Lack of mitigation of methamphetamine-induced neurotoxicity by ganglioside GM1 or vitamin E.
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3,4-Dihydroxyphenylacetic Acid↗
Biomedical subjects
S F Ali
Publications and source records attributed to S F Ali.
Low environmental temperatures or pharmacologic agents that produce hyperthermia decrease methamphetamine neurotoxicity in mice.
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3,4-Dihydroxyphenylacetic Acid↗
Placental transfer and fetal disposition of 2',3'-dideoxycytidine and 2',3'-dideoxyinosine in the rhesus monkey.
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Animals↗
Cerebral membranes isolated from rats consuming ethanol or gestationally exposed to ethanol have increased susceptibility to modulation by ethanol.
The actions of ethanol on membrane fluidity were examined. All assays were carried out using fluorescence techniques in the P2 fraction of crude synaptosomes isolated from rat brain. Subchronic treatment of rats with ethanol revealed a significant increase in order at the membrane interior. In vitro addition of ethanol to P2 fractions prepared from treated rats revealed a significant rise in fluidity at the membrane core that was not found in corresponding P2 fractions from untreated rats. The withdrawal of ethanol from subchronically treated rats revealed no significant alterations in membrane fluidity. However, in vitro addition of ethanol to P2 fractions prepared from these animals produced an increase in fluidity at the membrane centre. This effect was not observed in corresponding control rats. Rat pups that were gestationally exposed to ethanol also failed to show any significant differences in membrane fluidity compared with control rats. However, in vitro addition of a challenge dose of ethanol to P2 fractions resulted in a significant rise in fluidity not found in pups from untreated mothers. These findings suggest that the process of adaptation to chronic ethanol may be dissected into two separable events: one frequently reported effect that alters membrane fluidity and one that modulates membrane susceptibility to ethanol-induced perturbations.
Alcoholism↗
Low environmental temperatures or pharmacologic agents that produce hypothermia decrease methamphetamine neurotoxicity in mice.
Recently we have reported that methamphetamine (METH) neurotoxicity in rats depends on the environmental temperature. Here, we evaluate whether a cold environment (4 degrees C) or drugs which chloride and glutamate ion channel function block METH neurotoxicity in mice. Adult male CD mice received METH i.p. (4 x 10 mg/kg METH at 23 degrees C along with saline. 2.5 mg/kg (+)-MK-801, 40 mg/kg phenobarbital or 2.5 mg/kg diazepam and either 4 x 10 or 4 x 20 mg/kg METH at 4 degrees C). Multiple injections of METH (4 x 10 mg/kg i.p.) at room temperature (23 degrees C) produced a significant depletion of dopamine (DA) in striatum at 24, 72 h, 1 and 2 weeks. Three days post 4 x 10 mg/kg METH at 23 degrees C, an 80% decrease in striatal dopamine (DA) occurred while the same dose at 4 degrees C produced only a 20% DA decrease, and 4 x 20 mg/kg METH at 4 degrees C produced a 54% DA decrease. At 23 degrees C (+)MK-801 completely blocked while phenobarbital (40% decrease) and diazepam (65% decrease) partially blocked decreases in striatal DA produced by 4 x 10 mg/kg METH. Decreases in DOPAC and HVA were similar to the decreases in DA after METH and antagonists. Multiple injections of METH (4 x 10 mg/kg, i.p.) at room temperature also produced a significant depletion of serotonin (5-HT) in striatum at 24, 72 h, 1 and 2 weeks. This depletion of 5-HT at room temperature was blocked either by changing the environmental temperature to 4 degrees C, or by pretreatment with MK-801, diazepam and phenobarbital.(ABSTRACT TRUNCATED AT 250 WORDS)
3,4-Dihydroxyphenylacetic Acid↗
MPTP-induced oxidative stress and neurotoxicity are age-dependent: evidence from measures of reactive oxygen species and striatal dopamine levels.
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes marked depletion of dopamine (DA) levels and reduction in the activity of tyrosine hydroxylase (TH) in the nigrostriatal DA pathway. In the brain, the enzyme monoamine oxidase B converts MPTP to 1-methyl-4-phenylpyridinium (MPP+) which enters DA terminals via DA uptake sites. Within the DA terminals, MPP+ blocks the mitochondrial complex I and causes ATP depletion. This is thought to be the main cause of MPTP-induced terminal degeneration. In addition, reactive oxygen species (ROS) generated after blockade of the complex I as well as those generated due to DA oxidation may participate in MPTP-induced dopaminotoxicity. The present study sought to determine if a single injection of a large dose of MPTP generates ROS. We also sought to determine if these changes as well as changes in DA levels were correlated and age-dependent. Toward that end, we have used C57/B6N male mice that were 22 days or 12 months old. These animals were injected with a single dose of MPTP (40 mg/kg, ip). Animals were sacrificed at various times after drug administration. MPTP produced no significant increase in ROS nor decreases in DA or HVA concentrations in the striatum of the younger mice. However, DOPAC concentrations were significantly decreased from 15-120 min after drug administration. In the older mice, MPTP caused significant increases in ROS from the beginning to the end of the study period. DA concentrations were decreased from 60 min onward. DOPAC concentrations were decreased significantly after 15-120 min while HVA concentrations were significantly increased after 60 and 120 min.(ABSTRACT TRUNCATED AT 250 WORDS)
3,4-Dihydroxyphenylacetic Acid↗
Acute effects of perinatal hypoxic insult on concentrations of dopamine, serotonin, and metabolites in fetal monkey brain.
Seven monkeys (Macaca mulatta) were laparotomized under general anesthesia (halothane, nitrous oxide, oxygen). Fetal hypoxia was induced in four monkeys by occlusion of the umbilical cord with a hydraulic occluder for 5-6 min. Three sham-operated fetuses served as controls. After unclamping, the fetuses were allowed to reperfuse for 20-30 min. To monitor hypoxia, the fetal electrocardiogram was recorded continuously. Hypoxic insult was associated with a decrease in fetal heart rate during the occlusion. After reperfusion, fetuses were immediately sacrificed and neocortex regions dissected on ice, frozen on dry ice and stored at -70 degrees C. Dopamine, 3,4-dihydroxyphenylacetic acid, homovanillic acid, serotonin, and 5-hydroxyindoleacetic acid were assayed by high performance liquid chromatography with electrochemical detection (HPLC/EC) in hippocampus, caudate nucleus and cortical regions. In the hippocampus, there was a significant increase in 5-hydroxyindoleacetic acid concentration. In prefrontal cortex, there was a trend toward an increase in serotonin but no effects on dopamine and homovanillic acid concentrations. Dopamine, serotonin and metabolites were not altered in the caudate nucleus. These data demonstrate that fetal hypoxia followed by reperfusion produced an increase in serotonin concentration measured within the hippocampus and selected cortical areas known to be targets of hypoxic injury.
3,4-Dihydroxyphenylacetic Acid↗
Development of dopamine and N-methyl-D-aspartate systems in rat brain: the effect of prenatal phencyclidine exposure.
Phencyclidine (PCP) inhibits the uptake of the neurotransmitter dopamine (DA), and blocks N-methyl-D-aspartate (NMDA) receptor-regulated ion channels. PCP also binds to sigma receptors in vivo and in vitro in rat brain. Prolonged exposure to PCP in adults has been observed to reduce the number of PCP binding sites in brain. We designed these experiments to evaluate whether prolonged prenatal exposure to PCP produces alterations in the development of DA and NMDA systems in brain. To do so, we characterized the normal course of development of basal and stimulated DA release in striatal slices, the ontogeny of striatal DA concentrations, and the development of NMDA receptor channels and associated glutamate binding sites in frontal cortex. We compared these developmental profiles to those in rats exposed to prenatal PCP, in an attempt to characterize the effect of prenatal PCP exposure on the pattern of brain development. Pregnant CD rats were injected s.c. with either 0, 10 or 20 mg/kg PCP daily on gestational days 8 through 20. On postnatal days (PND) 8, 21, 45, or 100, rats were sacrificed and brain tissues isolated for in vitro assessment. In vitro [3H]DA release from striatal slices evoked by either 40 microM glutamate or 15 mM K+ increased over 250% from PND 8 to PND 45, and glutamate-stimulated release was still significantly below adult levels at PND 45. In contrast, D-methamphetamine (D-METH)-evoked [3H]DA release, frontal cortical glutamate binding sites and NMDA channels developed early, reaching adult levels on or before PND 21.(ABSTRACT TRUNCATED AT 250 WORDS)
3,4-Dihydroxyphenylacetic Acid↗
Age and dietary factors in hippocampal sensitivity to trimethyltin.
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Aging↗
Effect of methyl bromide on regional brain glutathione, glutathione-S-transferases, monoamines, and amino acids in F344 rats.
Both metabolic and neurotransmitter changes have been implicated in the pathogenesis of monohalomethane neurotoxicity in rodents. This study in male and female F344 rats examined the effects of methyl bromide (MeBr) on regional brain glutathione-S-transferase (GST) activities and concentrations of glutathione (GSH), monoamines, and amino acid. Inhalation exposure to 150 ppm MeBr (6 hr/day x 5 days) yielded no histologic evidence of brain lesions but resulted in a number of biochemical changes. GSH depletion and GST inhibition were detected in the frontal cortex, caudate nucleus, hippocampus (examined for GSH only), brain stem, and cerebellum from animals of both sexes. Differences between sexes were detected for GSH depletion. Simultaneous treatment of rats with the inhibitor of monohalomethane toxicity, BW 755C (3-amino-1-[m-(trifluoromethyl)phenyl]-2-pyrazoline; 10 mg/kg bw ip, 1 hr pre- and 1 hr postexposure) completely protected against GST inhibition in all brain regions of both sexes. Partial protection by BW 755C against GSH depletion was observed in the cerebral cortex and in the cerebellum only. In males, MeBr exposure had no effect on the regional concentrations of the monoamines dopamine and serotonin and the amino acids glutamate, glutamine, taurine, and gamma-aminobutyric acid. Regional increases of brain aspartate and glycine levels were observed after exposure of males to MeBr but BW 755C had no effect on these changes induced by MeBr. Thus, of all the parameters studied, only GST, and in some brain areas GSH, correlated with inhibition of toxicity. It is concluded that, in contrast to the monoamines and the amino acids, GST and GSH are sensitive and potentially relevant indicators of MeBr neurotoxicity which could explain sex and regional differences in response to the monohalomethanes.
Amino Acids↗
Deferoxamine inhibits methyl mercury-induced increases in reactive oxygen species formation in rat brain.
It has been suggested that methyl mercury may express its neurotoxicity by way of iron-mediated oxidative damage. Therefore, the effect of deferoxamine, a potent iron-chelator, on methyl mercury-induced increases in reactive oxygen species formation was studied in rat brain. The generation rate of reactive oxygen species was estimated in crude synaptosomal fractions using the probes 2',7'-dichlorofluorescin diacetate and dihydrorhodamine 123. The formation rate of the fluorescent oxidation products was used as the measure of reactive oxygen species generation. Seven days after a single injection of methyl mercury (5 mg/kg, ip), the formation rate of reactive oxygen species was significantly increased in the cerebellum. Pretreatment with deferoxamine (500 mg/kg, ip) completely prevented the methyl mercury-induced increase in cerebellar reactive oxygen species generation rates. The oxidative consequences of in vitro exposure to methyl mercury (20 microM) were also inhibited by deferoxamine (100 microM). The formation of the iron-saturated complex ferrioxamine was not affected by a 10-fold excess of methylmercuric chloride or mercuric chloride, suggesting that a deferoxamine-mercurial complex does not form. The findings in this study: (1) provide evidence that iron-catalyzed oxygen radical-producing reactions play a role in methyl mercury neurotoxicity, (2) demonstrate the potential of fluorescent probes as a measure of reactive oxygen species formation, and (3) provide support for iron-chelator therapy in protection against xenobiotic-induced oxidative damage.
Animals↗
No increase in carcinogen-DNA adducts in the lungs of monkeys exposed chronically to marijuana smoke.
Rhesus monkeys exposed to marijuana smoke either 7 or 2 days/weeks (HI and LO groups, respectively), or ethanol-extracted marijuana smoke for 7 days/week (EM) or sham treatment (SH) for 1 year were sacrificed 7 months following the last exposure. Pulmonary levels of carcinogen-DNA adducts were determined. Although mean or median adduct levels were not statistically different, 15 of 22 adduct measures were highest in the EM group and lowest 12 of 22 times in the SH group. The levels of aromatic carcinogen-DNA adducts seem no higher in the lungs of animals exposed to marijuana smoke than in untreated animals. Ethanol-extracted marijuana may have effects greater than marijuana itself.
Animals↗
The influence of environmental temperature on the transient effects of methamphetamine on dopamine levels and dopamine release in rat striatum.
When male rats were injected four times (once every 2 hr) with 5 mg/kg methamphetamine (METH) at an environmental temperature of 23 degrees C, transient changes occurred in the levels of striatal dopamine (DA) and the regulation of striatal DA release. Striatal DA levels were minimally affected 1 day after METH treatment, but 3 days after METH treatment, striatal DA levels decreased to approximately 40% of control. DA levels returned to 70% of control 2 weeks after METH. Similarly, striatal tyrosine hydroxylase (TH) activity decreased to approximately 50% of control activity 3 days after METH treatment at 23 degrees C, but did not differ from controls at 1 or 14 days after METH treatment. No changes in striatal DA levels were observed in rats treated with four doses of 5 mg/kg METH at an environmental temperature of 4 degrees C. Striatal DA levels decreased modestly to approximately 70% of controls 3 days after treatment with four doses of 10 mg/kg METH at 4 degrees C, but DA levels returned to control levels 14 days after METH treatment. Furthermore, striatal TH activity was not affected by 10 mg/kg METH at 4 degrees C. Thus, a cold environmental temperature (4 degrees C) reduced the effects of METH on striatal DA levels and striatal TH activity. Changes in the presynaptic regulation of DA release after either 5 mg/kg (23 degrees C) or 10 mg/kg (4 degrees C) METH treatment were determined in vitro using striatal slices.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Reactive oxygen species formation as a biomarker of methylmercury and trimethyltin neurotoxicity.
Reactive oxygen species (ROS) such as superoxide anion, hydrogen peroxide, and hydroxyl radicals are believed to be initiators of peroxidative cell damage. This paper focused on the use of 2',7'-dichlorofluorescein-diacetate (DCFH-DA) to quantitate cerebral ROS as an index for neurotoxicity. This technique employs an assay of dichlorofluorescein (DCF), the fluorescent product of dichlorofluorescein (DCFH). Data from studies using various free radical generating systems, several iron chelators and hydroxyl radical scavengers suggest that DCFH oxidation may result in several reactive intermediates. In a biological system (synaptosomes isolated from untreated rats) DCF fluorescence was stimulated by ascorbate or FeSO4, while deferoxamine inhibited the ascorbate/FeSO4-induced stimulation of DCF formation. Two organometals, methylmercury (MeHg) and trimethyltin (TMT), known to produce neurotoxicity were tested. In vitro exposure to MeHg (10-20 microM) increased the rate of formation of ROS while TMT (5-40 microM) had no effect. In vivo, 48 hr and 1 week after a single injection of MeHg (1 mg/kg, i.p.) in mice and 1 week after a single injection of MeHg (5 mg/kg, i.p.) in rats, the rate of formation of ROS in both rat and mouse cerebellum was significantly increased. Pretreatment with deferoxamine, a potent iron-chelator, prevented MeHg-induced increase of ROS. In hippocampus and frontal cortex, ROS formation rates were also elevated 48 hr after TMT injection (3 mg/kg, i.p.) in mice. These results demonstrate that DCF fluorescence provides a good measure of overall ROS formation in synaptosomes of both in vitro as well as in vivo systems. Since ROS formation was selectively increased in areas known to be specifically vulnerable to organometals (cerebellum in the case of MeHg and hippocampus in the case of TMT), these studies further support that oxidative damage may be the primary mechanism underlying the neurotoxicity induced by these organometals.
Animals↗
Chronic marijuana smoke exposure in the rhesus monkey. II: Effects on progressive ratio and conditioned position responding.
Sixty-two male rhesus monkeys were trained to respond in an operant test battery that included tasks thought to allow measurement of aspects of motivation and color and position discrimination. Subjects were assigned to eight treatment groups (n = 7-8) based upon behavioral performance. There were two behavioral groups: ACTIVE = behavior assessed throughout the 365 days of active exposure and beyond, and RESIDUAL = behavior assessed beginning 2 months after the last exposure. Each behavioral group had four dose groups: HI = smoke from one marijuana (MJ) cigarette/day 7 days/week; LO = MJ smoke only on weekends; EX = smoke from one extracted MJ (placebo) cigarette/day 7 days/week; SH = sham exposure 7 days/week. For the motivation task, both HI and LO ACTIVE groups earned significantly fewer reinforcers than did both ACTIVE control groups during the last several months of exposure. These effects disappeared within 2 to 3 months of cessation of treatment, and no similar effect was present when RESIDUAL groups were tested. Performance of the color and position discrimination task was adversely affected in one of eight HI ACTIVE subjects throughout most of the chronic exposure, and there was a trend toward residual deficits in performance of this task in the HI RESIDUAL group compared to both SH and EX RESIDUAL controls. These data could be interpreted to mean that during periods of chronic use, MJ produces an amotivational-like syndrome in rhesus monkeys and that this syndrome disappears only several weeks to months after the last exposure.
Animals↗
Chronic exposure to delta 9-tetrahydrocannabinol fails to irreversibly alter brain cannabinoid receptors.
The effects of chronic delta 9-tetrahydrocannabinol (delta 9-THC) and marijuana administration on the properties of brain cannabinoid receptor populations of the rat and monkey, respectively, were examined in this study. It was determined that the properties of the cannabinoid receptors in the striatum, cerebral cortex, cerebellum, hippocampus, and brainstem/spinal cord of the rat do not appear to be irreversibly altered by chronic exposure to delta 9-THC. Similarly, the cannabinoid receptors in the caudate, prefrontal cortex, and cerebellum of the monkey do not appear to be irreversibly altered by chronic exposure to marijuana smoke.
Analgesics↗
"Isolation stress" revisited: isolation-rearing effects depend on animal care methods.
Early reports of enhanced behavioral reactivity in isolation-reared rats attributed this syndrome to "isolation stress." In the studies reported here, this "isolation stress syndrome" was reliably obtained in adult rats reared from weaning in individual hanging metal cages. Such isolates showed behavioral and adrenocortical symptoms of profound fear during open-field testing, unlike group-housed controls or littermate isolates reared singly in plastic cages. Animals in hanging metal cages are never touched by human caretakers, whereas rats reared in plastic cages are picked up and put in clean cages twice weekly. Handling hanging-cage isolates twice weekly to model the handling associated with cage changes completely protected against this syndrome. Further, there was no hormonal, neurochemical or anatomical evidence of chronic stress even in hanging-cage isolates. Littermates housed in social groupings (three rats per plastic cage) also froze and defecated in the open field at rates comparable to hanging-cage isolates if they were the first animals to be tested from their social group cage. It is probable that odor cues from familiar cagemates in the open field protected socially reared animals tested subsequently from the same cage from this syndrome. It is concluded that isolates are not chronically stressed, and that rearing effects are the result of a complex interaction between prior handling, social experience and test conditions.
Animals↗
Acute effects of 3,4-methylenedioxymethamphetamine (MDMA) on monoamines in rat caudate.
Extracellular levels of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA) and serotonin (5-HT) were assayed in the caudate of freely moving rats using microdialysis and high performance liquid chromatography with electrochemical detection (HPLC-EC) to detect changes in their release. Dialysates were assayed at 20-minute intervals for four hours after an intraperitoneal (IP) injection of MDMA (10 mg/kg). In a separate study to determine MDMA effects on total caudate levels of the above neurochemicals, animals were injected IP with MDMA (10 mg/kg) and then sacrificed at 20, 60, 120 and 180 minutes after treatment. Brains were quickly removed, and caudate nuclei were dissected for neurochemical analysis using HPLC-EC. MDMA elicited an amphetamine-like increase in DA release, followed by an increase in DA content. DOPAC and HVA were both reduced in homogenate. 5-HT release was also increased, followed by a drop in caudate homogenate levels by three hours. DA extracellular content was 686% of control at 80 minutes; caudate homogenate levels were 122% at 120 minutes. 5-HT extracellular release was 123% at 20 minutes, then decreased thereafter. It is concluded that the acute effect of MDMA on caudate is at least as great on the DA as it is on the 5-HT system.
3,4-Dihydroxyphenylacetic Acid↗