Search PubMed⌕ Search

Biomedical subjects

Syed F Ali

Publications and source records attributed to Syed F Ali.

At least 55 records · Page 3Linked to original sources
PubMed2003

Fenfluramine-induced serotonergic neurotoxicity in mice: lack of neuroprotection by inhibition/ablation of nNOS.

Previous studies have implicated a role for nitric oxide (NO) and peroxynitrite in methamphetamine-induced dopaminergic neurotoxicity. The present study was undertaken to investigate whether NO is involved in serotonergic neurotoxicity caused by fenfluramine. In the first experiment, the effect of the neuronal nitric oxide synthase (nNOS) inhibitor 7-nitroindazole (7-NI; 25 mg/kg x 4) on fenfluramine (25 mg/kg x 4)-induced serotonergic neurotoxicity in Swiss Webster mice was investigated. In the second experiment, the effect of fenfluramine (25 mg/kg x 4) on nNOS (-/-) and wild-type (WT) mice was investigated. Fenfluramine induced hypothermia in all three mouse strains, and 7-NI had no thermoregulatory effect. Selective depletion of 5-HT and 5-HT transporter binding sites in the striatum, frontal cortex and hippocampus in all three mouse strains was observed, with no evidence of dopaminergic neurotoxicity. In the first experiment, 7-NI did not attenuate serotonergic neurotoxicity in Swiss Webster mice. In the second experiment, nNOS(-/-) and WT mice were equally sensitive to serotonergic neurotoxicity. These findings suggest that NO and peroxynitrite do not mediate fenfluramine-induced serotonergic neurotoxicity, and that NO is a selective mediator of amphetamines-induced dopaminergic neurotoxicity.

Animals↗
PubMed2002

Zinc potentiates 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine induced dopamine depletion in caudate nucleus of mice brain.

Present study describes the effect of zinc (Zn) on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced dopamine depletion in mice brain. MPTP is a known neurotoxicant primarily causing marked depletion of dopamine (DA) levels in nigrostriatal dopaminergic system. Adult Male C57-mice were intraperitonially injected with 25 mg/kg MPTP in the presence or absence of zinc acetate. Twenty-four hours after treatment animals were sacrificed and DA levels were determined by high performance liquid chromatography in caudate nucleus of control and treated mice. The results showed that there was a marked depletion of DA in MPTP treated mice, whereas no change was observed in DA levels in mice treated with Zn when compare to controls. Interestingly, mice receiving MPTP in conjunction with Zn showed significantly lower DA levels in brain when compare to animals receiving MPTP alone. In summary the data suggest that Zn treatment potentiates depletion of dopamine in MPTP treated mice.

Animals↗
PubMed2002

Cyclooxygenase-2-deficient mice are resistant to 1-methyl-4-phenyl1, 2, 3, 6-tetrahydropyridine-induced damage of dopaminergic neurons in the substantia nigra.

Cyclooxygenases (COX), key enzymes in prostanoid biosynthesis, may represent important therapeutic targets in various neurodegenerative diseases. In the present study, we explored the role of COX in Parkinson's disease (PD) by using 1-methyl-4-phenyl1, 2, 3, 6-tetrahydropyridine (MPTP) as a tool to create a rodent Parkinsonian model. MPTP (20 mg/kg, subcutaneously) was injected daily into COX-1- and COX-2-deficient mice and wild-type (WT) controls for five consecutive days. Immunocytochemical analysis of tissues collected 7 days after the final MPTP treatment showed that MPTP significantly decreased the number of tyrosine hydroxylase-immunoreactive (TH-ir) neurons in the substantia nigra pars compacta (SNc) of WT (40% decrease) and COX-1(-/-) (45% decrease) mutants. However, a much smaller loss of TH-ir neurons in COX-2(-/-) mutants (20% decrease) was observed. Furthermore, electrochemical analysis revealed a more than 70% decrease in the levels of dopamine and its metabolites (3,4-dihydroxyphenylacetic acid and homovanillic acid) in the striatum of the WT control COX-1(-/-) and COX-2(-/-) mutant mice. These results indicate that loss of COX-2 activity reduces MPTP-induced damage to the dopaminergic neurons of the SNc, but does not alter the levels of dopamine and its metabolites in the striatum. Interestingly, MPTP caused the same degree of loss of dopaminergic neurons in both COX-2(+/-) and COX-2(-/-) mice (20% loss). The results of this study indicate an important role of COX-2 in MPTP-induced neuronal degeneration and suggest the possibility that manipulation of the COX-2 could be an important target for therapeutic interventions in PD.

Animals↗
PubMed2002

Methamphetamine-induced dopaminergic neurotoxicity in mice: long-lasting sensitization to the locomotor stimulation and desensitization to the rewarding effects of methamphetamine.

High doses of methamphetamine (METH) cause the depletion of striatal dopaminergic markers; however, little is known about the behavioral consequences of METH-induced neurotoxicity. In the present study, the authors investigated the effect of a neurotoxic dose of METH (5 mg/kg; every 3 h x3) on the subsequent response of Swiss Webster mice to (a) the psychomotor-stimulating effect of METH and (b) the acquisition and maintenance of conditioned place preference (CPP) by METH. The latter is a paradigm for the assessment of the rewarding properties of abused substances. The administration of the high dose of METH resulted in significant depletion of dopamine (DA) and its metabolites and dopamine transporter (DAT) binding sites in the striatum. The dopaminergic markers were below control levels until the 95th day after METH administration. METH-pretreated mice were sensitized to the psychomotor-stimulating effect of METH (1 mg/kg) as determined on Days 3 and 74 after the initial exposure to the neurotoxic dose of METH. However, the acquisition of CPP by METH (0.5 mg/kg) was markedly reduced in the mice pretreated with the neurotoxic dose of METH compared with the control group. The CPP was maintained for 8 weeks in the control group but not in the METH group. A priming injection of METH (0.5 mg/kg) caused marked reinstatement of place preference in the control group; this response was maintained for three additional weeks. However, the priming injection of METH resulted in diminished place preference in the METH group and the conditioned response dissipated within 3 weeks. These findings suggest that METH-induced striatal dopaminergic neurotoxicity is associated with two opposing and long-lasting behavioral outcomes: (a) sensitization to the psychomotor-stimulating effect of the drug and (b) desensitization to the rewarding properties of the drug. These consequences may be relevant to the psychopathology of METH abuse.

Animals↗
PubMed2002

Peroxynitrite and the regulation of Na(+),K(+)-ATPase activity by angiotensin II in the rat proximal tubule.

NO reacts spontaneously with superoxide to produce the potent oxidant peroxynitrite. Studies were designed to examine the role of NO-derived oxidants and peroxynitrite on the regulation of Na(+),K(+)-ATPase activity by angiotensin II (ANG II) freshly isolated rat proximal tubules. At picomolar concentrations ANG II stimulates Na(+),K(+)-ATPase activity, but at nanomolar concentrations stimulation is lost. Superoxide dismutase (SOD) was used to examine the role of superoxide and deferoxamine (DFO) and uric acid (UA) were used to examine the role of peroxynitrite. SOD (200 U/mL, 5-min preincubation) restored the stimulatory effect of ANG II (1.31 +/- 0.08-fold; n = 4; P < 0.05 compared to 10(-7) M alone), suggesting a role for superoxide. DFO (100 microm, 5-min preincubation) also restored the stimulatory effect of ANG II (1.40 +/- 0.08-fold; n = 4; P < 0.05, compared to 10(-7) M alone), as did UA (1.22 +/- 0.07-fold; n = 5; P < 0.05, compared to 10(-7) M alone). The NO synthesis inhibitor, N-monomethyl-L-arginine (L-NMMA, 2 mM; 5-min preincubation), also unmasked a stimulatory effect of ANG II at 10(-7) M (1.4 +/- 0.1-fold; n = 7; P < 0.05, compared to 10(-7) M alone). The generation of peroxynitrite was further evidenced by the formation of 3-nitrotyrosine (3-NT). 3-NT increased 3.5-fold in tubules exposed to ANG II (10(-7) M) (0.0054 +/- 0.0019 3-NT/100 tyrosines for control and 0.019 +/- 0.0058 3-NT/100 tyrosines for ANG II, P < .05; n = 4) and L-NMMA prevented the increase. These data suggest that peroxynitrite signaling participates in the regulation of renal of Na(+),K(+)-ATPase activity.

Angiotensin II↗
PubMed2002

Acute administration of cocaine regulates the phosphorylation of serine-19, -31 and -40 in tyrosine hydroxylase.

Acute cocaine can inhibit catecholamine biosynthesis by regulating the enzymatic activity of tyrosine hydroxylase via alterations in the phosphorylation state of the enzyme. The mechanisms underlying acute cocaine-dependent regulation of tyrosine hydroxylase phosphorylation have not been determined. In this study, 0, 15 or 30 mg/kg cocaine was administered intraperitoneally to rats and the phosphorylation state of tyrosine hydroxylase in the brain was examined using antibodies specific for the phosphorylated forms of serine-19, -31 and -40 in tyrosine hydroxylase. In the caudate and nucleus accumbens, cocaine dose-dependently decreased the levels of phosphorylated serine-19, -31 and -40. In the ventral tegmental area, the levels of phosphorylated serine-19, but not serine-31 and -40, were decreased by 15 and 30 mg/kg cocaine. In the amygdala, the levels of phosphorylated serine-19, but not serine-31 or -40, were decreased. The functional effects of these alterations in phosphorylation state were assessed by measuring tyrosine hydroxylase activity in vivo (accumulation of DOPA after administration of the decarboxylase inhibitor NSD-1015). Acute administration of 30 mg/kg cocaine significantly decreased l-DOPA production in caudate and accumbens but not in amygdala. These data suggest that the phosphorylation of serine-31 or -40, but not serine-19, is involved in the regulation of tyrosine hydroxylase activity by acute cocaine.

Amygdala↗
PubMed2002

Ibogaine signals addiction genes and methamphetamine alteration of long-term potentiation.

The mapping of the human genetic code will enable us to identify potential gene products involved in human addictions and diseases that have hereditary components. Thus, large-scale, parallel gene-expression studies, made possible by advances in microarray technologies, have shown insights into the connection between specific genes, or sets of genes, and human diseases. The compulsive use of addictive substances despite adverse consequences continues to affect society, and the science underlying these addictions in general is intensively studied. Pharmacological treatment of drug and alcohol addiction has largely been disappointing, and new therapeutic targets and hypotheses are needed. As the usefulness of the pharmacotherapy of addiction has been limited, an emerging potential, yet controversial, therapeutic agent is the natural alkaloid ibogaine. We have continued to investigate programs of gene expression and the putative signaling molecules used by psychostimulants such as amphetamine in in vivo and in vitro models. Our work and that of others reveal that complex but defined signal transduction pathways are associated with psychostimulant administration and that there is broad-spectrum regulation of these signals by ibogaine. We report that the actions of methamphetamine were similar to those of cocaine, including the propensity to alter long-term potentiation (LTP) in the hippocampus of the rat brain. This action suggests that there may be a "threshold" beyond which the excessive brain stimulation that probably occurs with compulsive psychostimulant use results in the occlusion of LTP. The influence of ibogaine on immediate early genes (IEGs) and other candidate genes possibly regulated by psychostimulants and other abused substances requires further evaluation in compulsive use, reward, relapse, tolerance, craving and withdrawal reactions. It is therefore tempting to suggest that ibogaine signals addiction gene products.

Gene Expression Regulation↗
PubMed2002

Preclinical evaluation of GBR12909 decanoate as a long-acting medication for methamphetamine dependence.

Methamphetamine (METH) abuse is a growing health problem, and no treatments for METH dependence have been identified. The powerful addictive properties of METH are mediated by release of dopamine (DA) from nerve terminals in mesolimbic reward pathways. METH stimulates DA release by acting as a substrate for DA transporter (DAT) proteins, thereby triggering efflux of DA from cells into the synapse. We have shown that blocking DAT activity with high-affinity DA uptake inhibitors, like GBR12909, can substantially reduce METH-evoked DA release in vitro, suggesting GBR12909 may have potential as a pharmacotherapy for METH dependence. The purpose of the present study was to examine the neurobiological effects of a long-acting oil-soluble preparation of GBR12909 (1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-hydroxy-3-phenylpropyl) piperazinyl decanoate, or GBR-decanoate). Male rats received GBR-decanoate (480 mg/kg, i.m.) or its oil vehicle, and were tested using a variety of methods one and two weeks later. Ex vivo autoradiography showed that GBR-decanoate decreases DAT binding in DA-rich brain regions. In vivo microdialysis in the nucleus accumbens revealed that GBR-decanoate elevates baseline levels of extracellular DA and antagonizes the ability of METH to evoke DA release. The dopaminergic effects of GBR-decanoate were sustained, lasting for at least two weeks. Rats pretreated with GBR-decanoate displayed enhanced locomotor responses to novelty at one week, but not two weeks, postinjection. Administration of the D(2)/D(3) receptor agonist quinpirole (10 and 100 microg/kg, s.c.) decreased locomotor activity and suppressed plasma prolactin levels; quinpirole-induced responses were not altered by GBR-decanoate. Thus, GBR-decanoate is able to elevate basal synaptic DA levels and block METH-evoked DA release in a persistent manner, without significant perturbation of DA receptor function. The findings suggest that GBR-decanoate, or similar long-acting agents, should be evaluated further as potential treatment adjuncts in the management of METH addiction in humans.

Amphetamine-Related Disorders↗
PubMed2002

Behavioral consequences of methamphetamine-induced neurotoxicity in mice: relevance to the psychopathology of methamphetamine addiction.

Methamphetamine (METH) is a major drug of abuse in the United States. A high dose of METH given to mice and rats causes long-lasting depletion of tyrosine hydroxylase activity, dopamine (DA), and DA-transporter (DAT) binding sites in the striatum. In human METH-abusers, a marked decrease of the DAT in the caudate putamen was observed. Despite intensive investigations of the mechanism associated with METH-induced neurotoxicity, the behavioral consequences of this phenomenon are not clear. We used the mouse model of METH-induced neurotoxicity to investigate the response of the animals to the psychomotor-stimulating effect of METH and the rewarding effect of the drug. Mice pre-exposed to a neurotoxic dose of METH developed a marked sensitization to the psychomotor-stimulating effect of METH, which lasted for more than two months. The rewarding effect of METH was determined by the conditioned place preference (CPP) paradigm. Mice pre-exposed to the neurotoxic dose of METH showed reduced sensitivity to the rewarding effect of METH compared with control animals. While CPP was maintained for three months in the control group, the conditioned response in the METH pre-exposed animals lasted only a few days. These findings indicate that METH neurotoxicity is associated with opposing and long-lasting behavioral outcomes: (a) sensitization to the psychomotor-stimulating effect of the drug and (b) desensitization to the rewarding properties of the drug. These consequences may be relevant to the psychopathology of METH abuse. Sensitization is pertinent to compulsive drug-seeking behavior that is accompanied by desensitization to the rewarding effect of METH.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2002

Adaptation to repeated cocaine administration in rats.

Quantitative electroencephalogram (EEG) studies in cocaine-dependent human patients show deficits in slow-wave brain activity, reflected in diminished EEG power in the delta and theta frequency bands. In the present study, electrophysiological measures were monitored in 10 nonanesthetized, adult male Sprague-Dawley rats via bipolar, epidural electrodes implanted over the somatosensory cortex. Control electrocorticograms (ECoG) were recorded twice within a two-week interval to establish a baseline. Rats were subsequently injected daily with cocaine HCl at 15 mg/kg, i.p., for two weeks. The ECoG was recorded during a 1-h session one day after the last injection. Total concentrations of dopamine (DA) and its metabolites were assayed in caudate nucleus (CN) and frontal cortex (FC) using HPLC/EC. Compared with controls, marked increases in DA concentrations were observed in both regions. The DA turnover decreased significantly. The power spectra, obtained by use of a fast Fourier transformation, revealed a significant decrease in slow-wave delta frequency bands following repeated exposure to cocaine. These data are consistent with reported findings in humans that repeated exposures to cocaine result in a decrease in slow-wave brain activity. Further studies are necessary to establish whether regional alterations in blood flow and metabolic activity may underlie such observations.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2002

Methamphetamine-induced dopaminergic neurotoxicity and production of peroxynitrite are potentiated in nerve growth factor differentiated pheochromocytoma 12 cells.

Methamphetamine (METH) is a widely abused psychomotor stimulant known to cause dopaminergic neurotoxicity in rodents, nonhuman primates, and humans. METH administration selectively damages the dopaminergic nerve terminals, which is hypothesized to be due to release of dopamine from synaptic vesicles within the terminals. This process is believed to be mediated by the production of free radicals. The current study evaluates METH-induced dopaminergic toxicity in pheochromocytoma 12 (PC12) cells cultured in the presence or absence of nerve growth factor (NGF). Dopaminergic changes and the formation of 3-nitrotyrosine (3-NT), a marker for peroxynitrite production, were studied in PC12 cell cultures grown in the presence or absence of NGF after different doses of METH (100-1,000 microM). METH exposure did not cause significant alterations in cell viability and did not produce significant dopaminergic changes or 3-NT production in PC12 cells grown in NGF-negative media after 24 hours. However, cell viability of PC12 cells grown in NGF-positive media was decreased by 45%, and significant dose-dependent dopaminergic alteration and 3-NT production were observed 24 hours after exposure to METH. The current study supports the hypothesis that METH acts at the dopaminergic nerve terminals and produces dopaminergic damage by the production of free radical peroxynitrite.

Animals↗
PubMed2002

Calpain upregulation and neuron death in spinal cord of MPTP-induced parkinsonism in mice.

Parkinson's disease (PD) is a neurodegenerative disorder resulting in slowness, tremors, and imbalance. Treatment of mice with 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) is one of several models used to mimic PD in humans. Administration of MPTP leads to the production of 1-methyl-4-phenyl-2,3 dihydropyridinium (MPP(+)). MPP(+) is taken up by dopaminergic neurons, causing mitochondrial dysfunction and cell death. Because calpain is involved in neuronal cell death and mitochondrial dysfunction, we examined the level of calpain in neurons in the substantia nigra (SN) and hippocampus of MPTP-treated C57BL/6 mice. Because of the interconnections between spinal cord and upper central nervous system neurons, we examined morphology, calpain activity, and calpain expression in neurons by double immunofluorescence using calpain and neuron marker (NeuN) antibodies. In controls, calpain expression was low in SN, hippocampus, and spinal cord NeuN(+) cells, and the NeuN stain was concentrated around the nucleus. In mice sacrificed 24 h after administration of three 20 mg/kg doses of MPTP, calpain expression was slightly increased in SN and hippocampal neurons and moderately increased in spinal cord neurons. In these animals, the NeuN stain was less concentrated around the nuclear membrane. One week after MPTP treatment, calpain content in NeuN(+) cells was greatly increased in SN, hippocampus, and spinal cord. Morphologically, SN and spinal cord neurons, treated for one week, were necrotic with a granular cytoplasmic NeuN content. Also, MPTP treatment upregulated calpain activity and mRNA level in spinal cord. These data suggest that following MPTP treatment, calpain causes neuronal death in SN as well as in spinal cord.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2002

Serotonergic neurotoxicity of MDMA (ecstasy) in the developing rat brain.

The abused drug 3,4-methylenedioxymethamphetamine (MDMA) damages fine serotonergic fibers and nerve terminals in adult organisms; however, developing animals seem less susceptible to this effect. One proposed hypothesis is that neonates are less sensitive to MDMA neurotoxicity because they fail to show drug-induced hyperthermia. We tested this hypothesis by producing hyperthermia in neonatal rats for 2 hours after each of twice-daily MDMA (10 mg/kg sc) or saline injections given over the period from postnatal day (PD) 1 to 4. Other drug-treated and control litters were maintained at normothermic temperatures after injection. Differential core body temperatures were achieved by placing pups (without the dam) in humidified, thermostatically controlled incubators. Temperatures were monitored with a thermocouple probe at 30-minute intervals. Pups subsequently remained undisturbed until sacrifice at PD 25 and PD 60 for assessment of serotonergic damage by measuring 5-HT transporter (SERT) binding in the hippocampus and neocortex as well as 5-HT and 5-HIAA concentrations (PD 25 only). Neonatal MDMA exposure led to significant reductions in both SERT binding and 5-HT levels in the hippocampus at PD 25, independent of body temperature during treatment. Hippocampal SERT binding increased between PD 25 and PD 60 in both the MDMA and saline groups, but the MDMA-related deficit remained unchanged. Interestingly, the neocortex showed no effect of MDMA at PD 25, but SERT binding was significantly reduced at PD 60. Thus, MDMA can exert serotonergic neurotoxicity in developing animals in the absence of elevated body temperature. Hippocampal serotonergic innervation is damaged early, whereas neocortical effects emerge at a later time. Furthermore, the tendency for serotonergic recovery may be less after neonatal MDMA exposure than exposure of adult animals.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2002

Comparative effects of substituted amphetamines (PMA, MDMA, and METH) on monoamines in rat caudate: a microdialysis study.

Paramethoxyamphetamine (PMA) is a methoxylated phenethylamine derivative that has been used illicitly in Australia since 1994. PMA is also becoming popular at rave parties in the United States. PMA raised concern when a series of fatalities resulted after its use in South Australia, where it was marketed as "ecstasy," which is the colloquial name for MDMA. In the present study, we evaluated the comparative neurotoxicity of substituted amphetamines in rats. Extracellular levels of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), serotonin (5-HT), and 5-hydroxyindoleacetic acid (5-HIAA) were assayed in the caudate of freely moving rats using microdialysis and HPLC-EC. Dialysates were assayed every 20 minutes for 4 hours after an intraperitoneal (i.p.) injection of PMA (2.5, 5, 10, 20 mg/kg), MDMA (10 and 20 mg/kg), or METH (2.5 mg/kg). METH produced a significant increase in extracellular DA (700%), and significant decreases in extracellular DOPAC and HVA (30% and 50%), with no detectable changes in either 5-HT or 5-HIAA. MDMA produced significant increases in DA (700% at 10 mg/kg and 950% at 20 mg/kg) and decreases in DOPAC (15% for both 10 and 20 mg/kg), and HVA (50% at 10 mg/kg and 35% at 20 mg/kg). MDMA also increased 5-HT (350% at 10, and 575% at 20 mg/kg), and decreased 5-HIAA to 60% for both dose levels. PMA produced no detectable increases in DA at dose levels of 2.5, 5, or 10 mg/kg, but significantly increased DA (975%) at a dose of 20 mg/kg. However, PMA significantly decreased DOPAC at all dose levels (75% at 2.5; 40% at 5; 30% at 10; 10% at 20 mg/kg), with comparable decreases in HVA at all dose levels. PMA also produced significant increases in 5-HT at 10 and 20 mg/kg (350% for both dose levels), with no detectable changes in 5-HT at 2.5 or 5 mg/kg. All dose levels of PMA significantly decreased 5-HIAA (50 to 70%). These data suggest that PMA, like MDMA and METH, is capable of producing dopaminergic and serotonergic neurotoxicity.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2002

Repeated administration of gamma-hydroxybutyric acid (GHB) to mice: assessment of the sedative and rewarding effects of GHB.

Because of the sedative/hypnotic and euphoric effects of gamma-hydroxybutyric acid (GHB), the recreational use of the drug has increased significantly. In the current study we investigated the sedative and rewarding effects of GHB in Swiss Webster mice. Although the acute administration of GHB (200 mg/kg) caused marked hypolocomotion, repeated administration of the drug for 6 or 14 days produced tolerance to this effect. In addition, the administration of GHB 300 mg/kg to naive mice caused catalepsy, which dissipated in mice pre-exposed to GHB (200 mg/kg). Consequently, after repeated treatment with GHB, tolerance developed to both the hypolocomotion and cataleptic effects of the drug. The administration of GHB or its precursor gamma-butyrolactone for 14 days increased the striatal content of dopamine. The sedative effects of GHB may be due to hypodopaminergic activity from inhibition of dopamine release and a subsequent increase in the intraneuronal dopamine level. The rewarding effect of GHB was assessed in the conditioned place preference paradigm. Mice treated repeatedly with 250 mg/kg for 7 days developed conditioned preference for the GHB-paired compartment of the cage, suggesting that the GHB cue is rewarding. The development of tolerance to the sedative effects of GHB coupled with the rewarding properties of the drug support the abuse potential of GHB. Further studies are necessary to determine the mechanism underlying the development of tolerance to GHB and the rewarding effect of the drug.

Analysis of Variance↗
PubMedDate not supplied

Effects of mercury vapor inhalation on reactive oxygen species and antioxidant enzymes in rat brain and kidney are minimal.

Metals are known to induce the formation of reactive oxygen species (ROS) that initiate oxidative stress, an important mechanism of cell injury. The brain is particularly sensitive to oxidative attack because of its high level of unsaturated lipids and high rate of oxidative metabolism. The objective of this study was to determine if elemental mercury (Hg(0)) vapor inhalation increases ROS production and affects activities or levels of antioxidant-related biomolecules in the rat brain and kidney. Adult female Sprague-Dawley rats were exposed for 2 h per day for 11 consecutive days to Hg(0) vapor (1, 2, and 4 mg Hg(0) m(-3)). Brain regions (frontal cortex, cerebellum, brain stem) and kidney were assayed for total Hg, ROS and glutathione (GSH) levels, and for enzyme activities of glutathione peroxidase (GPx) and superoxide dismutase (SOD). Marked exposure-related increases (2500-5600-fold) in total Hg were detected in the brain regions and in kidney. A statistically significant increase in ROS production (ca. 30% above controls) was observed only in the cortex of rats exposed to 1 mg m(-3) Hg vapor, but no significant changes were apparent at other exposures. Although a trend towards increasing ROS production was observed in the kidney, these effects were not statistically significant. Mercury vapor exposure had no significant effects on GSH levels or GPx activity in the three brain regions, however, statistically significant decreases in GSH and GPx activity were detected in the kidneys of rats exposed to 2 mg m(-3). Mercury exposure did not cause significant effects on SOD activity in the brain or kidney. The data indicate that oxidative stress and changes in GSH and activities of antioxidant enzymes do not play a major role in Hg(0) vapor toxicity in brain and kidney.

Administration, Inhalation↗