Predictive in silico modeling of emetic potency of liquid cleaning products using an historical in vivo database.

The induction of vomiting by activation of mechanisms protecting the body against ingested toxins is not confined to natural products but can occur in response to manmade medicinal and non-medicinal products such as liquid cleaning products where it is a commonly reported adverse effect of accidental ingestion. The present study examined the utility of an historic database (>30 years old) reporting emetic effects of 98 orally administered liquid cleaning formulations studied in vivo (canine model) to objectively identify the main pro-emetic constituents and to derive a predictive model. Data were analysed by categorizing the formulation constituents into 10 main groups followed by using multivariate correlation, partial least squares and recursive partitioning analysis.

Evaluation of historic in vivo data to characterise the emetic properties of liquid cleaning products and provide a framework for the development of an in silico predictive algorithm.

Accidental ingestion of household cleaning products frequently results in emesis but the physicochemical properties responsible are not known. To investigate whether data collected during in vivo animal studies performed >30 years ago could provide novel insights into the components responsible, we re-analysed original studies from a total of 74 liquid cleaning formulations. The incidence of emesis was dose-related with ED values between 0.

Interactions of dopamine D1 and D2 receptor antagonists with D-methamphetamine-induced hyperthermia and striatal dopamine and serotonin reductions.

The effects of the dopamine D1 receptor antagonist R(+)-SCH-23390 and D2 receptor antagonist S(-)-eticlopride on d-methamphetamine-induced striatal monoamine reductions 72 h after treatment were investigated in relation to changes in body temperature. Rats were administered four 10-mg/kg doses of d-methamphetamine or saline with a 2-h interval between treatments; 0.5 mg/kg eticlopride or SCH-23390 was administered 15 min before each methamphetamine or saline injection.

Developmental D-methamphetamine treatment selectively induces spatial navigation impairments in reference memory in the Morris water maze while sparing working memory.

In previous studies, we have shown that P11-20 treatment with D-methamphetamine (MA) (10 mg/kg x 4/day at 2-h intervals) induces impairments in spatial learning and memory in the Morris water maze after the offspring reach adulthood. Using a split-litter, multiple dose, design (0, 5, 10, and 15 mg/kg MA administered s.c.

Developmental 3,4-methylenedioxymethamphetamine (MDMA) impairs sequential and spatial but not cued learning independent of growth, litter effects or injection stress.

Previously, we have shown that rats administered MDMA from postnatal (P) days 11-20 had reductions in body weight during the period of treatment and as adults they had deficits in sequential and spatial learning and memory. In the present study, to control for weight reductions, we used litters with double the number of offspring to induce growth restriction comparable to that of standard size litters treated with MDMA. Litters were treated twice daily from P11 to 20 with vehicle or MDMA (20 mg/kg) or only weighed.

3,4-methylenedioxymethamphetamine (ecstasy)-induced learning and memory impairments depend on the age of exposure during early development.

Use of 3,4-methylenedioxymethamphetamine (MDMA; ecstasy) has increased dramatically in recent years, yet little is known about its effects on the developing brain. Neonatal rats were administered MDMA on days 1-10 or 11-20 (analogous to early and late human third trimester brain development). MDMA exposure had no effect on survival but did affect body weight gain during treatment.

Adult learning deficits after neonatal exposure to D-methamphetamine: selective effects on spatial navigation and memory.

The effects of neonatal d-methamphetamine (MA) treatment on cued and spatial learning and memory were investigated. MA was administered to neonatal rats on postnatal days 11-20. All groups received four subcutaneous injections per day.

A single dose model of methamphetamine-induced neurotoxicity in rats: effects on neostriatal monoamines and glial fibrillary acidic protein.

The neurotoxic effects of a single administration of methamphetamine (MA) were studied under conditions conducive to MA-induced hyperthermia. After a single dose of MA (10, 20, 30, or 40 mg/kg, s. c.

Methamphetamine-induced dopamine and serotonin reductions in neostriatum are not gender specific in rats with comparable hyperthermic responses.

Methamphetamine (MA)-induced 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 mg/kg) or saline (3 ml/kg) was administered SC four times at 2-h intervals. Animals were sacrificed 3 days posttreatment for the determination of dopamine (DA), serotonin (5-HT), and metabolites.

Methamphetamine selectively damages dopaminergic innervation to the nucleus accumbens core while sparing the shell.

Dopaminergic innervation to the nucleus accumbens was investigated following a neurotoxic regimen of methamphetamine (MA) treatment. Four 10 mg/kg doses of MA were administered s.c.

alpha-Phenyl-N-tert-butyl nitrone attenuates methamphetamine-induced depletion of striatal dopamine without altering hyperthermia.

Methamphetamine (MA) administration to adult rats (4 x 10 mg/kg s.c.) induces neurotoxicity predominately characterized by a persistent reduction of neostriatal dopamine (DA) content.

Effect of methamphetamine on glutamate-positive neurons in the adult and developing rat somatosensory cortex.

The neurotoxic effects of methamphetamine (MA) on dopaminergic and serotonergic terminals have been well-documented. Another neurotoxic effect of MA is neuronal degeneration in the somatosensory cortex, as seen by silver staining. The neurochemical characteristics of these degenerating neurons are unknown.

Age-dependent sensitivity of rats to the long-term effects of the serotonergic neurotoxicant (+/-)-3,4-methylenedioxymethamphetamine (MDMA) correlates with the magnitude of the MDMA-induced thermal response.

The effects of developmental age on (+/-)-3,4-methylenedioxymethamphetamine (MDMA)-induced reductions in 5-hydroxytryptamine (5-HT) content and 5-HT reuptake sites were investigated in conjunction with the effects of developmental age on MDMA-induced thermoregulatory responses. MDMA was administered to rats at postnatal days (PND) 10, 40 and 70 in a range of ambient temperature environments (10 degrees C, 25 degrees C and 33 degrees C). Animals were monitored for alterations in body temperature and sacrificed 1 week after MDMA administration.

Age modulates the long-term but not the acute effects of the serotonergic neurotoxicant 3,4-methylenedioxymethamphetamine.

Tissue levels of serotonin (5-HT), levels of its metabolite 5-hydroxyindoleacetic acid (5-HIAA) and populations of 5-HT reuptake sites were measured in the brains of rats exposed to 3,4-methylenedioxymethamphetamine (MDMA) at selected developmental ages. MDMA exposure at postnatal day (PND) 10 did not result in altered 5-HT or 5-HIAA levels 1 week after administration in any brain region examined. However, MDMA exposure at PND 40 and PND 70 resulted in dose-dependent reductions in 5-HT and 5-HIAA levels at 1 week in all brain regions examined.

Further studies of the role of hyperthermia in methamphetamine neurotoxicity.

The depletion of striatal dopamine (DA) that can occur after methamphetamine (METH) administration has been linked to METH-induced hyperthermia. The relationship between METH-induced hyperthermia, neurotoxicity (striatal DA depletions) and compounds that protect against METH neurotoxicity was further investigated in this study. Typically, rats exposed to METH die when their body temperatures exceed 41.

Fluoro-gold and pentamidine inhibit the in vitro and in vivo release of dopamine in the striatum of rat.

Fluoro-Gold (FG), first developed as an antifungal/antiparasitic agent, is now also used extensively as a retrograde tracer in histological studies of nervous tissue. The fact that FG is taken up by dopamine (DA) terminals before its retrograde transport to DA cell bodies implies a presynaptic interaction, though the biochemical target(s) and mechanism(s) are unknown. To further elucidate, FG and another aromatic diamidine, pentamidine, were tested on [3H]DA release and uptake in vitro from striatal slices and synaptosomes.