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Treatment with methamphetamine (MA) on postnatal days P11-20 induces adult spatial learning and memory deficits without affecting monoamine levels in various brain regions. In this study, we examined the pituitary and adrenal response of animals administered MA four times daily on P11, P11-15, or from P11 to P20. Corticosterone (CORT) and adrenocorticotropin hormone (ACTH) levels were assessed over a 1-hour period following MA exposure. On P11, MA produced marked elevations of both CORT and ACTH; this is during the stress hyporesponsive period (SHRP). On P15 and P20, the maximal effect of MA on CORT titers was observed at 30 min, with lower, but still significantly increased, levels at 60 min compared to controls. Males receiving MA on P15 had higher levels of ACTH than did control males, while no differences were noted among females. On P20, MA treatment resulted in higher levels of ACTH relative to vehicle-injected controls, but levels were not different from controls that were only weighed at each drug administration. MA treatment inhibited body, but not brain weight gain, resulting in hippocampal weights that were heavier in the MA-treated animals when expressed as a percent of body weight. The elevations of adrenal steroids by MA, during late phases of hippocampal neurogenesis, may contribute to neuronal alterations that are later manifested in deficits of learning and memory.

Prenatal cocaine treatment produces equivocal effects on spatial learning and memory; however, no data are available on neonatal treatment as a model of human third-trimester exposure. Sprague-Dawley rats were treated on postnatal days (P) 1-10 or 11-20 with cocaine (15 mg/kg x 4 per day at 2-h intervals) or saline (P1-P20) and evaluated as adults in the Morris water maze and on tests of activity, startle, scent marking, swimming immobility, and sequential learning. Neonatal cocaine had no effect on mortality; however, early treatment reduced body weight, whereas later treatment did not. Neonatal cocaine had no effects on exploratory activity, swimming ability, sequential learning, multiday activity rhythms, scent marking, or swimming immobility, but augmented acoustic startle amplitude in the early-treated group. Neonatal cocaine also produced an interaction on spatial learning in which the cocaine early-treated males performed slightly more efficiently than controls. Plasma cocaine concentrations were significantly higher in the early-treated group than the later-treated group despite receiving the same weight-adjusted doses. It was concluded that neonatal cocaine, when administered during a stage of brain development analogous to human third trimester, induces few behavioral effects based on the assessments used in this study.

Previous research has shown that rats exposed to phenytoin (PHT) in utero demonstrate abnormal circling, decreased learning, hyperactivity, and delayed air righting reflex development. The effects of prenatal PHT on offspring learning have been found on multiple-T mazes (Biel and Cincinnati types) and on spatial navigation (Morris maze). However, the specificity of the latter effects is unknown. Herein, we tested the effects of prenatal PHT in a Morris maze using six different procedures: cued versus spatial reference memory-based learning, cued versus spatial working memory-based learning, and cued versus spatial discrimination learning. PHT-exposed offspring showed increased preweaning mortality, growth reduction, and abnormal circling as noted in previous studies. PHT offspring were separated into those exhibiting circling and those not. PHT noncircling offspring demonstrated impaired reference memory-based spatial learning (acquisition and reversal), but no other effects. By contrast, PHT circling offspring demonstrated not only impaired reference memory-based spatial learning, but also impaired cued platform learning, impaired spatial discrimination, and impaired working memory-based learning. These data confirm that prenatal PHT induces a specific reference memory-based spatial learning deficit even in asymptomatic (noncircling) offspring that is distinct from the impairment induced in littermates exhibiting the circling impairment.

d-Methamphetamine (MA) is one of more than two dozen drugs included in the cytochrome P450-mediated "debrisoquine oxidation polymorphism" panel. The human gene (CYP2D6) is responsible for the "poor metabolizer" (PM) and "extensive metabolizer" (EM) phenotypes for drugs such as MA; a similar polymorphism (the CYP2D1 gene) exists in rats. Female Black or Dark Agouti rats exhibit the PM phenotype, whereas Sprague-Dawley (SD) rats show the EM trait. We sought to test the possibility that these strains of rats might exhibit altered MA-induced developmental neurotoxicity. Neonatal exposure to MA on days 11-20 has previously been shown to induce spatial learning deficits in Sprague-Dawley rats when tested as adults. Therefore, in the present experiment, on postpartum days 11 through 20, ACI (Black Agouti) and SD progeny were administered 30 mg/kg MA twice daily. MA treatment caused larger increases in mortality in ACI than in SD rats, suggesting that decreased MA metabolism leads to enhanced toxicity and lethality. Female offspring were assessed behaviorally as adults. No differences were observed in acoustic startle or straight swimming channel performance. In the Morris maze, both MA-treated rat strains showed longer latencies to find the hidden platform during acquisition, reinstatement, and shift trials, and spent less time in the target quadrant on probe trials; no strain differences in learning were found. Although these data do not support our hypothesis that MA-induced developmental neurotoxicity might be enhanced in the ACI rat, this interpretation is tempered by the high mortality rate (65%) of MA-treated ACI neonates, suggesting a possible "survivor effect" in this strain.

Neonatal exposure to methamphetamine (MA) has previously been shown to induce acoustic startle facilitation when the animals were tested as adults. The present experiment sought to replicate and extend this effect using a lower dose of MA and to determine if the effect varied as a function of prepulse stimulus intensity. Sprague-Dawley CD rat offspring were culled on the day after birth to eight (preferentially retaining females). On days 1-10, progeny were injected SC with either 20 mg/kg of d-MA twice per day (doses spaced at least 8 h apart) or distilled water. On postnatal day 50, offspring were administered 51 acoustic startle trials followed by 36 prepulse trials. Prepulse intensities were 0, 70, 75, 80, 85, or 90 dB. MA progeny showed augmented startle response amplitudes on both paradigms but the effect was most pronounced on the prepulse trials. Prepulse intensity interacted with MA treatment in that significant facilitation in the MA animals occurred on 0 and 70 dB prepulse trials but was only a trend (p < 0.10) on 75, 80, 85, and 90 dB trials. This implies that the effect of MA is most likely upon the basic startle reflex and not upon inhibitory pathways that modify startle reactivity.

Gravid Sprague-Dawley CD (VAF) rats were administered sodium phenytoin suspended in corn oil by gavage once per day on embryonic days 7-18 at a dose of 100 mg/kg. Controls were administered corn oil alone by gavage on E7-18. Litters were randomly culled to 10. Offspring were regularly weighted, mortality noted, and males checked for preputial separation. At approximately 50 days of age offspring were evaluated in a straight water-filled channel for swimming proficiency and motivation to escape. Following this, rats were tested in the Cincinnati multiple T-water maze and scored for errors, latency to find the goal, and presence of phenytoin-induced abnormal circling behavior while swimming. Sodium phenytoin-exposed dams gained weight normally and delivered normally. Offspring mortality in the sodium phenytoin group was not increased above controls. No treatment effects on preputial separation or offspring growth were observed. No differences between groups in swimming proficiency in straight channel performance were obtained. In the Cincinnati maze, phenytoin offspring committed significantly more errors and had longer latencies to find the goal than controls. Among the phenytoin offspring, those exhibiting abnormal circling committed more errors than noncircling animals. When compared to previous data using the same maze and test protocol, it was found that 100 mg/kg of sodium phenytoin induced performance deficits similar to those induced by a dose of 200 mg/kg of phenytoin acid. Accordingly, the present data help explain why other investigators have reported sodium phenytoin to be more developmentally neurotoxic than phenytoin acid. Because the prenatal neurotoxic effects seen with the salt of phenytoin occur at lower doses, it suggests that phenytoin is more developmentally neurotoxic than previously believed.

The air-righting reflex has been used for many years to assess reflex integrity in rodent developmental neurotoxicity investigations. However, little refinement of the technique has occurred. We describe two methodological improvements: (a) an improvement in the method of positioning rats for air-righting, and (b) a stop-action photographic method to capture the rat's mid-air performance. We also compare results obtained using a visual scoring method to the newly developed photographically based scoring method. Prenatal phenytoin exposure has been shown to induce marked delays in air-righting development (14), therefore, phenytoin was used as a positive control treatment. Pregnant rats were administered 200 mg/kg phenytoin in propylene glycol or propylene glycol alone by gavage once/day on E7-18. Offspring were tested in the same apparatus twice and scored for air-righting success either by direct observation or photographed and the photographs scored subsequently. Rats were administered 6 trials per day (3 trials with each method) on days 16-24 of postnatal development. Detailed analyses of the two methods included subdividing phenytoin animals into those exhibiting the neurological abnormality of circling later in life and those that did not. Both methods revealed that phenytoin animals were delayed in air-righting development compared to controls and both methods revealed that phenytoin-circlers were more impaired than phenytoin-noncirclers. Advantages of the photographic method were that it provided a more precise method of scoring and a permanent record of the animal's response. One disadvantage was that it did not distinguish groups quite as well as the visual method.