Biomedical subjects

G C Wagner

Publications and source records attributed to G C Wagner.

At least 55 records · Page 3Linked to original sources

PubMed1993

Partial 6-hydroxydopamine-induced lesions and haloperidol-induced catalepsy.

Rats with partial (36%) 6-hydroxydopamine-induced lesions of the striatal dopamine system or sham-lesioned controls were tested for duration of catalepsy after 1.0, 2.0 and 4.0 mg/kg haloperidol. Thereafter, half of each group was given haloperidol (2.0 mg/kg) chronically for 84 days. The cataleptic responses to the 3 doses were tested again on days 13-15 and 74-76 of the chronic injections. Animals that were lesioned and treated with haloperidol chronically had longer durations of catalepsy at the first two dose-response determinations. At the third dose-response determination, there were no differences among the 4 groups. Additionally, all groups displayed an increase in duration of catalepsy at the second and third dose-response determinations, relative to the first. The increase in haloperidol-induced duration of catalepsy in the lesioned group suggests that lower levels of dopamine in the striatum may potentiate extrapyramidal side-effects.

Aging↗

PubMed1993

Ethanol consumption following acute fenfluramine, fluoxetine, and dietary tryptophan.

Male Sprague-Dawley rats fed a commercial diet with or without tryptophan supplementation (0.5% L-TRP) were treated with single IP injections of fenfluramine or fluoxetine. Rats had been water deprived prior to injection and food was removed during the period of fluid availability. They were offered, following drug or saline injection, water, a 5% ethanol solution, or an isocaloric sucrose solution (8.75%) for 1 h. Fenfluramine injection significantly reduced intake of all fluids, but its effect on ethanol was significantly greater than for water or sucrose solutions. Fluoxetine suppressed water and ethanol intake but not that of sucrose; the reduction in ethanol intake was significantly greater than for water. Ingestion of the tryptophan-supplemented diet in the absence of any drug treatment had no effect on fluid intake. However, the tryptophan supplementation significantly enhanced the reduction in ethanol intake induced by fenfluramine and fluoxetine. It appears that both fenfluramine and fluoxetine decrease ethanol intake more so than that of water or sucrose and that this effect is exacerbated by tryptophan supplementation.

Alcohol Drinking↗

PubMed1993

Propranolol-induced increases in target-biting attack.

The effect of a beta-adrenoreceptor blocking agent on defensive aggression in mice was evaluated. Acute doses of d,l-propranolol (0.2, 0.4, 0.8, 1.6, 3.2, 6.4, and 12.8 mg/kg) were administered to male Rockland-Swiss mice prior to testing in a target-biting paradigm. Baseline conditions established a high target-biting rate low biting rate during a 15-s tone stimulus preceding the next shock. Every dose of propranolol increased target-biting rates above baseline during each interval with one exception: 0.4 mg/kg decreased the biting rate immediately after delivery of the tail shock. The overall increase in aggression observed following dosing with propranolol was not expected from a review of the clinical literature. These results are discussed in reference to propranolol's known effects on the brain serotoninergic systems and the use of an animal model of defensive aggression.

Aggression↗

PubMed1993

Effects of monoaminergic agonists on alcohol-induced increases in mouse aggression.

Two sets of studies were conducted on alcohol-induced increases in aggression. In the first, the effects of alcohol on target biting and resident-intruder attack were assessed in mice fed a standard diet or one supplemented with 0.5% L-tryptophan. Mice attacked an inanimate target at a high rate following tail shock, an intermediate rate during the intershock interval and a low rate during a tone that preceded the shock. Alcohol increased target biting following shock and during the intershock interval, an effect partially blocked by tryptophan. Resident mice attacked intruders 27.2 +/- 5.3 times per 10-minute session with an average latency of 155 +/- 42 seconds. Alcohol increased the number of attacks and lowered the latency to the first attack. Again, tryptophan partially blocked these effects. Finally, in a second set of mice, the same tryptophan diet was found to potentiate the aggression-reducing effects of fluoxetine and fenfluramine without disrupting motor performance. In the second study, the effects of alcohol administered alone or in combination with tyramine were assessed in the resident-intruder paradigm. Again, it was observed that low doses of alcohol increased the resident attack of intruders. Although this effect was heightened by the co-administration of tyramine, the effect failed to reach statistical significance. These observations are discussed in reference to alcohol-induced increases in offensive and defensive aggression and the possible modulation of this effect by brain monoamines.

Aggression↗

PubMed1993

Uridine and stimulant-induced motor activity.

Chronic administration of uridine alters dopaminergic activity and related behavior. The present study investigated this effect using amphetamine and cocaine-induced activity and rotation in rats with unilateral dopaminergic lesions. Adult, female Sprague-Dawley rats with free access to food and water received daily intraperitoneal uridine (16 mg/kg) or an equal volume of saline. Activity was assessed for 10 min in a photocell chamber 30 min after intraperitoneal amphetamine or cocaine and 4 hr after the uridine or saline. Additional rats with unilateral dopaminergic lesions were treated comparably and assessed for stimulant-induced rotation. Uridine exerted no effect on body weight, activity, or rotation under baseline conditions. At higher doses, amphetamine and cocaine decreased activity and caused a dose-dependent increase in rotations. In the activity test, uridine-treated rats exhibited a significant increase in sensitivity to amphetamine but not to cocaine. In the rotation test, uridine-treated rats showed increased sensitivity to both stimulants. Finally, neurochemical analysis of a third set of comparably treated rats revealed that uridine blunted the amphetamine-induced increase in striatal dopamine. These observations are interpreted as indicating that chronic uridine modulates the stimulant-induced release of dopamine and, therefore, may be of therapeutic interest.

Amphetamines↗

PubMed1992

The effects of deprenyl on methamphetamine-induced dopamine depletions.

The effects of deprenyl on methamphetamine-induced dopamine depletions were studied in mice. Four SC injections of 12.5 mg/kg of methamphetamine at two-hour intervals caused substantial (72-82%) and long-lasting depletions of striatal dopamine. Pretreatment with either 25 or 40 mg/kg of deprenyl did not significantly alter the magnitude of this depletion. These results indicate that, unlike what is observed following MPTP, there is no protection afforded dopaminergic cells by deprenyl pretreatment in the methamphetamine model of parkinsonism.

Animals↗

PubMed1992

Ethanol intake of chickens treated with fenfluramine, fluoxetine, and dietary tryptophan.

Male, white leghorn chickens fed a standard diet with or without tryptophan supplementation were treated with single injections of 8 mg/kg fenfluramine in one series of experiments, or 8 mg/kg fluoxetine in another series. The birds had been food- and water-deprived prior to injection. They were offered, following the drug or saline injection, water, a 5% ethanol solution, or an isocaloric sucrose solution (8.75%) for 1 hr. Both fluoxetine and fenfluramine significantly reduced consumption of the ethanol solution, an effect exacerbated by tryptophan supplementation. Water or sucrose solution intake was also significantly reduced, but significantly less so than ethanol after fenfluramine injection. Since the birds drank significantly more of the sucrose solution after saline injection than of water, the consumption decrease caused by fenfluramine resulted, nevertheless, in a higher intake than that of either water or ethanol. Body temperature was decreased by ethanol intake and/or fluoxetine injection. Fenfluramine injection had an opposite, body temperature-increasing effect. It appears that both fenfluramine and fluoxetine decrease ethanol intake in a manner more specific than for water or sucrose, and that this effect is amplified by dietary tryptophan supplementation.

Alcohol Drinking↗

PubMed1992

Neurochemical and motor effects of high dose haloperidol treatment: exacerbation by tryptophan supplementation.

The neurochemical and motor effects of a high dose (25 mg/kg) of haloperidol were assessed in male Sprague-Dawley rats. In Experiment 1, this high dose of haloperidol caused dramatic increases in striatal dopaminergic and serotonergic turnover that only returned to control levels 100 hr after injection. In the second experiment, the same dose of haloperidol was administered twice over a 3-week interval in the presence or absence of a dietary tryptophan supplement added to the drinking water. Rats were assessed for disruption of locomotor behavior (using the rotorod) as well as the occurrence of spontaneous (dyskinetic-like) chewing and head twitching. It was observed that haloperidol impaired rotorod performance in a manner that paralleled the time course of the neurochemical changes in Experiment 1. In addition, the tryptophan (consumed at an average of 157 mg/kg/day) exacerbated the deficit in rotorod performance in haloperidol-treated rats after the first, but not after the second, haloperidol injection. Finally, the combination of haloperidol plus tryptophan was found to cause a long-lasting increase in spontaneous chewing movements that lasted 56 days after the first injection. These observations are interpreted in the context of tryptophan supplementation to antipsychotic therapy.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1992

Motor impairments after methamphetamine-induced neurotoxicity in the rat.

Methamphetamine is a psychomotor stimulant which, given in high doses, produces neurodegenerative changes in the dopamine and serotonin systems. This study was designed to assess motoric deficits in the rat following a high-dose regimen of methamphetamine. Long-Evans male rats received either four injections of saline or methamphetamine (12.5 mg/kg, every 2 hr), a dose sufficient to produce 45 and 36% reductions in striatal dopamine and serotonin, respectively. Before treatment, subjects were trained to perform one of the following motor tasks: one-way active avoidance, inhibitory avoidance, rotorod or the balance beam. After recovery, performance under base-line and drug challenge conditions revealed that methamphetamine treatment caused significant deficits in active avoidance performance (24% increase in response latency) and balance beam performance (2- to 3-fold increase in footfalls), but had no effect on inhibitory avoidance or rotorod performance. Administration of l-dopa (100 mg/kg) significantly improved the methamphetamine-treated subjects' performance on the balance beam, but had no effect on the control subjects' performance. The methamphetamine-treated subjects exhibited a significant decrease in sensitivity to the effects of fenfluramine in comparison to the controls on both the rotorod and active avoidance tasks. We conclude that high-dose methamphetamine treatment produces long-lasting motor deficits associated with chronic reductions of striatal dopamine and serotonin. These data and the utility of the motor tasks are discussed in reference to a laboratory model of Parkinson's disease.

Animals↗

PubMed1991

Evaluation of the effects of inhibition of monoamine oxidase and senescence on methamphetamine-induced neuronal damage.

The administration of high doses of methamphetamine causes long lasting damage to central dopaminergic and serotonergic neurons through a mechanism known to involve presynaptic, cytoplasmic stores of those transmitters and thought to be dependent upon a free radical reaction. The following studies were designed to determine if differential inhibition of the subtypes of monoamine oxidase would alter the magnitude of the methamphetamine induced neuronal damage. In addition, since monoamine oxidase type B increases with age, the effects of high dose administration of methamphetamine were evaluated in senescent mice. It was observed that inhibition of monoamine oxidase type A, and to a lesser degree, type B, increased the magnitude of methamphetamine-induced neuronal damage and that aged mice were more sensitive to the toxic action of methamphetamine. These results are interpreted with respect to the use of monoamine oxidase inhibitors in the treatment of Parkinson's disease.

Aging↗

PubMed1991

Suppression of ethanol intake in chickens by fenfluramine and dietary tryptophan.

Two groups of 10-week-old White Leghorn cockerels were fed a commercial grower diet with or without an L-tryptophan (0.5%) supplement. After a 24-hr water deprivation and 13 to 14 hr without food, the birds were randomly injected with 0 (saline) 4, 8, or 12 mg of fenfluramine/kg body weight. Thirty minutes after injections, water or a 5% ethanol solution was offered, no choice, to the birds and fluid consumption as well as skin and rectal temperature before and after fluid availability were measured. The ethanol solution in otherwise untreated animals was consumed in similar amounts as water was. Fenfluramine (8 mg/kg) significantly reduced ethanol consumption and tryptophan further significantly reduced ethanol intake. At 12 mg/kg fenfluramine, both water and ethanol intake were sharply reduced. Ethanol decreased body temperature, an effect that was reversed by both tryptophan alone and fenfluramine + tryptophan in a dose-dependent manner. These observations are discussed in reference to the effects of central serotonergic manipulations and ethanol consumption.

Alcohol Drinking↗

PubMed1990

Protein components of a cytochrome P-450 linalool 8-methyl hydroxylase.

The cytochrome P-450 heme-thiolate monooxygenases that hydroxylate monoterpene hydrocarbon groups are effective models for the cytochrome P-450 family. We have purified and characterized the three proteins from a P-450-dependent linalool 8-methyl hydroxylase in Pseudomonas putida (incognita) strain PpG777. The proteins resemble the camphor 5-exohydroxylase components in chemical and physical properties; however, they show neither immunological cross-reactivity nor catalytic activity in heterogenous recombination. These two systems provide an excellent model to probe more deeply the heme-thiolate reaction center, molecular domains of substrate specificity, redox-pair interactions, and the regulation of the reaction cycle.

Acyclic Monoterpenes↗

PubMed1990

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity in the rat: characterization and age-dependent effects.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a potent dopaminergic toxin that has been found to produce Parkinson's disease-like symptoms in humans and monkeys. The neurotoxic effects of MPTP appear to be reduced in rodents where multiple dosing procedures are required to demonstrate long-lasting neuronal deficits. In the present study, the neurotoxic effects of MPTP were further characterized in the rat. Following the repeated administration of MPTP, pronounced (60-80%) and dose-dependent depletions of striatal dopamine and serotonin concentrations were found in the rat brain. Time-course studies revealed that while striatal dopamine concentrations remained consistently reduced for at least 8 weeks following MPTP treatment, striatal serotonin depletions as well as MPTP-induced monoamine depletions in other brain regions were transient in nature. Pretreatment with the MAO-B inhibitor pargyline afforded a selective and complete protection of striatal dopamine levels without significantly affecting MPTP-induced striatal serotonin depletions. Similarly, treatment with ascorbic acid was found to selectively attenuate MPTP-induced dopamine depletions in rats. The neurotoxic effects of MPTP were also found to increase in the developing rat. No significant brain monoamine depletions were observed in neonatal rats following the repeated administration of MPTP. However, MPTP-induced neurotoxicity progressively increased in older rats. The present results indicate that when appropriate treatment procedures are used, a pronounced, selective, age-dependent, and long-lasting MPTP-induced reduction in striatal dopamine concentrations can be observed in the rat brain. The present results are discussed in reference to the putative mechanisms and species differences of MPTP-induced neurotoxicity.

Aging↗

PubMed1990

Evaluation of the pharmacological similarities between phenylpropanolamine and amphetamine: effects on schedule-controlled behavior.

In an effort to determine the degree to which the repeated administration of phenylpropanolamine (PPA) results in the development of tolerance to its disruptive effects on operant responding as well as cross-tolerance to the effects of acutely administered amphetamine, water-deprived rats were first trained on a fixed-ratio 5 (FR-5) schedule for water presentation. Dose-response curves for the effects of PPA and amphetamine (administered IP, 15 min presession) were then determined (ED50 = 35.0 and 2.6 mg/kg, respectively) followed by the chronic administration of 40.0 mg/kg PPA (administered IP, 15 min prior to each session). When responding returned to prechronic rates, the dose-response curves were redetermined for both PPA (ED50 = 220 mg/kg) and amphetamine (ED50 = 4.8 mg/kg). In a second set of rats, trained under similar conditions, it was observed that pretreatment with alpha-methyltyrosine (AMT, 100 mg/kg IP, 2 h presession) antagonized the disruptive effects of both PPA and amphetamine, whereas pretreatment with reserpine (0.31 mg/kg, IP, 12 h presession) antagonized the disruptive effects of PPA, but exacerbated the disruptive effects of amphetamine. In a separate experiment, the repeated administration of PPA 100 mg/kg or 200 mg/kg IP resulted in no long-lasting depletions of rat striatal dopamine, serotonin, or 3,4-dihydroxyphenylacetic acid (DOPAC) concentrations. These observations indicate that PPA and amphetamine share a similar mechanism of action to the degree that cross-tolerance develops, but which is nonetheless dissociable with respect to their differential sensitivity to antagonists and their neurotoxic efficacy.

Amphetamine↗

PubMed1989

Age-dependent effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP): correlation with monoamine oxidase-B.

The effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration on whole brain dopamine content and monoamine oxidase subtype B (MAO-B) activity were assessed in Swiss-Webster male mice. Groups of mice at six different ages (1,2,4,8,16, and 52 weeks) were treated with either MPTP (12.5 mg/kg) every 2 hours for four subcutaneous injections or with the saline vehicle in the same injection volume. A third group of subjects was untreated and sacrificed at the same ages. The animals were sacrificed 1 week following treatment. The brains were removed and divided into right and left halves. The right brain halves from all subjects of a given age were assayed for MAO-B activity. The left brain halves were assayed for dopamine content using high performance liquid chromatography. The results revealed a significant age-dependent increase in both dopamine content and MAO-B activity in the untreated controls. It was also found that the toxic effect of MPTP as measured by whole brain dopamine depletion was increased at each successive age tested. There was a significant correlation (r = +0.96) between the baseline levels of MAO-B activity and the degree of lesion induced by MPTP treatment. These results indicate that the increased sensitivity to MPTP reported in aged animals may, in part, be attributable to the increase in MAO-B activity in older animals.

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

PubMed1989

Functional consequences following methamphetamine-induced neuronal damage.

The functional consequences following methamphetamine-induced neuronal damage were evaluated under several different conditions known to affect the magnitude of the lesion. It was found that methamphetamine (6.25 mg/kg administered SC, four times at 2-h intervals) caused long-lasting depletions of striatal dopamine and serotonin and that pretreatment with the antioxidant, ascorbic acid (100 mg/kg), attenuated these depletions, whereas pretreatment with the superoxide dismutase inhibitor diethyldithiocarbamate (200 mg/kg) exacerbated these depletions. The dopamine depletions resulting from the repeated administration of methamphetamine under these various conditions did not result in any alteration in the consumption of a sweetened-condensed milk solution under baseline conditions. However, when these lesioned animals were challenged with acutely administered methamphetamine, it was observed that there was an altered sensitivity to the milk intake decreasing effects of this compound. That is, the degree to which the acutely administered methamphetamine reduced the intake of sweetened-condensed milk was highly correlated with the magnitude of the methamphetamine-induced dopamine and serotonin depletions. These observations support the hypothesis that methamphetamine-induced neuronal damage is mediated by free radical formation and indicate that behavioral measures may be employed to assess neuronal damage.

Animals↗

PubMed1989

Astrocytes as a primary locus for the conversion MPTP into MPP+.

The enzymatic conversion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine to 1-methyl-4-phenylpyridinium ion by monoamine oxidase-B is an essential step mediating the dopaminergic neurotoxicity. Since monoamine oxidase-B is located primarily in serotonergic neurons and astrocytes, the production of 1-methyl-4-phenylpyridinium ion is thought to be extra-dopaminergic. This study provides evidence in support of this conclusion. Pretreating mice with fluoxetine (a serotonergic uptake inhibitor) before the administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine attenuated the dopaminergic neurotoxicity. This was not the result of a nonspecific inhibition of dopaminergic uptake, as fluoxetine pretreatment did not attenuate the dopaminergic neurotoxicity resulting from the intrastriatal administration of the 1-methyl-4-phenylpyridinium ion. Further localization of the primary site of 1-methyl-4-phenylpyridinium ion production as being astrocytes was provided by the failure of 5,7-dihydroxytryptamine-induced serotonergic lesions to attenuate the neurotoxicity produced by administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, whereas, fluoxetine pretreatment in similarly lesioned subjects, continued to attenuate 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced dopaminergic neurotoxicity. These results are consistent with the hypothesis that astrocytes are a principle site of 1-methyl-4-phenylpyridinium ion production.

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

PubMed1989

Methamphetamine-induced neuronal damage: a possible role for free radicals.

The hypothesis that methamphetamine-induced neuronal damage is mediated by the production of free radicals was evaluated by pretreating rats with either antioxidants or a superoxide dismutase (SOD) inhibitor. It was found that methamphetamine (dose range 6.25-25.0 mg/kg) caused long-lasting depletions of dopamine and serotonin in the striatum and that pretreatment with the antioxidants, ascorbic acid (10-100 mg/kg), ethanol (1 g/kg), mannitol (2 g/kg), or vitamin E (2 g/kg), attenuated these depletions, whereas pretreatment with the superoxide dismutase inhibitor diethyldithiocarbamate (200-400 mg/kg) exacerbated the depletions. The alteration of this effect by four different antioxidants, as well as an inhibitor of superoxidase dismutase, indicated that oxygen-free radicals may have a role in the methamphetamine-induced neurotoxicity.

Animals↗