ABSTRACT Acoustic startle response (ASR) is a defensive reflex that occurs shortly after presentation of a brief intense acoustic stimulus. It consists of a sudden contraction of facial and skeletal muscle. ASR in rodents is a gross vibration-like movement of the body that is easy to elicit, record, and analyze quantitatively. It can also be used as a reliable and sensitive measure of physiological mechanism of developmental toxicity. The basic neural mechanisms of ASR have been elucidated. The cochlear nucleus and the reticular nucleus of pons are essential to the induction and regulation of ASR amplitude. Fear or anxiety augments ASR (fear potentiation) and functionally involves amygdala. A brief presentation of a weak acoustic stimulus shortly before the presentation of a startling stimulus suppresses ASR (prepulse inhibition). Prepulse inhibition is thought to be regulated by the dopaminergic mesolimbic system. Taken together, these phenomena suggest the use of ASR as a means of modeling anxiety/fear and the sensorymotor abnormalities that may present themselves in a condition such as schizophrenia. In this review, the fundamental behavioral and neural features of ASR are described and major findings in connection with the toxicology of ASR are reviewed. Finally, the significance of ASR in the study of developmental toxicology including behavioral teratology is discussed.
ABSTRACT In order to investigate methamphetamine (MA)-induced neurotoxicity, two studies were carried out. In the first study, MA-induced neostriatal monoamine depletions in male and female Sprague-Dawley CD rats were studied under conditions in which the magnitude of MA- induced hyperthermia was comparable between the sexes. MA (5 or 10 mgikg) or saline (3 ml/kg) was administered S.C. four times at two hr intervals. Rectal temperatures were monitored for 9 hours in a room with an ambient temperature of 23 f 2°C. Animals were sacrificed three days post-treatment for the determination of dopamine (DA) and serotonin (5-HT). MA induced significant monoamine reductions but the magnitude of these reductions and of the hyperthermic responses were not significantly different between males and females. Unlike reports in mice, gender does not play a role in MA-induced monoamine reductions in rat neostriatum when MA-induced hyperthermia is comparable across sexes. In the second study, the neurotoxic effects of a single administration of MA were investigated. After a single dose of MA (1 0, 20, 30, or 40 mgikg, s.c.) or saline (3 ml/kg) to Sprague-Dawley CD male rats, rectal temperatures were monitored for 9 hours. Neostriatal DA, 5-HT, tyrosine hydroxylase (TH), and glial fibrillary acidic protein (GFAP) were assayed 3 days following MA treatment. MA induced significant dose-dependent hyperthermia. MA also induced dose-dependent reductions of DA, 5-HT and TH, and increases of GFAP.
These results demonstrate that a single-dose of MA can be as effective as the widely used four-dose regimen, provided ambient temperature is modestly increased. A single-dose model offers advantages for mechanistic studies, especially those employing antagonists or other agents thought to be neuroprotective.
ABSTRACT 3-Chloro-4-(dichloromethyl)-5-hydroxy-2(5~)-furanone (MX) causes complete inhibition of rat embryonic midbrain (CNS) cell differentiation in the micromass in vitro test when applied at a concentration of 5 pg/ml under conditions where MX is rapidly degraded in culture medium with a half-life of 56 min. This study investigated whether or not degradation products of MX have inhibitory effects on CNS cell differentiation following pre-incubation of MX in culture medium for 0.5, 1 or 2 hr. When MX was pre-incubated for 0.5 hr, the mean number of differentiated foci was 0.2 against 62.5 for the control. However, the number increased to 44.7 when pre-incubation time was extended to 2 hr. These results suggest that MX, but not its degradation products, is a teratogen in vitro. MX manifested almost complete inhibitory effects on CNS cell differentiation by 0.5 hr of exposure.
ABSTRACT The 3 year old girl has hypohydrotic ectodermal dysplasia, cleft lip and palate, striking alopecia with total absence of eye brows and body hair (alopecia universalis), epicanthic folds, strabismus, malpositioned small square-shaped teeth with absent one in the upper jaw, small fingers with dysplastic nails and toes, pilonidal sinus, partial syndactyly between the 2nd and 3rd toes, and slight developmental delay.