Social behavior of offspring following prenatal cocaine exposure in rodents: a comparison with prenatal alcohol.

Clinical and experimental reports suggest that prenatal cocaine exposure (PCE) alters the offsprings' social interactions with caregivers and conspecifics. Children exposed to prenatal cocaine show deficits in caregiver attachment and play behavior. In animal models, a developmental pattern of effects that range from deficits in play and social interaction during adolescence, to aggressive reactions during competition in adulthood is seen.

Effects of pre- and neonatal nicotine exposure in rodents: inconsistent evidence.

This review presents an analysis of the literature on behavioral effects of developmental exposure to nicotine, as assessed in rodent models that mimic the consequences for human offspring of maternal cigarette smoking. Despite the frequency of reports of low birth weight, hyperactivity, cognitive deficits, and psychiatric problems, inconsistencies exist in both the clinical and experimental literature. Confounding socioeconomic and other demographic variables may account for discrepancies in clinical reports, and the choice of developmental exposure period and the method of nicotine administration may explain differences in experimental outcomes.

Statistical issues and techniques appropriate for developmental neurotoxicity testing: a report from the ILSI Research Foundation/Risk Science Institute expert working group on neurodevelopmental endpoints.

The data from developmental neurotoxicity (DNT) guideline studies present a number of challenges for statistical design and analysis. The importance of specifying the planned statistical analyses a priori cannot be overestimated. A review of datasets submitted to the US Environmental Protection Agency revealed several inadequate approaches, including issues of Type I error control, power considerations, and ignoring gender, time, and litter allocation as factors in the analyses.

Prenatal ethanol preferentially enhances reactivity of the dopamine D1 but not D2 or D3 receptors in offspring.

Reports of prenatal ethanol (ETOH) effects on the dopamine system are inconsistent. In an attempt to clarify this issue, dams were given 35% ethanol-derived calories as the sole nutrient source in a liquid diet from the 10th through the 20th day of gestation (ETOH). Controls were pair-fed (PF) an isocaloric liquid diet or given ad libitum access to laboratory chow (LC).

Behavioral response profiles following drug challenge with dopamine receptor subtype agonists and antagonists in developing rat.

As part of an investigation into the effects of gestational ethanol (ETOH) exposure on the developing dopamine (DA) system, pregnant Sprague-Dawley rats were exposed to one of three conditions: ETOH, pair-fed (PF) to the ETOH group, or ad libitum lab chow controls (LC). In this paper we report behavioral drug challenge effects for offspring of the two control groups (PF and LC). Male and female pups between postnatal days (PNDs) 21 and 23 in age were exposed to one of three intraperitoneal/subcutaneous doses of one of eight drugs chosen to assess the functional status of the DA D(1), D(2), and D(3) receptor subtype, or a saline control.

Phenobarbital and dizocilpine can block methamphetamine-induced neurotoxicity in mice by mechanisms that are independent of thermoregulation.

Body temperature profiles observed during methamphetamine (METH) exposure are known to affect dopamine and tyrosine hydroxylase (TH) levels in the striatum of mice; hyperthermia potentiates depletion while hypothermia is protective against depletions. In the current study, the doses of METH were sufficiently great that significant dopamine and TH depletions occurred even though hypothermia occurred. Four doses, administered at 2 h intervals, of 15 mg/kg (4x15 mg/kg) D-METH significantly decreased TH and dopamine levels to 50% of control in mice becoming hypothermic during dosing in a 13 degrees C environment.

Gestational retinoic acid exposure in the rat: effects of sex, strain and exposure period.

Effects of gestational exposure to all-trans retinoic acid (RA) were assessed in the Long-Evans (hooded) and Sprague-Dawley (albino) rat strains. Two exposure periods were evaluated against vehicle controls. Both involved three consecutive daily per os doses of either 2.

Neonatal dexamethasone on day 7 in rats causes behavioral alterations reflective of hippocampal, but not cerebellar, deficits.

Developmental glucocorticoid treatment in rats has been shown to cause body and brain weight decrements concurrent with behavioral alterations. Here, Sprague-Dawley rats were treated with the synthetic glucocorticoid, dexamethasone (DEX), on postnatal day (PND) 7 (1.5 mg/kg, sc, injected in the morning and afternoon).

Retinoic acid exposure on gestational days 11 to 13 impairs swallowing in rat offspring.

We have previously reported that exposure to 10 mg/kg of all-trans-retinoic acid (RA) daily on the 11th, 12th, and 13th days of rat gestation is lethal to all fetuses so exposed, due to an inability to suckle [R.R. Holson et al.

Gestational stage-specific effects of retinoic acid exposure in the rat.

Although, or perhaps because, retinoids are among the earliest known behavioral teratogens, there is still little agreement about the behavioral effects of stage-specific exposure to these compounds. In these studies, pregnant albino rats were gavaged once daily with retinoic acid (RA) for 3 consecutive gestational days (GD), GD 8-10), GD 11-13, or GD 14-16. Dose levels were maximal levels compatible with survival (10, 2.

Pharmacokinetic considerations of dexamethasone-induced developmental toxicity in rats.

Dexamethasone (DEX) has been shown to elicit growth stunting and cleft palate in rat fetuses. This investigation characterized DEX dosimetry as various pharmacokinetic parameters and evaluated their impact on developmental toxicity endpoints. DEX pharmacokinetics was evaluated as a single dose on either gestation day (GD) 9 or 14, as well as on GD 14 after multiple daily dosing from GD 9 to GD 14.

Neonatal dexamethasone on day 7 causes mild hyperactivity and cerebellar stunting.

To investigate the effects of glucocorticoid treatment on central nervous system development, rats were injected with dexamethasone (DEX) (1-3 mg/kg) on postnatal day (PND) 3 or 7. DNA and protein content and concentration were measured in the cerebellum and hippocampus on PND 28 and 112. Whole and regional brain weights were measured at PND 28, 84, and 112.

Gestational exposure to cocaine or pharmacologically related compounds: effects on behavior and striatal dopamine receptors.

Gestational cocaine (COC) exposure has been reported to alter behavior and possibly dopamine (DA) receptors. In this paper, we further examined the effects of prenatal COC (40 mg/kg, s.c.

Minimal behavioral effects from moderate postnatal lead treatment in rats.

Developmental lead exposure continues to be a worldwide problem. This study investigated the behavioral effects resulting from developmental lead treatment in rats with corresponding physiological measures of lead exposure. Sprague-Dawley rats were treated with 350 ppm lead acetate from birth to weaning via the dam's drinking water.

Declines in stimulated striatal dopamine release over the first 32 h following microdialysis probe insertion: generalization across releasing mechanisms.

In a recent paper [R.R. Holson, J.

Behavioral effects of low-dose gestational day 11-13 retinoic acid exposure.

In a comparison article we report that maternal PO exposure to 2.5 mg/kg all-trans retinoic acid (RA) daily for 3 consecutive days over gestational days (GD) 11-13 produces a 10% reduction in weight of cerebellum at 4 weeks of age, not accompanied by other malformations. Here we report the results of a preliminary behavioral analysis of offspring exposed gestationally to RA as above.

A behavioral and neuroanatomical investigation of the lethality caused by gestational day 11-13 retinoic acid exposure.

In a companion article, we report that there is a sensitive period for all-trans retinoic acid (RA) lethality on gestational days (GD) 11-13. When dams were given 10 mg/kg RA daily for 3 consecutive days on GD 11-13, a number of pups were found dead in the home cage on the day of birth, and the remainder inevitably died due to an apparent inability to nurse. Here we report a set of experiments further investigating these effects.

Gestational retinoic acid exposure: a sensitive period for effects on neonatal mortality and cerebellar development.

This is the first in a series of studies investigating the developmental stage-specific neurobehavioral effects of all-trans retinoic acid (RA) exposure. Because high doses of this compound are known to be lethal to the developing organism, we first conducted a dose-response study to identify RA doses that produce low enough levels of gestational/postnatal mortality to make a behavioral analysis possible in survivors. Secondarily, at doses found to produce sufficient survivors on PND 28, effects on body and regional brain weights were examined.

Methylazoxymethanol-induced micrencephaly in the brown Norway strain: behavior and brain weight.

A single injection of 20 mg/kg methylazoxymethanol acetate (MAM) on gestational day 14 in Brown Norway rats produced micrencephalic offspring (whole brain approximately equal to 65% of control). Despite the micrencephaly, MAM-induced alterations in behavior assessed here were relatively mild. The MAM-treated rats exhibited increased activity under darkened conditions in a complex maze and marginally increased activity after a challenge of methamphetamine.

Prenatal fumonisin (FB1) treatment in rats results in minimal maternal or offspring toxicity.

To investigate the neurobehavioral and developmental effects of the mycotoxin, FB1, Sprague-Dawley rats were treated with FB1 on gestational days 13-20. In Experiment 1, FB1 was obtained from culture material and pregnant rats were gavaged with 0, 0.8 or 1.

Methamphetamine-stimulated striatal dopamine release declines rapidly over time following microdialysis probe insertion.

To investigate changes in striatal dopamine release over a series of brief methamphetamine (METH) exposures, METH was pulsed three times at 2-h intervals, with the first exposure occurring 2 h after microdialysis probe insertion. Whether METH was administered directly into the striatum via the microdialysate (20 microM of METH for 10 min), or via peripheral intraperitoneal (i.p.

Individual differences in dopamine release but not rotational behavior correlate with extracellular amphetamine levels in caudate putamen in unlesioned rats.

It has been postulated that differences in pharmacokinetics do not contribute to the well-known individual variability in response to amphetamine (AMPH), but this is yet to be investigated thoroughly. Therefore, rotational behavior of outbred rats (Sprague-Dawley, 4 months old) was recorded during microdialysis sessions and striatal microdialysate was analyzed concomitantly for AMPH and dopamine concentrations after a single injection of 2.5 mg/kg AMPH SC.

Functional effects of methylazoxymethanol-induced cerebellar hypoplasia in rats.

The behavioral effects of a series of methylazoxymethanol acetate (MAM) injections in neonatal rats were investigated. Pups were injected twice daily on days 5-8 after birth with 4 mg/kg MAM or saline. Similar treatment paradigms cause cerebellar hypoplasia, which is a result of a depletion of granule cells.

Effects of ischemia-hypoxia induced by interruption of uterine blood flow on fetal rat liver and brain enzyme activities and offspring behavior.

The effects of acute perinatal ischemia-hypoxia on fetal liver and brain energy metabolism, fetal brain total free fatty acid concentration and subsequent offspring behavior were investigated in rats. Ischemia-hypoxia was induced at term either by ligation of the uterine blood vessels or submersion of the entire uterine horn in warmed saline. Fetuses of the adjacent horn served as within-dam controls for all assessments and fetuses of dams which had not undergone the surgical stress served as independent controls for enzyme assays.

Nitric oxide regulation of methamphetamine-induced dopamine release in caudate/putamen.

A possible role for NO modulation of dopamine (DA) release in the caudate/putamen (CPU) during methamphetamine (METH) exposure was investigated using in vivo microdialysis in rats. Inclusion of the nitric oxide synthase (NOS) inhibitors NG-nitro-L-arginine (NOARG), NG-nitro-L-arginine methyl ester (L-NAME) or D-NAME (less potent inhibitor) in the microdialysis buffer prior to METH minimally affected basal levels of DA, DOPAC or HVA in CPU microdialysate. However, L-NAME and NOARG produced concentration-dependent decreases of up to 64% (100 microM) in CPU DA levels in microdialysate during exposure to four doses of METH (5 mg/kg i.