Search

Gamma-hydroxybutyric acid (GHB) is normally found in the brain in low concentrations and may function as a neurotransmitter, although the mechanism of action has not been completely elucidated. GHB has been used as a general anesthetic and is currently used to treat narcolepsy and alcoholism. Recreational use of GHB is primarily as a "club drug" and a "date rape drug," due to its amnesic effects. For this study, the hypothesis was that behavioral and neurochemical alterations may parallel gene expression changes in the brain after GHB administration. Adult male C57/B6N mice (n=5/group) were administered a single dose of 500 mg/kg GHB (i.p.) and were sacrificed 1, 2 and 4 h after treatment. Control mice were administered saline. Brains were removed and regionally dissected on ice. Total RNA from the hippocampus, cortex and striatum was extracted, amplified and labeled. Gene expression was evaluated using Agilent whole mouse genome 4x44K oligonucleotide microarrays. Microarray data were analyzed by ArrayTrack and differentially expressed genes (DEGs) were identified using P < or = 0.01 and a fold change > or = 1.7 as the criteria for significance. Principal component analysis (PCA) and Hierarchical Cluster Analysis (HCA) showed that samples from each time point clustered into distinct treatment groups with respect to sacrifice time. Ingenuity pathways analysis (IPA) was used to identify involved pathways. The results show that GHB induces gene expression alterations in hundreds of genes in the hippocampus, cortex and striatum, and the number of affected genes increases throughout a 4-h time course. Many of these DEGs are involved in neurological disease, apoptosis, and oxidative stress., (Published by Elsevier Ltd.)

Nanoparticles are small scale substances (<100 nm) used in biomedical applications, electronics, and energy production. Increased exposure to nanoparticles being produced in large-scale industry facilities elicits concerns for the toxicity of certain classes of nanoparticles. This study evaluated the effects of silver-25 nm (Ag-25) nanoparticles on gene expression in different regions of the mouse brain. Adult-male C57BL/6N mice were administered (i.p.) 100mg/kg, 500 mg/kg or 1,000 mg/kg Ag-25 and sacrificed after 24h. Regions from the brain were rapidly removed and dissected into caudate nucleus, frontal cortex and hippocampus. Total RNA was isolated from each of the three brain regions collected and real-time RT-PCR analysis was performed using Mouse Oxidative Stress and Antioxidant Defense Arrays. Array data revealed the expression of genes varied in the caudate nucleus, frontal cortex and hippocampus of mice when treated with Ag-25. The data suggest that Ag-25 nanoparticles may produce neurotoxicity by generating free radical-induced oxidative stress and by altering gene expression, producing apoptosis and neurotoxicity.

L-carnitine (LC) plays an important regulatory role in the mitochondrial transport of long-chain free fatty acids (FFA). 3-Nitropropionic acid (3-NPA) is known to induce cellular energy deficit and oxidative stress related neurotoxicity via an irreversible inhibition of the mitochondrial enzyme succinate dehydrogenase (SDH). Protective effects of L-carnitine on the neurotoxicity induced by 3-NPA have been shown in vitro. Here, the activities of SDH as well as the activity of the antioxidant enzymes, catalase (CAT), and superoxide dismutase (SOD) were measured in order to evaluate the protective action of LC against 3-NPA-induced neurotoxicity. Male, CD Sprague-Dawley rats, 3-month old, were injected with either 50 or 100 mg/kg of LC, i.p., 30-60 min prior to 3-NPA (30 mg/kg, s.c.) or with 3-NPA alone. Enzyme activities were assayed in caudate nucleus (CN), frontal cortex (FC), and hippocampus (HIP) post sacrifice. Increased activities of CAT and SOD were observed after treatment with 3-NPA alone. Pretreatment with low or high doses of LC was associated with attenuation of these increases equivalent to, or below, the control levels. In rats treated with 3-NPA alone, SDH activity was inhibited by 62% (CN), 50% (FC), and 65% (HIP) of controls. Pretreatment with LC prior to 3-NPA attenuated decreases of SDH activity in a dose-dependent manner. However, compared with control, the activity of SDH remained significantly lower in brain regions of treated rats despite the attenuation of inhibition by LC pretreatment (P<0.05). These data suggest protective effect of LC against 3-NPA-induced oxidative stress. It appears that the protective effect of LC against 3-NPA-induced oxidative stress is not mediated by the direct action of LC preventing the SDH inhibition but rather is achieved due to the actions of LC downstream of the SDH inhibition.

Methamphetamine (METH) is one of the most commonly abused psychostimulant, and is known to induce dopaminergic neurotoxicity by generating oxidative stress and free radicals. In the present study we investigated the effects of METH on egr-1 and c-fos immediate early gene induction in different regions of mouse brain, at different doses and different time courses. We also measured the tissue levels of monoamines in order to correlate their changes with gene expression. A single injection of METH (40 mg/kg) significantly increased egr-1 and c-fos mRNA expression within 30 min in frontal cortex, nucleus accumbens, caudate putamen, septum and CA1 region of hippocampus. Time course studies showed that in most cases, both genes were expressed within 30 min and decreased after 60 min. METH produced a significant decrease in striatal dopamine level, reaching a very low level after 24 h. Striatal serotonin level significantly increased and returned to control levels after 2 h. These data show that METH induced egr-1 and c-fos mRNA expression in selective brain areas, which correlated with an alteration in monoamines.

Nicotine is a neuroteratogen that targets synaptic function during critical developmental stages and recent studies indicate that CNS vulnerability extends into adolescence, the time that smoking typically commences. We administered nicotine to pregnant or adolescent rats via continuous minipump infusions, using dose rates that replicate the plasma nicotine levels found in smokers. Fetal nicotine exposure (gestational days 4-21) decreased the cerebrocortical binding of paroxetine (PXT), a marker for the serotonin (5HT) transporter, likely indicative of a decrease in nerve terminals in that region; the effect lasted into adulthood. There was a corresponding increase in PXT binding in the midbrain/brainstem, the region containing the 5HT cell bodies that project to the cerebral cortex, a pattern typical of reactive sprouting in response to nerve terminal damage. After adolescent nicotine treatment (postnatal days 30-47), PXT binding was reduced in the hippocampus and striatum instead of the cerebral cortex, again accompanied by increased binding in the midbrain and brainstem; the patterns of effects within each region were gender-selective, although both males and females displayed abnormalities. Superimposed on this overall effect, there were transient increases in PXT binding, likely due to acute stimulant effects of nicotine. We also assessed 5HT presynaptic activity (5HIAA/5HT ratio). Withdrawal from adolescent nicotine treatment led to suppression of activity in the cerebral cortex and activation in the midbrain. These results indicate that both fetal and adolescent nicotine exposure elicit apparent damage to 5HT projections with reactive increases in regions containing 5HT cell bodies. Long-term changes in 5HT innervation and/or synaptic activity may play a role in the subsequent development of depression in the offspring of women who smoke during pregnancy or in adolescent smokers.

The neurotoxic effects of excessive exposure to manganese (Mn) include degeneration of dopaminergic neurons, impairment of energy metabolism, and perturbations in phosphoinositide (PI) hydrolysis leading to altered calcium (Ca2+) homeostasis. This study is designed to assess the in vitro and in vivo effects of Mn on Ca2+/calmodulin-dependent neuronal nitric oxide synthase (nNOS) activity and on the regulation of inositol 1,4,5-trisphosphate (InsP3) and inositol 1,3,4,5-tetrakisphosphate (InsP4) receptors involved in intracellular and extracellular mobilization of Ca2+. In vivo Mn exposure significantly increased 3H-InsP3 and 3H-InsP4 binding in the cerebellum and the cerebral cortex in a dose-dependent manner. However, in vitro Mn decreased 3H-InsP3 binding and increased 3H-InsP4 binding. In vitro and in vivo exposure of Mn inhibited nNOS activity in the cerebellum and the cerebral cortex. Immunohistochemical studies also showed a notable decrease in nNOS immunoreactivity in the granule cell layer of the cerebellum, whereas no significant changes were observed in the cerebral cortex. These data suggest that Mn neurotoxicity may be due to altered calcium homeostasis by its modulation of inositol polyphosphate receptors. Further, the inhibition of nNOS by Mn is of considerable importance because NO regulates a number of neurotransmitter functions.

Methylazoxymethanol (MAM), an aglycone of cycasin extracted from Cycad seed, is reported to induce microencephaly in rats after prenatal or postnatal administration. Forty postnatal day (PND) 1 rats derived from 8 timed-pregnant rats were used to evaluate the effect of a single subcutaneous injection of MAM on PND 1 on cell proliferation in rat brain. All dams were fed NIH-31 diet. In the MAM-treated group, each pup received a single injection of MAM at 10 mg/kg body weight. In the control group, pups were injected with saline solution. Body weight of pups was recorded on PNDs 1, 7, 14, 21, 28, and 60. One male pup in each litter was removed for sacrifice by decapitation on PNDs 7, 14, 21, 28, and 60. The brain was removed and dissected to obtain the brain stem, caudate nucleus, cerebellum, frontal cortex, hippocampus, hypothalamus, and olfactory bulb. The percentage (%) of S-phase cells in the cell cycle for each region was measured as index of cell proliferation. A significant (p<0. 05) reduction in body weight was detected on PND 7. The % S-phase cells in cerebellum on PND 7 and olfactory bulb on PND 14 initially increased and then later decreased. There were significant decreases in the % S-phase cells in both cerebellum and caudate nucleus on PND 21 and olfactory bulb on PND 28. No significant changes were found in other brain regions in cell proliferation activity between the control and MAM-treated groups. The % of S-phase cells in cerebellum decreased 65% on PND 60 but lacked statistical significance due to small number of animals used in each group. The results indicated that a single injection of MAM at 10 mg/kg/body weight on PND 1 inhibited cell proliferation in the cerebellum in a manner that could lead to microencephaly.

Senescence is accompanied by the loss of neurons and synapses, and the maintenance of function depends on adaptive change at the levels of synaptic activity and cellular responsiveness. In the current study, we administered the neurotoxin MDMA, to young and aged mice and assessed the effects on indices of neuronal activity and cell signaling mediated through adenylyl cyclase. Young mice given MDMA showed 80% depletion of dopamine in the caudate and 30% depletion in the cerebral cortex; measurements of dopamine turnover indicated a compensatory upregulation of the activity of the remaining neurons in the caudate but downregulation in the cerebral cortex. Serotonin levels were comparatively less affected but serotonin turnover was decreased significantly in both regions. At the level of cell signaling, the young mice showed heterologous upregulation of adenylyl cyclase activity and a consequent enhancement of responses mediated through neurotransmitter receptors. In aged mice, MDMA treatment produced the same degree of lesioning but substantially different changes in neuronal activity and cell signaling. In the cerebral cortex, dopamine turnover was increased, and serotonin turnover decreased, effects opposite in direction to those seen in young mice. In the aged group, MDMA elicited heterologous loss of adenylyl cyclase responses instead of displaying the supersensitivity that had been seen in the young group. The aging brain thus displays maladaptation to the loss of monoaminergic input, effects that may augment the functional impairment associated with neurodegenerative disorders or stroke.

Ibogaine is a plant-derived alkaloid with putative 'anti-addictive' properties. Although ibogaine binds to multiple targets in the brain, recent evidence suggests the drug acts as an N-methyl-D-aspartate (NMDA) antagonist similar to MK-801. The purpose of the present study was to compare neurochemical and neuroendocrine effects of ibogaine and MK-801 in vivo. Male rats received either i.p. saline, ibogaine (10 and 100 mg/kg), or MK-801 (0.1 and 1 mg/kg). Groups of rats (N=6-8/group) were decapitated 30 or 60 min after injection. Brains were harvested for analysis of dopamine (DA) and its metabolites, while trunk blood was collected for analysis of plasma corticosterone and prolactin. Ibogaine produced marked dose-dependent reductions in tissue DA with concurrent increases in the metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). This profile of ibogaine-induced effects on DA metabolism was consistently observed in the cortex, striatum, olfactory tubercle, and hypothalamus. MK-801, on the other hand, did not reduce DA levels in any brain region but did cause modest region-specific elevations in DA metabolites. Ibogaine and MK-801 caused comparable elevations in circulating corticosterone, but only ibogaine increased prolactin. The present findings show that the effects of ibogaine on DA neurotransmission and neuroendocrine secretion are not fully mimicked by MK-801. Thus, the wide spectrum of in vivo actions of ibogaine can probably not be explained simply on the basis of antagonism at NMDA receptors.

The aim of the present study was to evaluate if an acute injection of ibogaine (IBO) induces immediate early gene expression in different regions of mouse brain. Adult male C57 mice received a single injection of IBO and were perfused transcardially with 1% paraformaldehyde 30 min after the drug administration. A single injection of IBO produced a significant increase of egr-1 messenger RNA induction in nucleus accumbens (NAc), caudate-putamen (CPu), frontal cortex (FCx), septum, dentate gyrus (DG) and CA3 region of hippocampus, whereas c-fos gene was induced in CPu, FCx, DG, septum and CA1 region of hippocampus. This gene expression may be due, in part, to the stimulant properties of IBO, as we found with other psychostimulants.

Inhalation of high concentrations of manganese (Mn) is associated with an extrapyramidal motor disorder in humans. Oxidative damage, mediated by increased levels of Mn in dopaminergic brain regions and mitochondria, is a hypothesized mechanism of action for Mn-induced neuronal degeneration and loss. To test this proposed mechanism, developing CD rats, which may be at an increased risk for Mn-induced neurotoxicity, were exposed orally to 0, 25, or 50 mg/kg/day of MnCl2 from postnatal day (PND) 1 to 49 Brain regional and mitochondrial Mn levels, brain regional reactive oxygen species (ROS) levels, and whole-brain nuclear and mitochondrial 8-OHdG levels were used to evaluate Mn-mediated oxidative damage. High-dose Mn exposure was associated with increased spontaneous motor activity on PND 21 and decreased body weights on PND 49. On PND 21, Mn concentrations were increased in brain regions and mitochondrial fractions in both low- and high-dose groups. ROS levels were elevated in cerebellum but not striatum. On PND 49, Mn concentrations in brain regions and mitochondrial fractions were increased only in the high-dose group. Mn exposure did not significantly alter 8-OHdG levels in either mitochondrial or nuclear DNA. Selective uptake of Mn by the striatum or mitochondrial fraction was not demonstrated at either time point. These data allow us to conclude that oral exposure to high levels of Mn in developing CD rats resulted in increased brain regional and mitochondrial Mn levels, increased motor activity, and decreased body weights but not in selective accumulation of Mn in the striatum or mitochondrial fraction of any brain region or elevations in striatal ROS or whole-brain 8-OHdG levels. These findings do not support the hypothesis that oxidative damage, as assessed by ROS and 8-OHdG levels, is a mechanism of action in Mn-induced developmental neurotoxicity in the CD rat.

Phencyclidine (PCP) is a potent psychotomimetic drug of abuse and has profound effect on the functioning of the central nervous system (CNS). Many of the CNS functions are known to be mediated by calcium (Ca2+). In the present study we have investigated the effects of PCP on Ca2+ ATPase activity in rat brain both in vitro and in vivo. For in vitro studies, synaptic membrane fractions prepared from normal rat brain were incubated with PCP at different concentrations (25-100 microM) before the addition of substrate. For in vivo studies, rats were treated with a single moderate dose of PCP (10 mg/kg, i.p.) and animals were sacrificed at 1,2, 6 and 12 h after treatment. Ca2+ ATPase activity in synaptic membrane fractions was assayed by estimation of inorganic phosphate. PCP inhibited the Ca2+ ATPase in vitro in a concentration dependent manner with significant effect at 50 and 100 microM. A significant time-dependent reduction of the Ca2+ ATPase activity was evident in vivo. As early as 2 h after the treatment of rats with PCP the ATPase activity was significantly reduced. The reduction of Ca2+ ATPase observed even at 12 h after treatment suggesting a prolonged presence of the drug in the brain tissue. Further, kinetic studies in vitro indicated PCP to be a competitive inhibitor of Ca2+ ATPase with respect to the substrate, ATP. The present findings indicate that PCP inhibits synaptic membrane Ca2+ ATPase thus altering cellular Ca2+ homeostasis in CNS which may partially explain the pharmacological effects of the drug and/or its neurotoxicity.

The present study was designed to determine if chronic exposure of weanlings and adult rats to Mn produces significant alterations in amino acid concentrations in different regions of the rat brain. Weanling (30 day old) and adult (90 day old) male rats were exposed to 10 and 20 mg Mn/kg body weight per day, by gavage, for 30 days. Forty-eight hours after the last dose, animals were sacrificed by decapitation and brains were dissected into different regions to determine the concentration of amino acids by HPLC/EC. A dose dependent decrease in body weight gain was found in the adult, but not in the weanling rats. Significant increases occurred in concentrations of aspartate, glutamate, glutamine, taurine and gamma-aminobutyric acid (GABA) in the cerebellum of the adult rats dosed with 20 mg/kg per day, Mn. A significant decrease in the concentration of glutamine was observed in caudate nucleus and hippocampus of weanling rats dosed with 10 mg/kg, Mn. These data suggest that chronic Mn exposure can produce a decrease in body weight gain in adult rats and alterations in amino acids in different regions of weanling and adult rat brains.

The response of endogenous antioxidants to acute exposure of the mitochondrial inhibitor, 3-nitropropionic acid (3-NPA), was investigated in selected rat brain regions. Rats treated with 3-NPA (30 mg/kg, s.c.) were sacrificed at 30, 60, 90 and 120 min after injection to examine the alterations in reduced glutathione levels (GSH), and activities of antioxidant enzymes, superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT) in the hippocampus (HIP), frontal cortex (FC), and caudate nucleus (CN). CAT activity increased in the HIP 90 min after 3-NPA treatment. While cytosolic copper/zinc SOD (CuZn-SOD) and mitochondrial manganese SOD (Mn-SOD) levels increased in the FC at 120 min, only the Mn-SOD increased in the CN 90 min after treatment. The activity of GPx decreased in the HIP 120 min after 3-NPA injection. When compared with the control, administration of 3-NPA led to GSH depletion in HIP within 120 min. The depletion of GSH and induction of antioxidant enzyme activities after the 3-NPA exposure suggest conditions favorable for oxidative stress.

In an attempt to delineate the capacity of aluminum (Al) to promote pro-oxidant events, several indices of oxidative stress have been determined in brains and livers of rats exposed to an Al salt, either alone or in combination with an iron (Fe) compound. Treatment with Al over a 3-wk period increased both cortical levels of glutathione (GSH) and the rates of generation of reactive oxygen species (ROS). Dosing with an Fe compound resulted in no parallel changes, and concurrent exposure to Fe together with Al prevented these elevations. Both Fe and Al dosing elevated glutamine synthetase activity in the cortex. Levels of creatine kinase, another enzyme susceptible to oxidative stress, were also elevated in cortices of Al-treated rats. These data are in contrast to the changes found in liver fractions where exposure to Fe greatly enhanced hepatic pro-oxidant events as judged by changes in all three of the test indices used. Concurrent treatment with Al did not potentiate the pro-oxidant effects of Fe in liver. Al treatment had very minor effects on hepatic parameters of oxidative events. The results suggest that the presence of Al may exert deleterious pro-oxidant changes within the brain, which may be related to induction of oxidant species. These changes are tissue-specific and appear to be independent of any promotion of pro-oxidant status induced by exogenous Fe.

Cocaine is a widely abused psychomotor stimulant which acts in the central nervous system (CNS) by blocking the reuptake site. It has been estimated that between 30-60 million people have abused cocaine in the United States. Unfortunately, an effective therapy for cocaine abuse is not available. The calcium channel antagonists (CCAs) are commonly used in the therapy of various cardiovascular diseases and are under investigation due to their potential in modulating calcium-dependent neurotransmitter release. The purpose of this study was to evaluate the acute effect of isradipine on cocaine-induced locomotor and stereotypic activity and correlate the changes in dopamine, serotonin and their metabolites--dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), AND 5-hydroxyindoleacetic acid (5-HIAA)--levels in the rat brain. Animals were pretreated intraperitoneally (i.p.) with vehicle or CCAs. After 30 minutes they were administered cocaine (20 mg/kg, i.p.). During this period, motor and stereotypic activity was monitored. In a separate experiment, animals were dosed as described above and were sacrificed by decapitation after the 30-minute treatment period. The nucleus accumbens and caudate nucleus were dissected and analyzed for monoamines using a high-performance liquid chromatography-electrochemical detector (HPLC-ECD). Isradipine (5mg/kg, i.p.) inhibited cocaine-induced locomotor and stereotypic activity by 49% and 36%, respectively, as compared to controls. In the nucleus accumbens cocaine (20 mg/kg, i.p.) increased extracellular dopamine and serotonin levels in the nucleus accumbens by 8% while decreasing serotonin levels by 9%. Cocaine (20 mg/kg, i.p.) produced increased levels of both extracellular dopamine and serotonin (9% and 4%, respectively) in the caudate nucleus. Isradipine (5 mg/kg, i.p.) pretreatment decreased cocaine (20 mg/kg i.p.)-induced extracellular dopamine and serotonin levels in the caudate nucleus by 18% and 8%, respectively. These experiments suggest that a central mechanism may involved in attenuation of cocaine-induced motor behaviors by isradipine.

Although the alkaloid ibogaine is a potent hallucinogenic agent some indications suggest that it may be useful for the treatment of opioid and cocaine addiction. The neurochemical mechanism(s) underlying ibogaine effects remain unclear. In the present study we investigated the interaction of ibogaine with the phencyclidine (PCP) site located in the ionophore of the N-methyl-D-aspartate (NMDA) receptor complex, with the NMDA receptor binding site, and with sigma binding sites. In well-washed membrane preparations of rat cortex and cerebellum, the PCP sites were labeled with [3H]MK-801 or [3H]1-[1(2-theinyl)-cyclohexyl]-piperidine ([3H]TCP), and the NMDA receptor with [3H]-CGP 39653. The sigma-1 and sigma-2 binding site in rat cortex and cerebellum were labeled with [3H]pentazocine and [3H]1,3-di-o-tolyl-guanidine ([3H]DTG), respectively. Results indicated that ibogaine interacts with high- and low-affinity PCP binding sites in the cortex: Ki(H) = 0.01-0.05 microM; Ki(L) = 2-4 microM, and only with low-affinity sites in the cerebellum: Ki = 2-4, microM. In contrast, ibogaine (> 100 microM) had no affinity for [3H]-CGP 39653 binding sites (cortex and cerebellum). The affinity of ibogaine for sigma-1 and -2 binding sites in cortex and cerebellum ranged from 1.5-3 microM. Since NMDA receptor antagonists (e.g., MK-801) are thought to attenuate opioid withdrawal symptoms and cocaine sensitization, it is possible that binding of ibogaine to the PCP sites contributes to its potential 'endabuse' properties. In turn, ibogaine interaction with sigma binding sites may be associated with its adverse effects.

Ibogaine (IBO) is a psychoactive indole alkaloid that has antiaddictive properties. However, treatment with IBO may lead to neurotoxicity, since IBO and its metabolites interact persistently with many neurotransmitter systems. Here, we recorded cortical electroencephalogram (EEG) signals from rats anesthetized with isoflurane. The heart rate (HR) was monitored via electrocardiogram (EKG) electrodes. After the baseline EEG was recorded, rats received one intraperitoneal (i.p.) dose of 50 mg/kg IBO. EEG signals were recorded for 2 hr. Rats were then sacrificed and brains dissected into frontal cortex (FC), caudate nucleus (CN), hippocampus (HIP), and brain stem (BS). The level of dopamine (DA), serotonin (5-HT), and their metabolites were determined by high-performance liquid chromatography with electrochemical detection (HPLC-ECD). Compared with baseline, a decrease in HR immediately after IBO injection and a decrease in delta, theta, alpha and beta power spectra frequency bands (1-4, 4-8, 8-13, 13-32 Hz) during the first 30 min after IBO administration was observed. EEG recovered within the next 15 min. In CN, the level of DA decreased and DA turnover rate increased significantly. The levels of 5-HT increased in FC. The pattern of EKG AND EEG response to IBO may be due to multiple receptor interactions of IBO.

Ibogaine (IBO) is a naturally-occurring indole compound that is being evaluated as a potential medication for substance use disorders. Although the precise mechanism of IBO action is unclear, recent in vitro data show this drug displays properties similar to the noncompetitive N-methyl-D-aspartate (NMDA) antagonist MK-801. The purpose of the present work was to compare in vivo neurobiological effects of IBO and MK-801 in rats. Groups of male rats (n = 6-8/group) were decapitated 30 and 60 min after receiving intraperitoneal (i.p.) IBO (10 & 100 mg/kg), MK-801 (0.1 & 1.0 mg/kg) or vehicle. Trunk blood was collected for the analysis of plasma prolactin and corticosterone; brains were harvested and dissected for determination of dopamine (DA), serotonin (5-HT) and their metabolites. Both IBO and MK-801 increased corticosterone secretion, but only IBO elevated plasma prolactin. IBO produced dramatic reductions in tissue DA levels with concurrent increases in the metabolites, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). This profile of IBO-induced changes in DA transmission was observed in the striatum, olfactory tubercle, and hypothalamus. The effects of MK-801 on DA metabolism did not mimic IBO, as MK-801 tended to increase DA and its metabolites. Neither drug appreciably affected 5-HT systems. Our results suggest that the effects of IBO on neuroendocrine function and DA transmission are not due to MK-801-like properties of IBO. Thus, the in vivo mechanism of IBO action cannot be explained simply on the basis of antagonism at NMDA receptors.

The present study was undertaken to determine if in vitro exposure to mercuric chloride produces reactive oxygen species (ROS) in the synaptosomes prepared from various regions of rat brain. The effects of in vivo exposure to mercury on antioxidant enzymes such as superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities in different regions of rat brain were also investigated. Adult male Sprague-Dawley (CD) rats were dosed with 0, 1, 2.0 or 4.0 mg HgCl2/kg body weight, for 7 days. One week after the last dose, animals were sacrificed by decapitation, their brains were removed and dissected and frozen in dry ice prior to measuring the activities of these enzymes. The results demonstrated that in vitro exposure to mercury produced a concentration-dependent increase of ROS in different regions of the rat brain. In vivo exposure to mercury produced a significant decrease of total SOD, Cu, Zn-SOD and Mn-SOD activities in the cerebellum of rats treated with different doses of mercury. SOD activity did not vary significantly in cerebral cortex and brain stem. GPx activity declined in a dose-dependent manner in the cerebellum with a significant reduction in animals receiving the 4 mg HgCl2/kg body weight. The activity of GPx increased in the brain stem while unchanged in the cerebral cortex. The results demonstrate that inorganic mercury decreased SOD activity significantly in the cerebellum while GPx activity was affected in both cerebellum and brain stem. Therefore, it can be concluded that oxidative stress may contribute to the development of neurodegenerative disorders caused by mercury intoxication.

It has been proposed that neurodegenerative processes of aging are associated with the generation of reactive oxygen species (ROS) during cellular metabolism. These reactive oxygen species are scavenged by antioxidant enzymes in biological systems. The present study was designed to determine the selective distribution of the antioxidant enzymes superoxide dismutase, catalase and glutathione peroxidase activity and reduced glutathione (GSH) levels in different regions of the C57BL/6N mouse brain and to determine if any alterations occurred with age. Catalase activity did not show any significant change except in cerebellum. Activity of superoxide dismutase was increased with age in all regions of the brain except in hippocampus of 2-yr-old mice. The glutathione peroxidase activity in the caudate nucleus increased in all regions of the brain, however, the activity did not change at one, six and 12 months. A significant increasing pattern of glutathione content was found in the cerebellum and brain stem with age. These data demonstrate that although the level of antioxidant enzymes varied in different regions of the brain, overall the enzyme activities tend to increase with age.

3-nitropropionic acid (3-NPA) neurotoxicity and long-term effects of perinatal hypoxia were evaluated in 18 adult rats. Hypoxia-insulted (I) and noninsulted (NI) rats were delivered by cesarean section. Hypoxic insult was effected by submerging dissected uterine horns in warmed saline for 15 min. NI rats were delivered from the adjacent nonsubmerged horns. At postnatal day 90, I and NI rats were trained to perform tasks thought to measure behaviors dependent upon aspects of time estimation (TE), motivation, and learning. At 12 months of age, rats were injected i.p. with escalating doses of 3-NPA (5 mg/kg/day to a maximum of 30 mg/kg/day) immediately after each test session and sacrificed at the end of treatment. Additional male rats were used as untreated controls. Although 3-NPA produced a dose-dependent impairment of performance in each task, the effects were qualitatively similar for each group. A significant difference between I and NI rats was, however, observed in the TE task where NI rats completed less of the task at high doses of 3-NPA compared to I rats. Compared to untreated controls, dopamine concentrations were decreased in caudate nucleus of both I and NI rats after 3-NPA. Specific areas most frequently damaged included cerebral cortex, hippocampal subfield CA1, thalamus, caudate nucleus, and the cerebellum. Lesions usually were less extensive in the I rather than NI members of a littermate pair, suggesting a possible protective effect of perinatal hypoxia against subsequent 3-NPA neurotoxicity.

Drugs of abuse, such as phencyclidine (PCP), methamphetamine (METH), and cocaine (COC) are known to affect several behaviors in rats, such as motor activity, stereotypy, and circling. In this study, we evaluated whether these drugs produce circling preferences in the presence or absence of unilateral 6-hydroxydopamine (6-OHDA)-induced lesions of the caudate nucleus. Adult male CD rats were lesioned with 10 micrograms 6-OHDA/site. Animals were dosed with PCP (15 mg/kg, ip) its congener (+) MK-801 (0.15 mg/kp, ip), METH (2 mg/kg, ip) COC (60 mg/kp, ip), or apomorphine (0.2 mg/kg, ip). Circling preference was recorded in control and lesioned rats for 2 h before animals were sacrificed to determined monoamine levels by HPLC/EC. In control animals, administration of these drugs produced 60-70% left circling. In lesioned animals, these drugs produced 78-90% ipsilateral (toward the lesion) circling, except apomorphine, which produced 60-80% contralateral (away from the lesion) circling. Dopamine (DA) and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) concentrations significantly decreased ipsilaterally in lesioned caudate nucleus (CN) and substantia nigra (SN). However, no significant changes were observed in nucleus accumbens (NA) and olfactory tubercles (OT). These data demonstrate that drugs of abuse like PCP, its congener (+) MK-801, METH, and COC produce a greater preference to turn toward the left than the right, a finding similar to that found in human psychosis. Since 6-OHDA lesions enhanced the circling bias and depleted DA and its metabolites DOPAC and HVA, it also suggests that the dopaminergic system may be involved in the circling behavior.

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.

Work on neonatal MAM exposure has focused primarily on exposure within the first week postpartum, and on resulting hypoplasia or stunting of the cerebellum. Rats in this study were exposed to MAM on 4 consecutive postnatal days (PND), beginning at one of six ages, from birth through weaning (PND 1, 5, 9, 13, 17, or 21). MAM was administered subcutaneously in doses of 3, 4, or 5 mg/kg twice per day. Rats were sacrificed at PNDs 28 or 84. The most sensitive age for MAM-induced stunting was determined to be PNDs 1-4. When 5 mg/kg MAM was administered twice daily on PNDs 1-4, body weight was reduced by 24% at age 28 days. Additionally, when compared to control rats, brains of the 28-day-old rats were stunted as follows: whole brain (11%), cerebellum (35%), hippocampus (11%), and olfactory bulb (27%). The effects of PND 1-4 MAM exposure were still evident at 84 days of age when cerebellum and olfactory bulbs from treated rats weighed 30% less than those same regions in control rats. These findings indicate that neonatal exposure to MAM results in permanent stunting in select regions of developing rat brain. This stunting, along with other known MAM effects, can be tailored by exposure age and dose to augment the use of MAM as a positive control for investigation of compounds with neurotoxic potential.

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.

These experiments examined the relationship between behavioral alterations and neurochemical changes in rats exposed repeatedly to disulfoton, an organophosphate cholinesterase inhibitor. Male Long-Evans rats were injected ip for 30 days with 0, 0.5, 1, or 2 mg/kg of disulfoton in corn oil. Clinical signs and motor activity were measured during the course of repeated exposure. Cognitive function, as measured in the Morris water maze, and passive avoidance procedures were assessed near the end of the dosing regimen. Regional brain acetylcholinesterase (AChE) activity was measured during the course of dosing while the total number of muscarinic receptors was measured at the end of the dosing regimen. Tolerance developed rapidly to the clinical signs produced by disulfoton, but not to the disulfoton-induced decrease in motor activity. Disulfoton affected the acquisition of water maze performance, but had no effect on passive avoidance acquisition or retention. Repeated exposure to disulfoton decreased brain AChE activity and the number of [3H]quinuclidinyl benzilate binding sites. These data indicate that, in spite of muscarinic receptor down-regulation that followed repeated exposure to disulfoton, animals become tolerant to only some of the functional effects produced by this chemical.

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.

Monoamines may exert a trophic effect on early brain development. To assess the role of dopamine in prenatal neurological development of the rat, haloperidol (HAL) was given in daily 2.5 or 5 mg/kg SC doses to dams over gestational days 6 to 20. This treatment regime did not enhance fetal mortality, but did produce reliable, if modest, stunting of the body and brain weight of offspring. The 5 mg/kg HAL dose consistently reduced offspring brain weight to roughly 90% of controls. This effect was probably permanent, in that it was seen throughout maturation and in adults as late as 140 days of postnatal age. Appropriate controls showed that this effect was not due to drug-induced reductions in food intake, to the presence of HAL in maternal milk, or to behavioral abnormalities in HAL-exposed dams. These effects had, at best, modest regional specificity, in that most brain regions were affected, independently of degree of dopaminergic innervation. Closer investigation of HAL effects on the striatum suggested that this permanent weight reduction was not accompanied by alterations in striatal concentrations of monoamines, monoamine metabolites, amino acids, choline, acetylcholine, DNA, protein, or water. It is concluded that prenatal HAL does stunt growth, but that this effect may not involve a direct drug influence restricted to the fetal dopamine system in the brain.

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.

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.

Trimethyltin (TMT) is a neurotoxic compound known to cause marked alterations in brain chemistry. We have previously demonstrated that a single oral dose of TMT produced a dose-dependent decrease in muscarinic cholinergic receptors in mouse brain and significantly elevated glutamine in several regions of the rat brain. This study was designed to determine if TMT produced dose- and time-related alterations in amino acid concentrations in the adult male C57BL/6N mouse brain and in peripheral organs and plasma. In the dose-response study, TMT was administered orally as a single dose of 0, 0.5, 1.0, 3.0 or 5.0 mg/kg and animals were sacrificed 24 hr after treatment. In the time-course study, mice were dosed with TMT at 3.0 mg/kg and sacrificed 4, 12, 24, 48 or 96 hr after dosing. Amino acid concentrations were quantified by HPLC/EC following precolumn derivatization with o-phthalaldehyde-tert-butylthiol. TMT produced dose-dependent increases in aspartate, glutamine and glycine in the caudate nucleus (CN), frontal cortex (FC) and hippocampus (HIP) at 3.0 and 5.0 mg/kg. TMT at 3.0 mg/kg produced significant increases of aspartate in FC and HIP after 48 hr. Glutamine concentrations were significantly increased at 24 and 48 hr in HIP and at 48 hr in CN. Glycine and GABA concentrations were significantly increased at 48 and 96 hr respectively in the HIP. Glutamine was increased in plasma at 4 and 12 hr and in liver at 24 hr. Hyperammonemia occurred in plasma after 8 hr and continued through 24 hr and was accompanied by an increase in serum urea nitrogen.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

MDMA is a hallucinogenic drug that is used by the general public as a recreational drug of abuse. The neurobehavioral consequences of prenatal MDMA exposure are unknown. Groups of pregnant rats were gavaged with 0, 2.5, or 10 mg/kg MDMA during gestation on alternate gestational days 6-18. Gestational duration, litter size, neonatal birth weights and physical appearance at birth were unaffected by MDMA treatments. Pregnancy weight gain was significantly reduced by MDMA treatment. Progeny growth, maturational parameters (eye opening and incisor eruption times), surface righting reflex, swimming performance, forelimb grip strength, milk-induced behaviors, passive avoidance behavior, figure-8 maze activity over 48 hours, the density of brain serotonin (5-HT) uptake sites, and brain 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) levels were unaffected by MDMA treatments. Olfactory discrimination on postnatal days (PND) 9-11 was enhanced in both male and female MDMA-treated progeny, while negative geotaxis (PND 7-10) was delayed in female pups. In contrast to progeny, MDMA caused dose-dependent decreases in 5-HT and 5-HIAA levels in discrete brain areas of the dam. It is concluded that prenatal exposure to MDMA at the levels used here produces only subtle behavioral alterations in developing rats. The dam is more at risk for MDMA-induced 5-HT depletion than is the conceptus.

The pre- and postnatal developmental course of cerebral ornithine decarboxylase (ODC) has been studied in infant rats after treatment of pregnant dams with cocaine. Levels of cocaine attained in brains and serum of embryos were not initially increased over corresponding maternal values, but were more persistent. However, cocaine was not longer detectable in these tissues 4 days after administration. The cerebral ODC level of treated pups was initially depressed and subsequently elevated relative to control values. These changes were apparent at times when cocaine was not detected in the developing brain. Results indicate that a transient exposure to cocaine in utero may lead to prolonged developmental abnormality.

Commonly used organophosphate pesticide dichlorvos is known to cause neurologic lesions. However, the exact mechanism of its neurotoxicity is, as yet, unclear. Using dose-dependent inhibition of acetylcholinesterase activity as an index of its neurotoxicity, effects of three different doses of dichlorvos (0.6 mg, 1.5 mg, and 3.0 mg/kg body weight i.p. daily for 10 days) have been observed on the rate of lipid-peroxidation in the cerebrum, cerebellum and brain stem of albino rats. Simultaneously, electron microscopic study of the dichlorvos intoxicated rat cerebellum was also carried out. Dose-dependent increase in the rate of lipid peroxidation was found in all the brain regions, and increased incidence of lipofuscin-like pigment granules was discernible in the Purkinie cells of the cerebellar cortex.

Acrylamide administration of 10 and 20 mg/kg body weight i.p. in the male rat induced alteration in the levels of dopamine (DA), serotonin (5-HT), and 5-hydroxyindole acetic acid (5-HIAA) in different regions of the brain. Selective but widespread changes were observed in 5-HIAA levels in all regions of the brain studied. 5-HT levels were significantly increased in the brain stem. The DA content also showed a significant increment in the caudate nucleus. These data suggested that the neurotoxicity of acrylamide might be correlated with the overall disturbances of serotonergic system.

Adult male Fisher 344 rats (8-10 wk old) were dosed ip with 1.75 mg/kg body weight of triethyllead chloride (TEL) for 5 consecutive days. Rats were sacrificed 1, 7, or 21 d after the last injection. The rate of lipid peroxidation was significantly elevated in frontal cortex at all three time points assayed (1, 7, or 21 d). However, hippocampal and cerebellar membranes showed no changes in peroxidative capacity at these time points. In order to determine whether cortical membrane damage was reflected in alteration of a restricted protein population, a series of high-affinity receptor binding sites was determined in cortical membranes derived from treated rats 7 d after the last injection of triethyllead. The rate of lipid peroxidation was significantly increased in the frontal cortex of triethyllead treated rats; however, no changes in the binding of [3H]spiroperidol, [3H]quinuclidinyl benzilate, and [3H]benzodiazepine were seen in animals exposed to triethyllead. The cortical wet weight, protein content, and cell number were also unchanged by TEL treatment, reflecting an absence of gross damage.

MDMA is an amphetamine analog prescribed by some health professionals in the field of psychotherapy and used as a recreational drug by the general public. In recent reports, investigators have suggested that MDMA produces acute neurotoxicity when administered by subcutaneous injection. In order to determine if MDMA produces lasting neurochemical alterations after oral administration, groups of six rats (adult male Sprague-Dawley) were dosed by gavage with either 40 or 80 mg/kg of MDMA or saline vehicle once every 12 hr for 4 days. These rats were terminated 2 weeks after the first dose along with an additional group of rats (80 mg/kg) terminated 4 weeks after the first dose. Brain regions including the hippocampus (H), caudate nucleus (CN), hypothalamus (HY), frontal cortex (FC), and brain stem (BS) were analyzed by HPLC with electrochemical detection for concentrations of dopamine (DA), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), and norepinephrine (NE). In the CN, 40 mg/kg MDMA produced no change in DA, DOPAC, or HVA, but a 50-60% decrease in 5-HT and 5-HIAA concentrations was observed at 2 weeks. Similar effects were observed at 80 mg/kg at both 2 weeks and 4 weeks. A temporary decrease was also seen in DA (21%) and in HVA (34%) 2 weeks but not 4 weeks after the 80 mg/kg dose regimen. In the H, MDMA (40 or 80 mg/kg) produced no change in NE, but a 50-60% decrease was seen in 5-HT and 5-HIAA concentrations at 2 weeks. Concentrations of 5-HT and 5-HIAA were significantly decreased in the HY and FC by all MDMA treatments, but DA and DOPAC concentrations were not altered as compared to vehicle controls. BS was least affected by treatment with no change in DA, DOPAC, or 5-HIAA concentrations and only a slight decrease in 5-HT (19-33%) concentrations at 2 weeks but not at 4 weeks. To determine the sensitivity of the nonhuman primate to MDMA, a total of nine rhesus monkeys were dosed with vehicle or 5 or 10 mg/kg MDMA (n = 3) by gastric intubation twice per day for 4 days. One month after MDMA dosing, a dose-related reduction from vehicle control values for 5-HT and 5-HIAA was observed. These results indicate that the monkey may be more sensitive than the rat to the persistent serotonergic neurotoxicity of MDMA.(ABSTRACT TRUNCATED AT 400 WORDS)

Phencyclidine is a widely used drug of abuse and is known to produce a wide variety of psychoactive effects. PCP abuse by pregnant women has been reported to result in the birth of infants exhibiting irritability, jitteriness and hyperactivity with high pitched cries. The present study was designed to evaluate the distribution of PCP in the maternal and fetal brain and the neurochemical effects produced by gestational exposure. Pregnant Sprague-Dawley rats were treated sc with 5 mg/kg PCP on 3 consecutive days (GD 9-11, 12-14, 15-16, or 18-20). On gestational day (GD) 21 all rats were killed by decapitation and maternal and fetal blood was collected for PCP analysis. Brains were dissected from dams and fetuses for PCP and neurochemical analyses. On GD 21 after exposure on GD 18-20, the fetal: maternal ratio of brain PCP concentrations was 11:1. PCP exposure on GD 12-14, 15-17, and 18-20 significantly decreased fetal brain PCP binding sites on GD 21, whereas maternal values were unchanged. Fetal dopaminergic and muscarinic cholinergic receptor binding and neurotransmitter concentrations were unaffected by prenatal PCP exposure. These data demonstrated that maternal PCP exposure resulted in prolonged exposure of the developing CNS and also indicated that gestational exposure to PCP decreased high affinity binding sites of PCP in term fetal brain.

Pregnant rats were treated on either gestational day (GD) 7, 12, or 17 with single doses of trimethyltin chloride (TMT) ip at either 0, 5, 7, or 9 mg/kg. A significant effect of dose was manifest as decreased maternal weight at term, which persisted during lactation until postnatal day (PND) 15 in some groups. For all treatments combined, term weights of dams exposed on GDs 7 and 12 were greater than those treated on GD 17. Litter sizes were decreased for groups treated on GD 17 with 9 mg/kg TMT. Pups treated in utero and exhibiting treatment-induced decreases in weight at or near birth remained smaller than untreated animals into adulthood (PND 280). By PND 20, weights of pups treated on GD 7 greater than GD 12 greater than GD 17. Neuropathology of pups sacrificed on PND 1 was minimal in all animals with lesions only identified in animals treated on GDs 12 or 17 which consisted of subtle degenerative changes in the CA3 and CA4 regions of Ammon's horn of the hippocampus. Muscarinic cholinergic receptor binding in whole brains from pups on PND 1 did not show any significant changes compared to controls for any dose or day of exposure. These data indicate that prenatal TMT exposure results in postnatal toxicity in treated pups but only in the presence of maternal toxicity.

Adult male Fischer-344 rats were dosed sc with 1 or 2.5 mg/kg of triethyl lead chloride (TEL) for 5 consecutive days. One week after the last dose, TEL-exposed rats had decreased Met-enkephalin in the hypothalamus, septum, and frontal cortex, while substance P was decreased in the hippocampus and frontal cortex. Dopamine (DA) and dihydroxyphenylacetic acid (DOPAC) in the caudate nucleus were not altered by TEL nor were serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) in the caudate nucleus, hypothalamus, hippocampus, or frontal cortex. In a second experiment, rats were dosed with 1.75 mg/kg sc for 5 days. Subsequent assay of brain tissue indicated that TEL decreased met-enkephalin levels in the septum of rats one and seven days after cessation of dosing; effects on substance P were not observed. TEL-induced decreases in Met-enkephalin in the septum were temporally associated with increased hot plate latencies. One day after cessation of dosing with TEL, concentration of 5-HIAA in the caudate nucleus, hippocampus, frontal cortex, and brain stem, and 5-HT in the hippocampus and brain stem were increased. Biogenic amine concentrations were not affected in any other region or at any other time postdosing. A third experiment indicated that TEL-induced analgesia could be attenuated by 10 mg/kg chlordiazepoxide or 10 mg/kg of naloxone. The present results suggest that TEL-induced analgesia may be due to alterations in emotionality or reactivity to noxious stimuli, which may be associated with the alteration in delta opiate mechanism in the limbic system, such as the change of septal enkephalin neuronal activities.

Male C57B1/6N mice, 8-10 weeks old were given a single oral dose of 0, 1.0 or 3.0 mg/kg body weight of trimethyltin hydroxide (TMT). Levels of ornithine decarboxylase (ODC) activity were measured in several brain areas, 1, 2 and 7 days later. The lower dose of TMT produced a decrease of ODC in the caudate nucleus and hippocampus at all time points studied. Hypothalamus, cerebellum and brain stem levels of this enzyme were unaltered. At the higher dose of TMT, ODC activity in hippocampus, cerebellum and brain stem were increased relative to controls at 1 and 2 days after treatment, while other regions were not significantly affected. These elevated ODC levels returned to control values within 7 days. Thus, trimethyltin treatment causes changes in ODC activity in a region and dose-specific manner.

The levels of dopamine, noradrenaline and 5-hydroxytryptamine were estimated in the hypothalamus and limbic areas, corpus striatum, cerebellum and the brain-stem of rats administered thallous acetate (5 mg/kg i.p.) daily for 7 days. Significant decreases in the concentration of dopamine occurred in the hypothalamus, limbic areas and corpus striatum. Noradrenaline did not reveal significant alteration in any of the regions of the brain examined. The concentration of 5-hydroxytryptamine was significantly lowered in the corpus striatum, cerebellum and the brain-stem.