Biomedical subjects

G C Wagner

Publications and source records attributed to G C Wagner.

At least 19 recordsLinked to original sources

PubMed2006

Trimethyltin-induced alterations in behavior are linked to changes in PSA-NCAM expression.

The neurotoxic heavy metal trimethyltin (TMT) primarily damages neurons of the hippocampus and limbic areas of the temporal lobe, and causes a dose-dependent decrease in the polysialated form of the neural cell adhesion molecule (PSA-NCAM) in the mouse hippocampus. In the current study, we attempted to associate deficits in spatial learning following TMT exposure at various stages in learning with changes in levels of NCAM-180 and PSA-NCAM in both the hippocampus and frontal cortex. Mice were treated with TMT either before or after training on a spatial learning paradigm and examined for changes in NCAM and PSA-NCAM 12h later. In the first set of experiments, male BALB/c mice were injected with TMT (2.25 mg/kg) or saline i.p. and tested 24-168 h later using hidden and visible versions of the water maze, as well as light avoidance and motor activity. Mice in both treated and control groups which demonstrated a significant improvement in water maze performance also showed an elevation in hippocampal PSA-NCAM at all time points examined. TMT exposure impaired spatial learning and blocked learning-induced elevations in PSA-NCAM expression 24-96 h post-treatment, but these deficits disappeared by 168 h post-treatment. Mice exposed to TMT during reconsolidation of spatial learning (after repeated water maze training) demonstrated a mild and transient difference in escape latency compared to saline exposed mice. TMT administration during this period did not result in the attenuation of PSA-NCAM expression observed when animals were exposed before training. These results confirm a specific role for PSA-NCAM in acquisition and consolidation of spatial memory.

Animals↗

PubMed2006

Alterations in alcohol consumption, withdrawal seizures, and monoamine transmission in rats treated with phentermine and 5-hydroxy-L-tryptophan.

We have previously shown that coadministration of the dopamine (DA) agonist phentermine plus the serotonergic agonist fenfluramine suppresses alcohol intake and withdrawal seizures in rats. In the present study, phentermine and the serotonin (5-HT) precursor, 5-hydroxy-L-tryptophan (5-HTP), were administered alone, or in combination, to rats fed on a 6% alcohol-containing diet or an isocaloric control diet. Following a 9-h withdrawal period from the alcohol-containing diet, phentermine enhanced the effects of 5-HTP on both reduction of alcohol withdrawal seizures as well as changes in striatal serotonin. Food intake was monitored for 24 h after drug treatment, and neurochemical measures were examined at various time points. Phentermine alone reduced food intake in all diet conditions, but this anorectic effect was followed by hyperphagia in control rats. Phentermine plus 5-HTP reduced the consumption of the alcohol-containing diet, while its effects on consumption of control diets were mixed. In vivo microdialysis in rat nucleus accumbens revealed that phentermine increased extracellular DA, whereas 5-HTP caused marked elevations in extracellular 5-HT. Coadministration of phentermine and 5-HTP evoked simultaneous elevations in extracellular DA and 5-HT that mirrored the effects of each drug alone. Collectively, these findings show that coadministered phentermine plus 5-HTP is effective in reducing alcohol intake and suppressing alcohol withdrawal seizures. These therapeutic actions may be related to elevations in synaptic DA and 5-HT in critical brain regions.

5-Hydroxytryptophan↗

PubMed2005

Increased excretion of a lipid peroxidation biomarker in autism.

It is thought that autism could result from an interaction between genetic and environmental factors with oxidative stress as a potential mechanism linking the two. One genetic factor may be altered oxidative-reductive capacity. This study tested the hypothesis that children with autism have increased oxidative stress. We evaluated children with autism for the presence of two oxidative stress biomarkers. Urinary excretion of 8-hydroxy-2-deoxyguanosine (8-OHdG) and 8-isoprostane-F2alpha (8-iso-PGF2alpha) were determined in 33 children with autism and 29 healthy controls. 8-iso-PGF2alpha levels were significantly higher in children with autism. The isoprostane levels in autistic subjects were variable with a bimodal distribution. The majority of autistic subjects showed a moderate increase in isoprostane levels while a smaller group of autistic children showed dramatic increases in their isoprostane levels. There was a trend of an increase in 8-OHdG levels in children with autism but it did not reach statistical significance. There was no significant correlation between the levels of the biomarkers and vitamin intake, dietary supplements, medicine, medical disorders, or history of regression. These results suggest that the lipid peroxidation biomarker is increased in this cohort of autistic children, especially in the subgroup of autistic children.

8-Hydroxy-2'-Deoxyguanosine↗

PubMed2004

Neurochemical and behavioral deficits consequent to expression of a dominant negative EphA5 receptor.

The Eph family tyrosine kinase receptors and their ligands have been linked to axon guidance and topographic mapping of the developing central nervous system. More specifically, the EphA5 receptor has been shown to play a role in development of hippocamposeptal, retinotectal and thalamocortical projections. Recently, a line of transgenic mice was developed which expresses a truncated EphA5 receptor lacking a functional tyrosine kinase domain. In a previous study, axonal tracing revealed that medial hippocampal axons in this strain projected laterally and ventrally away from their normal target area. In the current study, both transgenic and wild-type controls were evaluated in unconditioned (rotorod and locomotor activity) and conditioned (water maze and active avoidance) behavior tasks which tested hippocampal and striatal functioning. Compared to controls, the transgenic strain did not show differences in rotorod motor activity but did show a transient deficit in spatial navigation ability and a consistent impairment in active avoidance. The dominant-negative mutant receptor also resulted in a decrease in striatal dopamine and serotonin concentrations with no change in hippocampal monoamines. Collectively, these data suggest that animals expressing a truncated EphA5 receptor show deficits related to striatal functioning.

Animals↗

PubMed2001

Altered sensitivity of CD81-deficient mice to neurobehavioral effects of cocaine.

CD81, also known as target of the antiproliferative antibody, is known to be expressed in astrocytes and involved in cell adhesion and, recently, we demonstrated its induction exclusively in the accumbens following cocaine. In the present study, the sensitivity of CD81-deficient mice to behavioral effects of cocaine was evaluated. It was found that CD81-deficient mice exhibited altered sensitivity to cocaine as assessed in the place preference conditioning paradigm and locomotor activity. This deficit in place preference conditioning was not accompanied by a deficit in acquisition or retention of water maze behavior. In addition, CD81 knockout mice exhibited higher levels of nucleus accumbens dopamine as compared to their controls. These observations are discussed in the context of the role of CD81 in cocaine-mediated behaviors.

Animals↗

PubMed2001

Cocaine-induced expression of the tetraspanin CD81 and its relation to hypothalamic function.

CD81, a tetraspanin transmembrane protein involved in cell adhesion, was found by differential display to be upregulated in the nucleus accumbens of rat brain following acute cocaine treatment (four injections of 30 mg/kg every 2 h followed by 24 h withdrawal). Cocaine-induced expression of CD81 in adult rat brain was confirmed by quantitative real-time RT-PCR. Its expression in neurons and its function in the brain are unknown. In situ hybridization shows a neuron-specific expression pattern in brain regions functionally related to the regulation of cardiovascular function and fluid homeostasis. CD81 displays codistribution to galanin and, to a lesser extent, to vasopressin. These findings add to data that suggest a connection between the brain reward pathway and the centers regulating endocrine and autonomic functions, in relation to neurochemical, behavioral, and somatic consequences of drug abuse.

Animals↗

PubMed2001

Role of monoamine oxidase inhibition and monoamine depletion in fenfluramine-induced neurotoxicity and serotonin release.

The role of both monoamine synthesis and monoamine oxidase inhibition in mediating the fenfluramine-induced damage to serotonin neurones was examined; as pretreatment agents, both alpha-methyl-para-tyrosine (AMPT) and parachlorophenylalanine (PCPA) were used to deplete dopamine and serotonin, respectively, while clorgyline and deprenyl were used to inhibit monoamine oxidase types A and B. While both AMPT and deprenyl did not alter fenfluramine induced serotonin or 5-hydroxyindoleacetic acid (5-HIAA) depletion in any area, PCPA did partially reduce the serotonin depletion in the hippocampus and hypothalamus. Although pretreatment with clorgyline did not significantly alter fenfluramine-induced serotonin depletion, it did produce a 65% mortality rate in animals treated with both drugs. Both PCPA and clorgyline significantly increased the depletion of striatal 5-HIAA concentration consequent to fenfluramine; however, these drugs also produced a long-term depletion of striatal 5-HIAA when administered alone, therefore, the changes seen after the coadministration with fenfluramine may be viewed as additive. Finally, acute PCPA pretreatment attenuated the rapid rise in 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (homovanillic acid) induced by fenfluramine, and acute clorgyline reversed the drop in serotonin and rise in 5-HIAA induced by fenfluramine. These results indicate that the rapid increase in dopamine activity induced by fenfluramine is partially dependent on serotonin concentration and release and that the mechanism of fenfluramine-induced toxicity is unlike that of the other substituted amphetamines.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2000

Regulation of EphB1 expression by dopamine signaling.

The Eph family tyrosine kinase receptors and their ligands have been implicated in axon guidance and neuronal migration during development of the nervous system. In the current study, we aim to characterize the nature of changes in EphB1 receptor expression following increases or decreases in dopamine activity. Neonatal mice (P3) were injected with 6-hydroxydopamine and allowed 13 days to recover. These animals show a profound depletion of dopamine in all areas assayed, with a corresponding dose-dependent decrease in EphB1 expression. Day 3 pups were also injected either chronically (P3-P16) or acutely (P3 only) with cocaine to determine how enhancing dopamine signaling would affect EphB1 signal density. It was found that both treatments significantly increased expression of EphB1 in the cortex, striatum and substantia nigra. Finally, animals were treated prenatally (E15-E17) with cocaine and sacrificed on P7. These animals also showed an increase in EphB1 signal density, but only in the dopaminergic terminal areas in the cortex and striatum. These studies indicate that dopamine activity regulates developmental expression of the tyrosine kinase receptor EphB1.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2000

Evaluation of the effects of alpha-phenyl-N-tert-butyl nitrone pretreatment on the neurobehavioral effects of methamphetamine.

A relationship between formation of reactive oxygen species (ROS) and energy depletion has been proposed to play an important role in mediating methamphetamine (METH)-induced neurotoxicity. To evaluate this relationship, we examined the effect of the spin-trap agent, alpha-phenyl-N-tert-butyl nitrone (PBN) on hyperthermia and self-injurious behavior (SIB) and striatal dopamine (DA) depletion produced by METH (4 injections of 4 mg/kg, 2 hr intervals, s.c.) in BALB/c mice. Repeated administration of METH induced hyperthermia, incidence of SIB and striatal DA depletion (84% after 3 days). Pretreatment with PBN (4 injections of 60 or 120 mg/kg, i.p.) reduced METH-induced hyperthermia, but did not significantly attenuate METH-induced SIB or the striatal DA depletion. On the other hand, pretreatment with high doses of PBN (4 injections of 180 or 240 mg/kg, i.p.) protected against METH-induced hyperthermia and SIB, and PBN (180 mg/kg) also completely protected against the acute striatal DA depletion 60 min after the last injection of the drug. However, the long-lasting striatal DA depletion was only attenuated by 52 or 56%, respectively. These results indicate that METH-induced hyperthermia contributes to, but is not solely responsible for METH-induced neurotoxicity, and supports a role for formation of ROS and other mechanisms in the generation of METH-induced striatal dopaminergic neurotoxicity. In addition, the difference in the efficacy of PBN to protect against the acute or long-lasting striatal DA depletion induced by METH may indicate that both ROS formation and other mechanisms are required for METH-induced neurotoxicity to develop.

Animals↗

PubMed2000

Acute effects of aspartame on aggression and neurochemistry of rats.

The inverse relationship between serotonin and aggression was investigated in rats treated with aspartame, a sweetener thought to interfere with the synthesis of this neurotransmitter. Eleven adult, male Long-Evans rats received either aspartame (200-800 mg/kg, IP) or the vehicle prior to testing in a standard resident-intruder paradigm. Contrary to our hypothesis, aspartame significantly decreased aggression as shown by increased latencies to the first attack and decreased number of bites per session. Corresponding with the effects on aggression, aspartame significantly increased striatal levels of serotonin. It was concluded that high doses of aspartame reduced aggressive attack via a serotonergic mechanism while the lower dose was without effect on either variable.

Aggression↗

PubMed2000

Effect of gestational and lactational 2,3,7, 8-tetrachlorodibenzo-p-dioxin exposure on the level and catalytic activities of hepatic microsomal CYP1A in prepubertal and adult rats.

We determined the inducibility, as well as the persistence of the induction, of hepatic microsomal CYP1A1 and CYP1A2 (by western blot analysis), and their catalytic activities (as measured by resorufin ether O-dealkylation) in prepubertal (25-day-old) and adult (120-day-old) offspring of timed-pregnant Sprague-Dawley rats treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). TCDD treatment was subcutaneous, at a low dose of 0.1 microg/kg, on gestational days 7, 14, and 20, and on lactational days 7 and 14. CYP1A1 protein was induced significantly (23-fold) in prepubertal but not in adult offspring of TCDD-exposed dams, whereas ethoxyresorufin O-deethylase (EROD) activity, which is CYP1A1-preferential, was induced less extensively (5-fold) and slightly (1.7-fold) in the prepubertal and adult offspring, respectively. Benzyloxyresorufin O-debenzylase (BROD) activity, which is CYP2B-preferential but has been reported to be catalyzed by CYP1A1, was also induced 5- and 6-fold in prepubertal and adult offspring, respectively, of TCDD-exposed dams. However, the induced BROD activity was neither inhibited by antibody against CYP1A1 nor accompanied by an elevated level of microsomal CYP2B. CYP1A2 was induced slightly only in prepubertal offspring of TCDD-treated dams. There was suggestive evidence of enhanced lipid peroxidation in hepatic microsomes from prepubertal but not adult offspring of TCDD-treated dams. These data showed that in utero plus lactational TCDD exposure effected transient induction of hepatic microsomal CYP1A1 but sustained induction of BROD activity, which may be catalyzed by enzymes other than CYP1A or CYP2B.

Animals↗

PubMed2000

Methamphetamine-induced striatal dopamine neurotoxicity and cyclooxygenase-2 protein expression in BALB/c mice.

The expression of cyclooxygenase-2 (COX-2) and striatal dopamine (DA) depletion in BALB/cAnNcrj (BALB/c) mice following a neurotoxic dose of methamphetamine (METH) was investigated. METH-treatment (4 mg/kg x 4, 2 h intervals, s.c.) induced a significant hyperthermia and a persistent depletion of striatal DA levels 72 h after the treatment. COX-2, a marker of the cytotoxic effect of inflammation and oxidative stress and thiobarbituric acid (TBA) were significantly induced in the striatum 72 h after the METH-treatment, but not in the hippocampus. These results suggest that COX-2 may participate in METH-induced neurotoxicity in striatum.

Animals↗

PubMed2000

Monoaminergic changes associated with audiogenic seizures in ethanol-dependent rats.

1. A previous report demonstrated the efficacy of combining dopaminergic and serotonergic agonists in suppressing audiogenic seizures induced in ethanol-dependent rats undergoing withdrawal. Moreover, an increase in dopamine and a reduction in serotonin levels in the striatum were associated with such seizures. 2. The present study was designed to examine neurochemical changes in the striatum associated with repeated episodes of ethanol withdrawal seizures in untreated ethanol-dependent rats as well as in those treated with amphetamine and fenfluramine in combination. 3. Ethanol-dependent rats undergoing audiogenic seizures exhibited an increase in striatal dopamine and a reduction in striatal serotonin as compared to control and ethanol-dependent rats not undergoing seizures. Amphetamine and fenfluramine in combination effectively suppressed the audiogenic seizures by reversing the neurochemical changes in the striatum in ethanol-dependent rats. However, increased dopamine but decreased serotonin levels in the striatum were observed in rats undergoing one episode of ethanol withdrawal, but not in those experiencing multiple episodes of ethanol withdrawal. 4. Thus, alterations in striatal dopamine and serotonin levels were, at best, necessary but not sufficient to predispose audiogenic seizure susceptibility in ethanol-dependent rats.

Acoustic Stimulation↗

PubMed2000

Methamphetamine-induced striatal dopamine release, behavior changes and neurotoxicity in BALB/c mice.

The behaviors associated with the neurotoxic effects of methamphetamine were evaluated in BALB/c mice. Hyperthermia and behavioral observations were measured 60 min after each subcutaneous injection of methamphetamine (4x4 or 8 mg/kg) or saline, each given 2 h apart. The behavioral observations included stereotyped behaviors, incidence of hemorrhage in breast, salivation and self-injurious behavior (SIB). Repeated administration of methamphetamine produced these behavioral changes and hyperthermia, but resulted in hypothermia by the final injection (8 mg/kg). In addition, the methamphetamine treatment induced a long-lasting dopamine depletion of similar magnitude in the 4 and 8 mg/kg-treated animals. In a time course study striatal monoamine levels were measured 60 min after each injection of these doses. The first and second injections of methamphetamine (8 mg/kg) produced a drastic increase in striatal 3-methoxytyramine; this failed to occur after the third or fourth injection of the same dose. In contrast, 4 mg/kg of methamphetamine also produced an increase in 3-methoxytyramine after the second and third injections of the drug and, in this case, these were maintained for the duration of the treatment. Striatal 3, 4-dihydroxyphenylacetic acid levels also drastically decreased following both doses of methamphetamine, suggesting inhibition of monoamine oxidase in striatum. Moreover, a single injection of methamphetamine increased striatal 2,3-dihydroxybenzoic acid formation. These results suggest that the incidence of hyperthermia, SIB and striatal dopamine neurotoxicity are closely linked to striatal dopamine release and inhibition of monoamine oxidase produced by methamphetamine in BALB/c mice.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2000

Effects of phentermine and fenfluramine on alcohol consumption and alcohol withdrawal seizures in rats.

The drug combination of phentermine plus fenfluramine has been used clinically in both the treatment of obesity and alcoholism. The aim of the current study was to assess the interaction of the two drugs on consumption of both an alcohol-containing and a nonalcoholic diet. Furthermore, the efficacy of the drug combination on suppression of withdrawal seizures was determined. Animals were either maintained on a 6% alcohol-containing diet, free-fed an isocaloric control, or pair-fed the control diet. It was observed that, with regard to body weight growth curves, alcohol provides about 2.5 kcal/g. Both phentermine and fenfluramine caused a decrease in consumption 1 h after administration; however, during the next 23 h, 4 mg/kg phentermine significantly increased consumption of all diets. At doses of 1 and 2 mg/kg, fenfluramine selectively reduced consumption of the alcohol-containing diet as compared to the isocaloric diets. Lower doses of fenfluramine blocked the increases in consumption induced by phentermine. Furthermore, in animals fed the nonalcoholic diet, the drug combination of 2 mg/kg fenfluramine plus 8 mg/kg phentermine produced a 63-82% reduction in consumption, an effect not seen when either drug was administered alone. This greater than additive effect was also seen in the earlier time periods in animals pair-fed the control diet. Neurochemical analysis from these animals revealed that the alcohol-dependent animals displayed a significant reduction of DOPAC and 5-HIAA levels in the striatum, frontal cortex, and hypothalamus after a 9-h withdrawal period, further implicating the serotonergic and dopaminergic systems in mediation of withdrawal symptoms and alcohol craving. Finally, 8 mg/kg phentermine plus 8 mg/kg fenfluramine completely abolished alcohol withdrawal seizures, compared to a 78% rate in saline treated rats. In conclusion, the coadministration of phentermine plus fenfluramine produced a moderate reduction of alcohol consumption and was completely effective at reducing alcohol withdrawal seizures.

Alcohol Drinking↗

PubMed2000

Avoidance responding following amphetamine-induced dopamine depletion.

The effect of an amphetamine-induced depletion of striatal dopamine on active and passive avoidance responding of rats was examined. Sixteen animals received two sets of 4 injections each of 15 mg/kg d-amphetamine, administered at 2 hr intervals with each set delivered one week apart. One week after the last injection, animals were given 50 consecutive active avoidance trials in a shuttle box. Animals treated with amphetamine exhibited a 50%, depletion of striatal dopamine and showed a slower learning curve, as evidenced by significantly fewer avoidances and a slower escape latency during trials 21-30. Both groups demonstrated a 90% avoidance rate by trials 41-50. A separate group of rats was treated as above and trained for several weeks on the active avoidance procedure. Haloperidol (0.01-0.10 mg/kg intraperitoneally) dose-dependently decreased avoidance number and increased avoidance and escape latency in both groups, an effect that was exaggerated in those animals previously treated with amphetamine. Finally, these animals were tested in the same apparatus using a passive avoidance procedure. The amphetamine treatment produced a significantly higher mean number of avoidances in this procedure compared to saline-treated animals during trials 1-20. These results suggest that the impairment in conditioned avoidance following amphetamine treatment is due to a motoric, rather than a cognitive deficit.

Amphetamine↗

PubMed1999

Specification of distinct dopaminergic neural pathways: roles of the Eph family receptor EphB1 and ligand ephrin-B2.

Dopaminergic neurons in the substantia nigra and ventral tegmental area project to the caudate putamen and nucleus accumbens/olfactory tubercle, respectively, constituting mesostriatal and mesolimbic pathways. The molecular signals that confer target specificity of different dopaminergic neurons are not known. We now report that EphB1 and ephrin-B2, a receptor and ligand of the Eph family, are candidate guidance molecules for the development of these distinct pathways. EphB1 and ephrin-B2 are expressed in complementary patterns in the midbrain dopaminergic neurons and their targets, and the ligand specifically inhibits the growth of neurites and induces the cell loss of substantia nigra, but not ventral tegmental, dopaminergic neurons. These studies suggest that the ligand-receptor pair may contribute to the establishment of distinct neural pathways by selectively inhibiting the neurite outgrowth and cell survival of mistargeted neurons. In addition, we show that ephrin-B2 expression is upregulated by cocaine and amphetamine in adult mice, suggesting that ephrin-B2/EphB1 interaction may play a role in drug-induced plasticity in adults as well.

Animals↗

PubMed1999

Neurotoxic effects of amphetamine plus L-DOPA.

1. Male Swiss Webster mice were administered a series of amphetamine injections preceded by either saline or L-DOPA. 2. This injection regimen was performed for either one, two or three consecutive weeks and neurotoxic effects of the drugs were determined one week later. 3. Amphetamine treatment for two weeks produced a greater striata-dopaminergic lesion that treatment for only one week. Three weeks of treatment did not exacerbate the lesion, indicating that the damage had reached maximal levels. 4. L-DOPA pretreatment did not significantly alter any of the toxic effects of the amphetamine. Therefore, some dopaminergic neurons may be resistant to the toxic effects of amphetamine.

3,4-Dihydroxyphenylacetic Acid↗