Methamphetamine (MA) is a powerful and highly addictive psychostimulant. However, the neural subs... more Methamphetamine (MA) is a powerful and highly addictive psychostimulant. However, the neural substrate mediating MA-induced conditioned effects, an essential part of addiction, remain unclear. The present study investigated the involvement of the anterior cingulate cortex (ACC), the lateral nucleus of amygdala (LNA), and the mediodorsal nucleus of the thalamus (MD) in MA-conditioned place preference (CPP). Rats underwent bilateral radio-frequency lesions of the ACC, LNA, or MD followed by MA CPP training. Lesions of the MD, but not the ACC or LNA, disrupted MA CPP learning. To clarify the role of the MD on the different stages of the MA CPP memory process, bilateral microinfusions of lidocaine into the MD were performed 5 min prior to each conditioning trial, immediately after the conditioning trial, or 5 min before the testing phase. Pretesting, but not pre- or post-conditioning, infusions of lidocaine into the MD impaired MA CPP. Furthermore, a clear preference for the previously ...
Hair cells are highly sensitive to environmental insults and other therapeutic drugs. The adverse... more Hair cells are highly sensitive to environmental insults and other therapeutic drugs. The adverse effects of drugs such as aminoglycosides can cause hair cell death and lead to hearing loss and imbalance. The objective of the present study was to evaluate the protective activity of L-ascorbic acid, N-acetylcysteine (NAC) and apocynin on neomycin-induced hair cell damage in zebrafish (Danio rerio) larvae at 5 days post fertilization (dpf). Results showed that the loss of hair cells within the neuromasts of the lateral lines after neomycin exposure was evidenced by a significantly lower number of neuromasts labeled with fluorescent dye FM1-43FX observed under a microscope. Co-administration with L-ascorbic acid, NAC and apocynin protected neomycin-induced hair cell loss within the neuromasts. Moreover, these three compounds reduced the production of reactive oxygen species (ROS) in neuromasts exposed to neomycin, indicating that their antioxidant action is involved. In contrast, the n...
Recent advances in somatic cell reprogramming have highlighted the plasticity of the somatic epig... more Recent advances in somatic cell reprogramming have highlighted the plasticity of the somatic epigenome, particularly through demonstrations of direct lineage reprogramming of adult mouse and human fibroblasts to induced pluripotent stem cells (iPSCs) and induced neurons (iNs) under defined conditions. However, human cells appear to be less plastic and have a higher epigenetic hurdle for reprogramming to both iPSCs and iNs. Here, we show that SH2B adaptor protein 1β (SH2B1) can enhance neurite outgrowth of iNs reprogrammed from human fibroblasts as early as day 14, when combined with miR124 and transcription factors BRN2 and MYT1L (IBM) under defined conditions. These SH2B1-enhanced iNs (S-IBM) showed canonical neuronal morphology, and expressed multiple neuronal markers, such as TuJ1, NeuN, and synapsin, and functional proteins for neurotransmitter release, such as GABA, vGluT2, and tyrosine hydroxylase. Importantly, SH2B1 accelerated mature process of functional neurons and exhibit...
Honokiol, a constituent of Magnolia obovata, has various pharmacological effects, including prote... more Honokiol, a constituent of Magnolia obovata, has various pharmacological effects, including protection against cerebral ischemia. However, few studies have been conducted to evaluate the possible neuroprotective effects of honokiol against cerebral ischemia. We recently reported that cerebral ischemic neuronal damage could be triggered by glucose intolerance that develops after the onset of ischemic stress (i.e., post-ischemic glucose intolerance). In addition, suppression of post-ischemic glucose intolerance significantly ameliorated ischemic neuronal damage. Here, we investigated the effects of honokiol on the development of post-ischemic glucose intolerance and neuronal damage. Mice were subjected to middle cerebral artery occlusion (MCAO) for 2 h. The development of post-ischemic glucose intolerance on day 1 and neuronal damage on day 3 after MCAO were significantly reduced by intraperitoneal administration of honokiol (10 mg/kg) compared with the vehicle-treated group. Honokiol did not affect serum insulin or adiponectin levels. However, honokiol significantly decreased the expression of phosphoenolpyruvate carboxykinase and increased the expression of 5'-AMP-activated protein kinase (AMPK) on day 1 after MCAO, compared with the vehicle-treated MCAO group. The results of this study suggest that honokiol could prevent post-ischemic glucose intolerance in an AMPK-dependent manner, which may be involved in the neuroprotective effects of honokiol against cerebral ischemia.
N-methyl-D-aspartate (NMDA) glutamate receptors mediate fast neurotransmission and regulate synap... more N-methyl-D-aspartate (NMDA) glutamate receptors mediate fast neurotransmission and regulate synaptic plasticity in the brain. Disruption of NMDA receptor-mediated signaling by noncompetitive antagonists, such as PCP or ketamine, evokes psychotomimetic behaviors, although the cellular mechanisms by which hypofunctional NMDA receptor signaling drives behavioral pathology are still unclear. Activation of glycogen synthase kinase-3 (GSK-3) has been implicated in the cellular neurotoxicity of NMDA receptor antagonists. Accordingly, in the present study we examined the ability of GSK-3 inhibitors, SB216763 and 1-azakenpaullone, to reverse the behavioral aberrations induced by ketamine. Male NMRI mice received intracerebroventricular (i.c.v.) injection of the GSK-3 inhibitors, SB216763 and 1-azakenpaullone, 5 min prior to ketamine administration. Locomotor activity, rotarod performance, prepulse inhibition, novel object recognition, and duration of loss of righting reflex were monitored. GSK-3 inhibitors attenuated ketamine-induced locomotor hyperactivity, motor incoordination, sensorimotor impairment, and cognitive deficits, but did not affect ketamine anesthesia. These data support an important role of GSK-3 in the expression of behavioral aberrations associated with NMDA receptor hypofunction, and suggest that GSK-3 inhibitors may ameliorate certain behavioral and cognitive dysfunctions in patients with schizophrenia.
Although toluene is a widely abused substance, the neuronal populations and pathways mediating it... more Although toluene is a widely abused substance, the neuronal populations and pathways mediating its effects are not well understood. Using c-Fos protein as a marker for neuronal activation, the present study investigated the pattern of c-Fos induction at 1h after various doses (0, 300, 750, and 1000 mg/kg, i.p.) of toluene injection in adult male rats. Quantitative analysis of Fos-immunoreactive neurons indicated toluene dose-related induced c-Fos immunoreactivity in the majority of structures examined. The structures included several cortex subareas (primary motor cortex, secondary motor cortex, somatosensory cortex, frontal association cortex, cigulate cortex area 1, cigulate cortex area 2, prelimbic cortex, infralimbic cortex, retrosplenial agranular cortex, ventral orbital cortex, lateral orbital cortex, and piriform cortex), ventral tegmental area, nucleus accumbens shell, thalamic nuclei (mediodorsal, lateral posterior, and laterodorsal ventrolateral) and pontine nuclei. Howeve...
Toxicological sciences : an official journal of the Society of Toxicology, 2005
Toluene has been reported to antagonize the function of N-methyl-D-aspartate (NMDA) receptors. In... more Toluene has been reported to antagonize the function of N-methyl-D-aspartate (NMDA) receptors. In this study, the effects of neonatal toluene exposure on NMDA receptors in primarily cultured cerebellar granule neurons were examined. Sprague-Dawley rats were treated with toluene (0, 200, 500, and 1000 mg/kg, i.p.) from postnatal day (PN) 4 to PN 7. Under toluene-free conditions, Ca2+ signals of cultured neurons in response to glutamate and NMDA were measured for up to 14 days. The expression of NMDA receptor subunits (NR1, NR2A, and NR2B) at 5-14 days in vitro (DIV) were also determined. Neonatal toluene exposure dose-dependently reduced intracellular Ca2+ signals in response to glutamate/glycine and NMDA/glycine in cultured cerebellar granule neurons, and these effects were gradually decreased with time. Such toluene exposure did not influence the inhibition of Mg2+ or MK801 on NMDA-evoked responses, but it decreased the potency of ifenprodil (an NR2B preferring antagonist). The pro...
The effects of toluene on the sensitivity to seizures induced by aminophylline were investigated.... more The effects of toluene on the sensitivity to seizures induced by aminophylline were investigated. Mice were pretreated with an ip injection of corn oil or toluene (100-500 mg/kg) followed by a timed intravenous infusion of aminophylline at various time intervals to assess the seizure thresholds and lethal doses. Toluene increased seizure susceptibility to aminophylline in a dose- and time-dependent manner. Toluene-induced enhancement of seizure susceptibility to aminophylline occurred as early as 30 min and persisted for at least 3 days after a single administration of toluene (500 mg/kg). Treatment of benzaldehyde, one of toluene's metabolites, also showed an increase in the susceptibility to aminophylline. The enhancing effect was also observed in caffeine-induced seizures 1 h, but not 1 day after toluene treatment. These results suggest that individuals with toluene exposure may increase the risk for convulsive and even lethal complications associated with the therapeutic use...
Toluene is an abused solvent widely used in several commercial products. Recent evidence indicate... more Toluene is an abused solvent widely used in several commercial products. Recent evidence indicates that this solvent is a noncompetitive inhibitor of N-methyl-D-aspartate (NMDA) receptors and enhances gamma-aminobutyric acid(A) (GABA(A)) receptor-mediated synaptic currents. Since NMDA and GABA(A) receptors have been implicated in seizures, this study investigated whether toluene exposure during synaptogenesis period alters the NMDA and GABA(A) receptor-mediated seizure susceptibility in juvenile rats. Neonatal rats were administered toluene (1 g/kg ip) daily over postnatal days (PN) 4-9. Rats were administered NMDA (10 mg/ml), picrotoxin (2 mg/ml), pentylenetetrazol, (5 mg/ml) and 4-aminopyridine (4-AP; 2 mg/ml) via timed tail vein infusion on PN 34-36. Toluene exposure increased sensitivity to NMDA, picrotoxin and pentylenetetrazol, but did not affect 4-aminoyridine-induced seizures in both male and female rats. These results suggest that toluene may possess a risk to the developin...
The effects of a common industrial solvent, trichloroethylene (TCE), which was once used as an an... more The effects of a common industrial solvent, trichloroethylene (TCE), which was once used as an anesthetic agent but its in vivo mechanism is still unknown, on convulsant-induced seizures in mice were examined. Pretreatment with TCE (250-2000 mg/kg, i.p.) significantly increased pentylenetetrazol (PTZ)-, picrotoxin (PIC)-, bicuculline (BIC)-, strychnine (STY)-, 4-aminopyridine (4-AP)- and N-methyl-D-aspartate (NMDA)-induced convulsion thresholds and lethal doses. However, the increase in convulsion thresholds and lethal doses was much greater for GABAergic antagonists (PIC, BIC, and PTZ) than non-GABAergic convulsants (STY, 4AP, and NMDA) following 2000 mg/kg TCE administration. Pre-treatment of mice with disulfiram (an inhibitor of CYP 4502E1) but not 4-methyl pyrazole (an inhibitor of alcohol dehydrogenase) significantly prolonged the time required for TCE (5000 mg/kg, i.p.) to induce the loss of righting reflex. These results suggest that acute exposure to TCE differentially alter...
Sprague-Dawley rats were maternally and permanently exposed to Pb (1000 ppm in their drinking wat... more Sprague-Dawley rats were maternally and permanently exposed to Pb (1000 ppm in their drinking water as lead acetate). Behavioral functions were examined starting at post-natal day (PN) 84. Lead exposure did not change spatial learning in the radial arm maze, but induced higher locomotor activity as observed in the open-field and in the radial arm maze. Lead treatment did not impact motor coordination. Autoradiographic analysis of brain sections indicated that Pb-exposure did produce a decrease in [125I]sulpride (D2 receptor antagonist) binding in the cerebral cortex, but not in the striatum and thalamus nucleus. No change was found in [125I]SCH-23982 (D1 receptor antagonist) binding. Since the cortical dopaminergic system is critical for cognitive processes and motor behavior, it is possible that Pb-related change in D2 receptors may mediate to it induced hyperlocomotor activity.
The NMDA receptor non-competitive antagonist, [3H]MK-801, was used as a ligand for an autoradiogr... more The NMDA receptor non-competitive antagonist, [3H]MK-801, was used as a ligand for an autoradiographic study to determine the effects of lead on NMDA receptor in rat brain. Adult male rats were given lead acetate, 100 mg/kg, or sodium acetate, 36 mg/kg (control), by i.p. for 7 days. Lead levels were detected in blood (41.1 micrograms/dl) and brain (16.7-29.4 micrograms/g). Concentrations of lead in various brain regions did not differ. [3H]MK-801 binding was heterogeneous throughout the brain with the following order of binding densities: hippocampal formation > cortex > caudate-putamen > thalamus > brainstem. Lead exposure caused a decrease in [3H]MK-801 binding to NMDA receptors in the hippocampal formation including CA2 stratum radiatum, CA3 stratum radiatum and presubiculum, and in the agranular insular, cingulate, entorhinal, orbital, parietal and perirhinal areas of cerebral cortex. In another experiment, female rats were exposed pre- and post-natally from the 4th +/- 1 post conception day with 1,000 ppm lead in their drinking water. This treatment continued after weaning. No effects of lead on [3H]MK-801 binding were found at postnatal day (PM) 28. However, lead caused a significant increase in [3H]MK-801 binding in the hippocampus including CA1 and CA2, and in the occipital and temporal cortical areas at PN 56 and at PN 112. Increases in [3H]MK-801 binding were also found in entorhinal cortex and dentate gyrus at PN 112. The hippocampal formation is a critical neural structure for learning and memory processes, whereas cortical and subcortical regions are involved in the modulation of complex behavioral processes. NMDA receptors have been shown to play a key role in synaptic plasticity underlying learning and memory. Therefore, lead-induced alterations of ligand binding to NMDA receptors in the hippocampal formation and cortical areas may play a role in lead-induced neurotoxicity.
Recent studies have shown that metabotropic glutamate receptor 5 (mGluR5) can modulate N-methyl-D... more Recent studies have shown that metabotropic glutamate receptor 5 (mGluR5) can modulate N-methyl-D-aspartate receptor function. Our previous findings demonstrated that the selective mGluR5 agonist (RS)-2-chloro-5-hydroxyphenylglycine (CHPG) and the antagonist 2-methyl-6-(phenylethynyl)-pyridine can reduce and enhance the ketamine anesthesia, respectively. The purpose of this study was to examine whether CHPG and positive allosteric modulator 3,3'-difluorobenzaldazine (DFB) can reverse ketamine-induced behavioral responses including locomotor hyperactivity, motor incoordination, sensorimotor gating deficit, and learning impairment. Mice were pretreated with CHPG (5-50 nmol,) or DFB (40-100 nmol) followed by ketamine administration. Locomotor activity, rotarod test, prepulse inhibition (PPI) of acoustic startle test, and novel object recognition test were examined. CHPG and DFB had no effect on these behaviors when administered alone. Both of them attenuated the locomotor hyperactivity, motor incoordination, and cognitive impairment induced by ketamine. However, the ketamine-induced PPI deficit was reversed by CHPG (50 nmol) but not by DFB (up to 100 nmol). CHPG and DFB have distinct potency and efficacy in attenuating ketamine-induced behavioral response. These behavioral data extend previous findings and further suggest that positive modulation of mGluR5 may provide a novel approach for development of antipsychotic agents.
Chloroform has been reported to induce inhalation intoxication in the respiratory tract. The purp... more Chloroform has been reported to induce inhalation intoxication in the respiratory tract. The purpose of this study was to investigate the effects and mechanisms of chloroform on muscle contraction in isolated swine tracheal smooth muscle. Chloroform (30-1000 ppm) reversibly and concentration-dependently provoked smooth muscle contraction. Muscarinic and alpha-adrenergic receptor antagonists did not alter chloroform-induced muscle contraction, indicating muscarinic and alpha-adrenergic stimulation may not be involved in chloroform-induced responses. Caffeine (10 mM) was observed to directly evoke tracheal smooth muscle contraction, but ryanodine (1 microM) was not. However, ryanodine and caffeine abolished chloroform-induced smooth muscle contraction by 80.0 +/- 8.0 and 79.6 +/- 6.0%, respectively. Caffeine combined with ryanodine completely blocked chloroform-induced contractile responses. Thus, it suggests that chloroform released Ca(2+) from ryanodine-sensitive internal Ca(2+) pools. Although short-term removal of Ca(2+) from extracellular environment slightly decreased chloroform-induced contractile responses, L-type Ca(2+) channel blockers did not alter tracheal smooth muscle contraction induced by chloroform. Collectively, our results indicated that chloroform directly and concentration-dependently provoked muscle contraction in swine tracheal smooth muscle, which may result from the activation of ryanodine receptor Ca(2+) release channel in sarcoplasmic reticulum but may not depend on muscarinic and adrenergic activation and Ca(2+) entry from the extracellular environment.
Abuse of toluene-containing volatile solvents by adolescents is a significant public health probl... more Abuse of toluene-containing volatile solvents by adolescents is a significant public health problem. The present study characterized the long-term behavioural and neurochemical consequences of toluene exposure during adolescence. Male NMRI mice received one injection per day of either toluene (600 mg/kg) or corn oil during postnatal days (PN) 35-37 and (750 mg/kg) during PN38-39 and PN42-46. A variety of psychiatric disorder-relevant behavioural tests were examined at PN56-P84. The toluene-exposed mice were significantly deficient in the social interaction test, nesting behaviour, social dominance tube test, and novel objective recognition test. However, toluene exposure did not affect locomotor activity and behavioural profiles in the forced swimming test, tail suspension test, emergence test and elevated plus maze. Neurochemically, the turnover rates of dopamine in the prefrontal cortex, striatum and nucleus accumbens were reduced in toluene-treated mice. Adolescent toluene exposure leads to social deficits and cognitive impairment at adulthood as well as neurochemical dysfunction in mice, which correlate with the symptoms observed in patients suffering from solvent-induced psychosis. These findings highlight the need for understanding the effects of solvent abuse on the developing nervous system and reveal an animal model suitable for research into pathophysiology of neurological and psychiatric consequences of solvent abuse.
Methamphetamine (MA) is a powerful and highly addictive psychostimulant. However, the neural subs... more Methamphetamine (MA) is a powerful and highly addictive psychostimulant. However, the neural substrate mediating MA-induced conditioned effects, an essential part of addiction, remain unclear. The present study investigated the involvement of the anterior cingulate cortex (ACC), the lateral nucleus of amygdala (LNA), and the mediodorsal nucleus of the thalamus (MD) in MA-conditioned place preference (CPP). Rats underwent bilateral radio-frequency lesions of the ACC, LNA, or MD followed by MA CPP training. Lesions of the MD, but not the ACC or LNA, disrupted MA CPP learning. To clarify the role of the MD on the different stages of the MA CPP memory process, bilateral microinfusions of lidocaine into the MD were performed 5 min prior to each conditioning trial, immediately after the conditioning trial, or 5 min before the testing phase. Pretesting, but not pre- or post-conditioning, infusions of lidocaine into the MD impaired MA CPP. Furthermore, a clear preference for the previously ...
Hair cells are highly sensitive to environmental insults and other therapeutic drugs. The adverse... more Hair cells are highly sensitive to environmental insults and other therapeutic drugs. The adverse effects of drugs such as aminoglycosides can cause hair cell death and lead to hearing loss and imbalance. The objective of the present study was to evaluate the protective activity of L-ascorbic acid, N-acetylcysteine (NAC) and apocynin on neomycin-induced hair cell damage in zebrafish (Danio rerio) larvae at 5 days post fertilization (dpf). Results showed that the loss of hair cells within the neuromasts of the lateral lines after neomycin exposure was evidenced by a significantly lower number of neuromasts labeled with fluorescent dye FM1-43FX observed under a microscope. Co-administration with L-ascorbic acid, NAC and apocynin protected neomycin-induced hair cell loss within the neuromasts. Moreover, these three compounds reduced the production of reactive oxygen species (ROS) in neuromasts exposed to neomycin, indicating that their antioxidant action is involved. In contrast, the n...
Recent advances in somatic cell reprogramming have highlighted the plasticity of the somatic epig... more Recent advances in somatic cell reprogramming have highlighted the plasticity of the somatic epigenome, particularly through demonstrations of direct lineage reprogramming of adult mouse and human fibroblasts to induced pluripotent stem cells (iPSCs) and induced neurons (iNs) under defined conditions. However, human cells appear to be less plastic and have a higher epigenetic hurdle for reprogramming to both iPSCs and iNs. Here, we show that SH2B adaptor protein 1β (SH2B1) can enhance neurite outgrowth of iNs reprogrammed from human fibroblasts as early as day 14, when combined with miR124 and transcription factors BRN2 and MYT1L (IBM) under defined conditions. These SH2B1-enhanced iNs (S-IBM) showed canonical neuronal morphology, and expressed multiple neuronal markers, such as TuJ1, NeuN, and synapsin, and functional proteins for neurotransmitter release, such as GABA, vGluT2, and tyrosine hydroxylase. Importantly, SH2B1 accelerated mature process of functional neurons and exhibit...
Honokiol, a constituent of Magnolia obovata, has various pharmacological effects, including prote... more Honokiol, a constituent of Magnolia obovata, has various pharmacological effects, including protection against cerebral ischemia. However, few studies have been conducted to evaluate the possible neuroprotective effects of honokiol against cerebral ischemia. We recently reported that cerebral ischemic neuronal damage could be triggered by glucose intolerance that develops after the onset of ischemic stress (i.e., post-ischemic glucose intolerance). In addition, suppression of post-ischemic glucose intolerance significantly ameliorated ischemic neuronal damage. Here, we investigated the effects of honokiol on the development of post-ischemic glucose intolerance and neuronal damage. Mice were subjected to middle cerebral artery occlusion (MCAO) for 2 h. The development of post-ischemic glucose intolerance on day 1 and neuronal damage on day 3 after MCAO were significantly reduced by intraperitoneal administration of honokiol (10 mg/kg) compared with the vehicle-treated group. Honokiol did not affect serum insulin or adiponectin levels. However, honokiol significantly decreased the expression of phosphoenolpyruvate carboxykinase and increased the expression of 5'-AMP-activated protein kinase (AMPK) on day 1 after MCAO, compared with the vehicle-treated MCAO group. The results of this study suggest that honokiol could prevent post-ischemic glucose intolerance in an AMPK-dependent manner, which may be involved in the neuroprotective effects of honokiol against cerebral ischemia.
N-methyl-D-aspartate (NMDA) glutamate receptors mediate fast neurotransmission and regulate synap... more N-methyl-D-aspartate (NMDA) glutamate receptors mediate fast neurotransmission and regulate synaptic plasticity in the brain. Disruption of NMDA receptor-mediated signaling by noncompetitive antagonists, such as PCP or ketamine, evokes psychotomimetic behaviors, although the cellular mechanisms by which hypofunctional NMDA receptor signaling drives behavioral pathology are still unclear. Activation of glycogen synthase kinase-3 (GSK-3) has been implicated in the cellular neurotoxicity of NMDA receptor antagonists. Accordingly, in the present study we examined the ability of GSK-3 inhibitors, SB216763 and 1-azakenpaullone, to reverse the behavioral aberrations induced by ketamine. Male NMRI mice received intracerebroventricular (i.c.v.) injection of the GSK-3 inhibitors, SB216763 and 1-azakenpaullone, 5 min prior to ketamine administration. Locomotor activity, rotarod performance, prepulse inhibition, novel object recognition, and duration of loss of righting reflex were monitored. GSK-3 inhibitors attenuated ketamine-induced locomotor hyperactivity, motor incoordination, sensorimotor impairment, and cognitive deficits, but did not affect ketamine anesthesia. These data support an important role of GSK-3 in the expression of behavioral aberrations associated with NMDA receptor hypofunction, and suggest that GSK-3 inhibitors may ameliorate certain behavioral and cognitive dysfunctions in patients with schizophrenia.
Although toluene is a widely abused substance, the neuronal populations and pathways mediating it... more Although toluene is a widely abused substance, the neuronal populations and pathways mediating its effects are not well understood. Using c-Fos protein as a marker for neuronal activation, the present study investigated the pattern of c-Fos induction at 1h after various doses (0, 300, 750, and 1000 mg/kg, i.p.) of toluene injection in adult male rats. Quantitative analysis of Fos-immunoreactive neurons indicated toluene dose-related induced c-Fos immunoreactivity in the majority of structures examined. The structures included several cortex subareas (primary motor cortex, secondary motor cortex, somatosensory cortex, frontal association cortex, cigulate cortex area 1, cigulate cortex area 2, prelimbic cortex, infralimbic cortex, retrosplenial agranular cortex, ventral orbital cortex, lateral orbital cortex, and piriform cortex), ventral tegmental area, nucleus accumbens shell, thalamic nuclei (mediodorsal, lateral posterior, and laterodorsal ventrolateral) and pontine nuclei. Howeve...
Toxicological sciences : an official journal of the Society of Toxicology, 2005
Toluene has been reported to antagonize the function of N-methyl-D-aspartate (NMDA) receptors. In... more Toluene has been reported to antagonize the function of N-methyl-D-aspartate (NMDA) receptors. In this study, the effects of neonatal toluene exposure on NMDA receptors in primarily cultured cerebellar granule neurons were examined. Sprague-Dawley rats were treated with toluene (0, 200, 500, and 1000 mg/kg, i.p.) from postnatal day (PN) 4 to PN 7. Under toluene-free conditions, Ca2+ signals of cultured neurons in response to glutamate and NMDA were measured for up to 14 days. The expression of NMDA receptor subunits (NR1, NR2A, and NR2B) at 5-14 days in vitro (DIV) were also determined. Neonatal toluene exposure dose-dependently reduced intracellular Ca2+ signals in response to glutamate/glycine and NMDA/glycine in cultured cerebellar granule neurons, and these effects were gradually decreased with time. Such toluene exposure did not influence the inhibition of Mg2+ or MK801 on NMDA-evoked responses, but it decreased the potency of ifenprodil (an NR2B preferring antagonist). The pro...
The effects of toluene on the sensitivity to seizures induced by aminophylline were investigated.... more The effects of toluene on the sensitivity to seizures induced by aminophylline were investigated. Mice were pretreated with an ip injection of corn oil or toluene (100-500 mg/kg) followed by a timed intravenous infusion of aminophylline at various time intervals to assess the seizure thresholds and lethal doses. Toluene increased seizure susceptibility to aminophylline in a dose- and time-dependent manner. Toluene-induced enhancement of seizure susceptibility to aminophylline occurred as early as 30 min and persisted for at least 3 days after a single administration of toluene (500 mg/kg). Treatment of benzaldehyde, one of toluene's metabolites, also showed an increase in the susceptibility to aminophylline. The enhancing effect was also observed in caffeine-induced seizures 1 h, but not 1 day after toluene treatment. These results suggest that individuals with toluene exposure may increase the risk for convulsive and even lethal complications associated with the therapeutic use...
Toluene is an abused solvent widely used in several commercial products. Recent evidence indicate... more Toluene is an abused solvent widely used in several commercial products. Recent evidence indicates that this solvent is a noncompetitive inhibitor of N-methyl-D-aspartate (NMDA) receptors and enhances gamma-aminobutyric acid(A) (GABA(A)) receptor-mediated synaptic currents. Since NMDA and GABA(A) receptors have been implicated in seizures, this study investigated whether toluene exposure during synaptogenesis period alters the NMDA and GABA(A) receptor-mediated seizure susceptibility in juvenile rats. Neonatal rats were administered toluene (1 g/kg ip) daily over postnatal days (PN) 4-9. Rats were administered NMDA (10 mg/ml), picrotoxin (2 mg/ml), pentylenetetrazol, (5 mg/ml) and 4-aminopyridine (4-AP; 2 mg/ml) via timed tail vein infusion on PN 34-36. Toluene exposure increased sensitivity to NMDA, picrotoxin and pentylenetetrazol, but did not affect 4-aminoyridine-induced seizures in both male and female rats. These results suggest that toluene may possess a risk to the developin...
The effects of a common industrial solvent, trichloroethylene (TCE), which was once used as an an... more The effects of a common industrial solvent, trichloroethylene (TCE), which was once used as an anesthetic agent but its in vivo mechanism is still unknown, on convulsant-induced seizures in mice were examined. Pretreatment with TCE (250-2000 mg/kg, i.p.) significantly increased pentylenetetrazol (PTZ)-, picrotoxin (PIC)-, bicuculline (BIC)-, strychnine (STY)-, 4-aminopyridine (4-AP)- and N-methyl-D-aspartate (NMDA)-induced convulsion thresholds and lethal doses. However, the increase in convulsion thresholds and lethal doses was much greater for GABAergic antagonists (PIC, BIC, and PTZ) than non-GABAergic convulsants (STY, 4AP, and NMDA) following 2000 mg/kg TCE administration. Pre-treatment of mice with disulfiram (an inhibitor of CYP 4502E1) but not 4-methyl pyrazole (an inhibitor of alcohol dehydrogenase) significantly prolonged the time required for TCE (5000 mg/kg, i.p.) to induce the loss of righting reflex. These results suggest that acute exposure to TCE differentially alter...
Sprague-Dawley rats were maternally and permanently exposed to Pb (1000 ppm in their drinking wat... more Sprague-Dawley rats were maternally and permanently exposed to Pb (1000 ppm in their drinking water as lead acetate). Behavioral functions were examined starting at post-natal day (PN) 84. Lead exposure did not change spatial learning in the radial arm maze, but induced higher locomotor activity as observed in the open-field and in the radial arm maze. Lead treatment did not impact motor coordination. Autoradiographic analysis of brain sections indicated that Pb-exposure did produce a decrease in [125I]sulpride (D2 receptor antagonist) binding in the cerebral cortex, but not in the striatum and thalamus nucleus. No change was found in [125I]SCH-23982 (D1 receptor antagonist) binding. Since the cortical dopaminergic system is critical for cognitive processes and motor behavior, it is possible that Pb-related change in D2 receptors may mediate to it induced hyperlocomotor activity.
The NMDA receptor non-competitive antagonist, [3H]MK-801, was used as a ligand for an autoradiogr... more The NMDA receptor non-competitive antagonist, [3H]MK-801, was used as a ligand for an autoradiographic study to determine the effects of lead on NMDA receptor in rat brain. Adult male rats were given lead acetate, 100 mg/kg, or sodium acetate, 36 mg/kg (control), by i.p. for 7 days. Lead levels were detected in blood (41.1 micrograms/dl) and brain (16.7-29.4 micrograms/g). Concentrations of lead in various brain regions did not differ. [3H]MK-801 binding was heterogeneous throughout the brain with the following order of binding densities: hippocampal formation > cortex > caudate-putamen > thalamus > brainstem. Lead exposure caused a decrease in [3H]MK-801 binding to NMDA receptors in the hippocampal formation including CA2 stratum radiatum, CA3 stratum radiatum and presubiculum, and in the agranular insular, cingulate, entorhinal, orbital, parietal and perirhinal areas of cerebral cortex. In another experiment, female rats were exposed pre- and post-natally from the 4th +/- 1 post conception day with 1,000 ppm lead in their drinking water. This treatment continued after weaning. No effects of lead on [3H]MK-801 binding were found at postnatal day (PM) 28. However, lead caused a significant increase in [3H]MK-801 binding in the hippocampus including CA1 and CA2, and in the occipital and temporal cortical areas at PN 56 and at PN 112. Increases in [3H]MK-801 binding were also found in entorhinal cortex and dentate gyrus at PN 112. The hippocampal formation is a critical neural structure for learning and memory processes, whereas cortical and subcortical regions are involved in the modulation of complex behavioral processes. NMDA receptors have been shown to play a key role in synaptic plasticity underlying learning and memory. Therefore, lead-induced alterations of ligand binding to NMDA receptors in the hippocampal formation and cortical areas may play a role in lead-induced neurotoxicity.
Recent studies have shown that metabotropic glutamate receptor 5 (mGluR5) can modulate N-methyl-D... more Recent studies have shown that metabotropic glutamate receptor 5 (mGluR5) can modulate N-methyl-D-aspartate receptor function. Our previous findings demonstrated that the selective mGluR5 agonist (RS)-2-chloro-5-hydroxyphenylglycine (CHPG) and the antagonist 2-methyl-6-(phenylethynyl)-pyridine can reduce and enhance the ketamine anesthesia, respectively. The purpose of this study was to examine whether CHPG and positive allosteric modulator 3,3'-difluorobenzaldazine (DFB) can reverse ketamine-induced behavioral responses including locomotor hyperactivity, motor incoordination, sensorimotor gating deficit, and learning impairment. Mice were pretreated with CHPG (5-50 nmol,) or DFB (40-100 nmol) followed by ketamine administration. Locomotor activity, rotarod test, prepulse inhibition (PPI) of acoustic startle test, and novel object recognition test were examined. CHPG and DFB had no effect on these behaviors when administered alone. Both of them attenuated the locomotor hyperactivity, motor incoordination, and cognitive impairment induced by ketamine. However, the ketamine-induced PPI deficit was reversed by CHPG (50 nmol) but not by DFB (up to 100 nmol). CHPG and DFB have distinct potency and efficacy in attenuating ketamine-induced behavioral response. These behavioral data extend previous findings and further suggest that positive modulation of mGluR5 may provide a novel approach for development of antipsychotic agents.
Chloroform has been reported to induce inhalation intoxication in the respiratory tract. The purp... more Chloroform has been reported to induce inhalation intoxication in the respiratory tract. The purpose of this study was to investigate the effects and mechanisms of chloroform on muscle contraction in isolated swine tracheal smooth muscle. Chloroform (30-1000 ppm) reversibly and concentration-dependently provoked smooth muscle contraction. Muscarinic and alpha-adrenergic receptor antagonists did not alter chloroform-induced muscle contraction, indicating muscarinic and alpha-adrenergic stimulation may not be involved in chloroform-induced responses. Caffeine (10 mM) was observed to directly evoke tracheal smooth muscle contraction, but ryanodine (1 microM) was not. However, ryanodine and caffeine abolished chloroform-induced smooth muscle contraction by 80.0 +/- 8.0 and 79.6 +/- 6.0%, respectively. Caffeine combined with ryanodine completely blocked chloroform-induced contractile responses. Thus, it suggests that chloroform released Ca(2+) from ryanodine-sensitive internal Ca(2+) pools. Although short-term removal of Ca(2+) from extracellular environment slightly decreased chloroform-induced contractile responses, L-type Ca(2+) channel blockers did not alter tracheal smooth muscle contraction induced by chloroform. Collectively, our results indicated that chloroform directly and concentration-dependently provoked muscle contraction in swine tracheal smooth muscle, which may result from the activation of ryanodine receptor Ca(2+) release channel in sarcoplasmic reticulum but may not depend on muscarinic and adrenergic activation and Ca(2+) entry from the extracellular environment.
Abuse of toluene-containing volatile solvents by adolescents is a significant public health probl... more Abuse of toluene-containing volatile solvents by adolescents is a significant public health problem. The present study characterized the long-term behavioural and neurochemical consequences of toluene exposure during adolescence. Male NMRI mice received one injection per day of either toluene (600 mg/kg) or corn oil during postnatal days (PN) 35-37 and (750 mg/kg) during PN38-39 and PN42-46. A variety of psychiatric disorder-relevant behavioural tests were examined at PN56-P84. The toluene-exposed mice were significantly deficient in the social interaction test, nesting behaviour, social dominance tube test, and novel objective recognition test. However, toluene exposure did not affect locomotor activity and behavioural profiles in the forced swimming test, tail suspension test, emergence test and elevated plus maze. Neurochemically, the turnover rates of dopamine in the prefrontal cortex, striatum and nucleus accumbens were reduced in toluene-treated mice. Adolescent toluene exposure leads to social deficits and cognitive impairment at adulthood as well as neurochemical dysfunction in mice, which correlate with the symptoms observed in patients suffering from solvent-induced psychosis. These findings highlight the need for understanding the effects of solvent abuse on the developing nervous system and reveal an animal model suitable for research into pathophysiology of neurological and psychiatric consequences of solvent abuse.
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Papers by Hwei-Hsien Chen