneous behavior, and structured cognitive testing. No adverse effects of bupivacaine were detected for neonatal neurobehavior, early cognitive abilities, or performance of cognitive tasks by older infants. Bupivacaine infants directed more, shorter fixations at visual stimuli during visual novelty preference testing. Observation of behavior maturation patterns showed that the increase in manipulatory activity that normally occurs at 2 months of age was delayed in bupivacaine infants, and the increase in motor disturbance behaviors that normally occurs at 10 months of age was prolonged. These results are interpreted in terms of life-history and brain maturation landmarks that appear at these ages. The data suggest that epidural bupivacaine does not cause neonatal abnormalities or specific cognitive deficits but can alter the normal course of behavioral development.

Lethargy is characteristic of malnourished populations, but little is known about the biologic mechanism or consequences for cognitive performance. In the current experiment, 24-h activity patterns and performance of an attention task were studied in adolescent female monkeys (18-33 mo of age, n = 10/group) under conditions of moderate dietary zinc deprivation (2 micrograms Zn/g diet) and adequate dietary zinc (50 micrograms Zn/g). There were progressive decreases in daytime activity levels in the zinc-deprived group followed by slowing of growth around the time of the growth spurt. Attention performance was also impaired before the onset of growth retardation. Zinc-deprived monkeys failed to show the shift to later initiation of the rest phase of the diurnal cycle seen in controls in late adolescence. These data support previous findings that activity and attention can be affected during early stages of zinc deprivation before the onset of growth retardation.

Swiss Webster mice were exposed to excess dietary aluminum (500 or 1000 micrograms Al/g as Al lactate) from conception until weaning or from conception through adulthood (pre- and postweaning). Controls were fed a 7 micrograms Al/g diet. Excess Al diets did not influence pregnancy outcome, pup mortality, and body or organ weights. Al diets of 1000 micrograms/g led to enhanced cagemate aggression in offspring as adults. At 50 days of age, mice were trained for operant tasks and subsequently 35 sessions of delayed spatial alternation or discrimination reversal testing were conducted. Both the 500 and the 1000 micrograms Al/g diets led to faster attainment of criterion during the training phase of the operant studies, but did not influence performance of the two tasks. At the conclusion of the study (150-170 days of age), neurobehavioral measures and tissue trace metals (Al, Fe, Mn) were determined. Both the 500 and the 1000 micrograms Al/g diets led to reduced grip strength and the 1000 micrograms Al/g diet was associated with lower Fe concentrations in brain and spinal cord. Brain, spinal cord, and liver Al concentrations were elevated only in adults with continued exposure after weaning. Throughout the experiment, mice exposed before and after weaning were apparently no more affected on behavioral measures than those exposed only until weaning. It is concluded that developmental exposure to 500 and the 1000 micrograms Al/g diets had distinctive long-term effects on behavioral measures that were not dose dependent and were not further intensified by continuing exposure as adults.

Potential long-term effects of intrapartum meperidine were studied in rhesus monkey infants whose dams received 0, 2, or 3 mg/kg meperidine, i.v., during labor (n = 5, 5, 3). Spontaneous behavior and cognitive performance were evaluated at 3-12 months of age. Observation of spontaneous behaviors indicated less age-related increase in quiet activities in drug-exposed infants. In the discrimination reversal test, drug-exposed infants had more balks (p = 0.008) and fewer correct choices (p = 0.008) during initial phases of the first reversal. Due to sex differences in the delayed alternation test, evaluation of drug effects on short-term memory was not possible. In the continuous performance test, drug-exposed infants performed better (NS) and had fewer omission errors (p = 0.034) during the second half of the test period. These initial findings suggest that short-term opiate exposure during labor can alter later behavior of infant monkeys.

We investigated whether opiate analgesics as commonly administered to women during labor would affect later response to maternal separation in infant guinea pigs. Meperidine hydrochloride (10-15 mg/kg i.m.) was administered to late-pregnant guinea pigs 5 min prior to labor induction with oxytocin. On Day 11 or 12 postnatal, pup distress vocalizations, locomotor activity, and plasma cortisol were measured under one of two conditions: alone (alone in a novel environment for 30 min) or mother (with the dam in the novel environment). Female pups exposed to intrapartum meperidine emitted fewer vocalizations than controls in the alone condition. Plasma cortisol was higher in meperidine females in the alone condition than in controls at the end of the separation period, but the difference was not significant. There was no drug effect on vocalizations or cortisol in males. Neither test condition nor drug affected activity level. The data suggest that intrapartum opiates may alter separation-induced distress in female guinea pig infants.

Young rhesus monkeys (Macaca mulatta, n = 14) 25-30 mo of age were fed a zinc-deficient (ZD) diet (2 micrograms Zn/g diet) (moderate zinc deprivation) over 15 week. The ZD diet period was compared with a zinc-adequate (ZA) diet period (50 micrograms Zn/g diet) of the same duration, which either preceded or followed it (crossover design). Plasma zinc was lower at the end of the ZD than after the ZA period. There were no overt signs of zinc deficiency or effects on growth rate. Spontaneous motor activity was lower and performance of a visual-attention task and short-term-memory task were poorer during the ZD period than during the ZA period. Behavioral effects were detected as changes from individual baseline values, and often represented a failure to improve. The results suggests that dietary zinc deprivation can modulate behavior in prepubertal monkeys without affecting growth.

Studies in mice have suggested that both dietary Al excess and dietary Mn deficiency promote oxidative tissue damage. To determine if these factors can interact to produce functional nervous system damage, female mice (N = 10-12 per group) were fed diets with control or low Mn (35 or 3 micrograms Mn/g diet) and/or control or high Al (25 or 1000 micrograms Al/g diet, Al as Al lactate) content for a 90-day period. No overt signs of neurotoxicity were observed in any group. Excess Al produced a threefold Al accumulation in both liver and brain, a slight acceleration of growth, decreased motor activity, decreased grip strength, and decreased startle responsiveness. Manganese deprivation led to liver, brain, and femur Mn depletion and reduced liver MnSOD activity but no neurobehavioral changes. No interactive effects between Al excess and Mn deficiency were observed. Neither Al excess nor Mn deficiency altered brain or liver lipid peroxidation measures. This study suggests that (1) subchronic dietary Al at doses of 1000 micrograms Al/g diet produces elevated brain Al and altered neurobehavioral indices in adult mice; (2) brain lipid peroxidation is not altered by this treatment; (3) dietary Mn deficiency does not influence Al neurotoxicity in adult mice.

The endogenous opiate system is thought to play a unique role in the adaptive response to hypoxia during the fetal and neonatal period. Exogenous opiates used as analgesics during labor may also affect this adaptive response. Infant monkeys (Macaca mulatta) were exposed to oxygen deprivation (15-min period breathing 12% O2) on the day of birth. One half of the infants had been exposed to meperidine during parturition via treatment of the dam (2 mg/kg, i.v.). An additional control group received neither treatment. All infants were evaluated for growth, development and neurobehavioral performance over a subsequent 14-week period. Compared to controls, infants exposed to oxygen deprivation had somewhat slower weight gains during the early neonatal transition from weight loss to weight gain, were less responsive to sensory stimulation on the day of the oxygen deprivation episode, slept more on the first night after the episode, had fewer active and mature behaviors during a 3-week period of rapid motor development, and had impaired fine motor skills. Prior exposure to labor analgesia apparently prevented many of these effects. Use of opiate drugs during the perinatal period needs to take into account the unique properties and functions of the endogenous opiate system during this developmental period.

Rhesus monkey infants were marginally deprived of zinc (4 ppm diet) from conception and were compared to controls (100 ppm diet) during the first year of life in development of reflexes and motor patterns, mother-infant interaction, delayed response performance, discrimination learning and reversal, and open field behavior. Deficits in amount and variety of behavior were recorded in deprived infants; spontaneous locomotor activity was 50% below control levels in males at 1 mo of age; spontaneous activity was 7-10% lower in both males and females at 3 mo of age; response latencies were 50% lower than controls at 7-9 mo; failure to reach discrimination reversal criterion was seen in 71% of deprived infants as compared to 10% of controls at 10 mo of age; and abnormally low levels of climbing and exploration were seen in two of six deprived infants at 12 mo of age. No abnormalities in the rate of behavioral development or in emotional adaptability were observed. These and other results suggest that syndromes of lethargy, apathy, and hypoactivity are characteristic of behavioral effects of marginal zinc deprivation in primates.

Female rats exposed prenatally to low levels of chlorpromazine were less susceptible as adults to the rate-reducing effects of chlorpromazine and pentobarbital on fixed-interval performance of a food-reinforced operant. Males were not significantly affected by prenatal treatment.

Aluminum (Al) as Al lactate in a purified diet (25, 500 or 1000 micrograms Al/g diet) was fed to Swiss-Webster mice from conception through weaning. Weights, food intake and toxic signs were recorded at regular intervals and pregnancy outcome evaluated. Pups were assessed for growth, neurobehavioral development and toxic signs prior to weaning. Offspring were also evaluated with a multi-item neurobehavioral test battery immediately after weaning and again after a 2-week period during which they were all fed control (25 micrograms/g Al) diet. No maternal or reproductive toxicity was detected and there were no group differences in pup mortality, growth, toxic signs, or neurobehavioral development prior to weaning, with the exception of poor performance in a climbing test in the 1000 micrograms Al/g diet group. Parameters significantly affected by Al in the postweaning neurobehavioral testing were foot splay, forelimb and hindlimb grip strengths, and thermal sensitivity. Negative geotaxis was inconsistently affected and startle responses were not affected. These results show that maternal dietary exposure to excess Al during gestation and lactation which do not produce maternal toxicity can result in persistent neurobehavioral deficits in weanling mice.

The behavior of rhesus monkey infants exposed to high levels (20 to 100 X the human therapeutic dosage) of an estrogen-progesterone contraceptive (Norlestrin) during embryogenesis was compared to that of untreated controls. No serious deficiencies in regulation of activity, motor maturity, manual dexterity or discrimination learning were recorded in the 3 to 5 month old infants. In addition, age appropriate sex-differentiated behavior was observed in social groups of treated infants at 5 and 11 months of age. On the basis of this information it seems unlikely that accidental use of birth control pills during early pregnancy will seriously affect behavioral competence of offspring during infancy.

Neurobehavioral evaluations were conducted in neonatal monkeys (Macaca mulatta) exposed to narcotic analgesics during labor through their dams. Infants exposed to meperidine (2 mg/kg maternal dose) or alfentanil (0.1 mg/kg maternal dose) were compared with controls whose dams received no analgesic. Meperidine and alfentanil differ in pharmacologic properties related to maternal-fetal transfer and neonatal metabolism. Drug-exposed infants showed neurobehavioral effects over the first 3 days of life including depressed respiration (at birth), depressed environmental response to aversive stimuli (days 0, 1, and 2), more overnight sleep (day 1), and more quiet behavior patterns while awake (day 3). In addition, drug exposure was associated with increased elicited muscle tone early in the neonatal period and earlier maturation of sitting, standing, and walking. No effects on growth or health were noted, but drug-exposed infants had lower hematocrits and an earlier onset of a linear growth rate as reflected in body weight. No qualitative or quantitative differences were noted between the two drug treatments. Because behavioral effects were seen after the drug was eliminated, a direct pharmacologic action of the drug does not fully explain the findings.