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Biomedical subjects

G C Wagner

Publications and source records attributed to G C Wagner.

At least 19 recordsLinked to original sources
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

Acute and chronic effects of ginseng total saponin and amphetamine on fixed-interval performance in rats.

The effect of ginseng total saponin (GTS) on amphetamine (AMPH)-induced disruption of fixed-interval (FI) responding in rats was examined. GTS (50 mg/kg) significantly improved the temporal responding impaired by 2 mg/kg of AMPH. A higher dose of 100 mg/kg GTS disrupted performance when given alone; this disruption was reversed by a low dose of AMPH (0.5 mg/kg) and tolerance developed to the effects of GTS with its repeated administration. Neurochemical analysis revealed that GTS (50 mg/kg) attenuated the increase in striatal dopamine caused by AMPH leading to the conclusion that brain dopamine may partially mediate the behavioral effects of GTS.

Amphetamines↗
PubMed1998

L-DOPA exacerbates amphetamine-induced dopamine depletion.

Administration of L-DOPA to Parkinson patients has been suggested to exacerbate "functional denervation" of the nigrostriatal system. Therefore, experiments were conducted to determine if L-DOPA combined with the DOPA decarboxylase inhibitor, Ro4-4602 (benserazide hydrochloride) would potentiate amphetamine-induced neurotoxicity. Mice received two injections of saline or benserazide + L-DOPA (25.0 or 100.0 mg/kg) interspersed with four injections of amphetamine (15.0 mg/kg) at 2-h intervals. Significant depletion of striatal dopamine, DOPAC, and HVA was evident 1 wk following amphetamine administered with or without 25.0 mg/kg L-DOPA + benserazide, whereas 100.0 mg/kg L-DOPA + benserazide potentiated amphetamine-induced depletion of striatal dopamine (17 vs 28% of control values). This enhanced toxicity may be consequent to increased dopamine turnover following L-DOPA (360 vs 231%), a situation akin to that observed in compromised dopaminergic nigrostriatal systems of parkinsonian patients. Furthermore, striatal 5-HT was not altered by amphetamine alone, whereas concurrent administration of L-DOPA/ benserazide depleted 5-HT to 82% of control values. No changes were evident in the frontal cortex following amphetamine with or without concurrent L-DOPA/benserazide; however, L-DOPA/benserazide administered alone reduced 5-HT and 5-HT turnover to 58% of control values.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1998

Methamphetamine-induced neurotoxicity in BALB/c, DBA/2N and C57BL/6N mice.

Repeated administration of methamphetamine (METH; 2 and 4 mg/kg, s.c. four times every 2 h) caused hyperthermia and a dose-dependent depletion of striatal dopamine levels 3 days after the METH-treatment in both BALB/cAnNCrj (BALB) and DBA/2NCrj (DBA) mice, but these responses were lower in C57BL/6NCrj (C57BL) mice. An acute decrease of striatal dopamine levels 30 min after the last injection of METH (4 mg/kg) was observed in both BALB and DBA mice, while an increase in dopamine was observed in C57BL mice. Striatal 3-methoxytyramine levels were drastically increased in both DBA and C57BL mice after this same treatment. Moreover, pretreatment with the superoxide dismutase inhibitor, diethyldithiocarbamate (200 mg/kg, i.p.) exacerbated the METH (4 mg/kg)-induced striatal dopamine-depletion in BALB mice. In addition, pretreatment with an inhibitor of poly(ADP-ribose) polymerase, benzamide (160 mg/kg, s.c.), significantly attenuated the METH (4 mg/kg)-induced striatal dopamine depletion in both BALB and DBA mice. These results suggest that both BALB and DBA mice possess a higher sensitivity to the METH-induced striatal dopaminergic neurotoxicity compared to C57BL mice. In addition, the striatal dopaminergic neurons of BALB mice may be more vulnerable to METH-induced oxidative stress as compared to that in C57BL mice.

Animals↗
PubMed1998

Methamphetamine-induced changes in activity and water intake during light and dark cycles in rats.

1. The authors investigated the ambulatory activity and water intake of rats during each 12 hr light and dark cycle for one week following four s.c. injections of 4 or 8 mg/kg of methamphetamine (METH). 2. Administration of the higher METH dose caused an increase in activity during the dark cycle on days 1 through 6 with the maximal increase on day 3 while the increase in activity during the light cycle was observed only on day 1. 3. Water intake increased the first day after administration of both METH doses, but returned to baseline by day 3. 4. Administration of both METH doses induced hyperthermia and the 8 mg/kg dose produced depletions of striatal dopamine and striatal, hippocampal and hypothalamic serotonin on day 3 but only in hippocampal serotonin by day 7. 5. These results demonstrate that high doses of METH produce a long-lasting increase in activity during the dark cycle and a transient increase in water intake. The behavioral changes which occurred during the dark cycle appear to be related to the depletion of central dopamine and/or serotonin.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1998

Methamphetamine-induced modification of dopamine metabolism in cultured striatal astrocytes.

The role of striatal astrocytes in the metabolic processing (by deamination) of methamphetamine-released dopamine is not known. To investigate the relationship between methamphetamine and dopamine metabolism, we measured 6-hydroxydopamine, dopamine and, 3,4-dihydroxyphenylacetic acid (DOPAC) concentrations following methamphetamine treatment of cultured striatal astrocytes prepared from 1-2 day-old rats. Addition of low concentrations of dopamine (5 x 10(-5) to 5 x 10(-4) M) to cultured astrocytes increased DOPAC levels in a dose-dependent fashion while higher concentrations (5 x 10(-3) to 10(-2) M) inhibited its metabolism and induced formation of 6-hydroxydopamine. Under the same experimental conditions, 10(-4) M dopamine in combination with methamphetamine (10(-5) to 10(-3) M) inhibited DOPAC formation and increased dopamine levels in a dose-dependent fashion, but the formation of intracellular 6-hydroxydopamine was not evident. Deprenyl (10(-5) or 10(-4) M), an inhibitor of monoamine oxidase B, and pargyline (10(-5) or 10(-4) M), a non-selective monoamine oxidase inhibitor, completely inhibited DOPAC formation and increased dopamine levels, while clorgyline (10(-5) or 10(-4) M), an inhibitor of monoamine oxidase-A, only partially inhibited DOPAC formation (42 or 45% of control, respectively). These results support the hypothesis that methamphetamine inhibits monoamine oxidase and causes increases in dopamine levels in cultured striatal astrocytes.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1998

Interaction of phentermine plus fenfluramine: neurochemical and neurotoxic effects.

Previous studies have reported the use of combined serotonergic and dopaminergic agonists in the treatment of obesity and alcoholism. Along these lines, phentermine plus fenfluramine has been suggested as a possible clinical treatment for alcohol craving. To determine the neurochemical effects of a combined treatment of phentermine plus fenfluramine, animals were injected subcutaneously with saline, phentermine 12 mg/kg, fenfluramine 16 mg/kg, or a combination of phentermine plus fenfluramine. One hour after injection, animals were sacrificed and neurochemical analysis performed. Furthermore, separate groups of animals were given the same injections 8 times, 12 hours apart, to determine the effects on body weight and to detect a possible exacerbation of fenfluramine induced toxicity. The drug combination produced a significant rise in dopamine in the striatum, greater than that seen with either drug alone. Furthermore, the addition of phentermine reduced the fenfluramine induced rise in striatal 3,4-dihydroxyphenylacetic acid, homovanillic acid and 5-hydroxyindolacetic acid (5-HIAA). Phentermine plus fenfluramine combination produced a greater weight loss than either drug alone, however, it did not produce a significantly greater drop in striatal serotonin or 5-HIAA levels above that induced by fenfluramine alone. Thus, while previous studies report the potentiated neurotoxicity of phentermine plus fenfluramine over fenfluramine alone, the present study does not indicate that such an effect occurs following an administration regimen analogous to that of patients treated with the drug combination.

Adrenergic Agents↗
PubMed1995

Effects of pargyline and pyrogallol on the methamphetamine-induced dopamine depletion.

The formation of 6-hydroxydopamine (6-OHDA) from dopamine (DA) was investigated in the striatum of male Sprague-Dawley rats following a single administration of methamphetamine hydrochloride (100 mg/kg, sc). Rats were sacrificed 30, 60, and 90 min, and 1 wk after injection, and striatal 6-OHDA, DA, and 3,4-dihydroxyphenylacetic acid (DOPAC) were measured by HPLC with electrochemical detection. Methamphetamine decreased striatal DA and DOPAC levels (to 65 and 50% at 90 min, respectively) in the time-course study and also resulted in a long-lasting dopamine depletion (34%) 1 wk after its administration. However, endogenous 6-OHDA formation proved difficult to detect after administration of the methamphetamine alone. Pretreatment with the monoamine oxidase (MAO) inhibitor pargyline (100 mg/kg, ip) and the catechol-O-methyltransferase (COMT) inhibitor pyrogallol (25 mg/kg, ip) resulted in the HPLC detection of a 6-OHDA-like substance 30 min after methamphetamine administration when the oxidizing potential was set at 0.5 V, but not when it was set at 0.2 V. Moreover, pargyline (25 mg/kg, ip) alone or in combination with pyrogallol exacerbated the long-lasting dopamine depletion induced by methamphetamine (50 mg/kg, sc). These results indicate that simultaneous inhibition of MAO and COMT provides a cellular environment that encourages the autoxidation of dopamine to a 6-OHDA-like substance.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1995

Uridine reduces rotation induced by L-dopa and methamphetamine in 6-OHDA-treated rats.

The pyrimidine nucleoside uridine may reduce side effects associated with antipsychotic medication by interacting with dopamine or GABA neurotransmission. Male Sprague-Dawley rats were used to investigate coadministration of uridine with agents that alter food intake (amphetamine, haloperidol, and chlordiazepoxide) and locomotor activity (methamphetamine and L-dopa). Results indicated that chronic uridine [32.0 mg/kg, intraperitoneally (IP)] alone did not alter milk intake or reduction of milk intake induced by amphetamine (dose range 0.5-2.0 mg/kg, IP) or haloperidol (0.125-1.0 mg/kg, IP), nor did it alter the biphasic response induced by chlordiazepoxide (5.0-40.0 mg/kg, IP). However, uridine-treated animals with unilateral striatal lesions exhibited no rotational behavior in the absence of drug challenge, but showed decreased rotation induced by the dopamine agonist, L-dopa (50.0-200.0 mg/kg, IP) compared with controls. In addition, uridine-treated rats exhibited reduced rotation after repeated injections of methamphetamine (4.0 mg/kg, IP) in contrast to increasingly greater rotation observed in control animals. These results are further evidence that chronic uridine may alter drug-induced dopaminergic activity without exerting effects itself.

Animals↗
PubMed1995

Novel synergistic treatment of ethanol withdrawal seizures in rats with dopamine and serotonin agonists.

A recent observation in this laboratory of a simultaneous increase in striatal dopamine and a decrease in serotonin in ethanol-dependent rats during ethanol withdrawal prompted studies with combined dopaminergic + serotoninergic agonists to stop withdrawal seizures. Amphetamine (2 mg/kg) + fenfluramine (8 mg/kg) given jointly, but not separately, prevented ethanol withdrawal seizures as effectively as benzodiazepines (chlordiazepoxide), the current drugs of choice. The combination of amphetamine and fenfluramine, unlike chlordiazepoxide, significantly reduced intake of ethanol during and immediately following ethanol withdrawal.

Alcohol Withdrawal Delirium↗
PubMed1994

Uridine potentiates haloperidol's disruption of conditioned avoidance responding.

The pyrimidine nucleoside, uridine, has been proposed as a potential supplement in the treatment of psychosis based on its ability to reduce haloperidol-induced dopamine release. These experiments investigated the effect of uridine (32 mg/kg, i.p.) coadministered with the neuroleptic haloperidol, on rats engaged in one way conditioned avoidance responding. Uridine itself had no effect on animals' performance, while haloperidol (dose range 0.05-0.4 mg/kg, i.p., 90 min before test session) decreased number of avoidances and increased avoidance and escape latencies in a dose-dependent manner. When coadministered with haloperidol, uridine significantly potentiated the disruption of avoidance and avoidance latency induced by haloperidol. This potentiation was still evident after chronic (27 days) uridine treatment. Importantly, coadministration of uridine did not potentiate haloperidol-induced increase of escape latency. The potentiation of haloperidol-induced disruption of conditioned avoidance responding suggests that uridine coadministration might enhance the antipsychotic action of traditional neuroleptics. This would allow for a reduction in the therapeutic dose of the antipsychotic, thereby reducing side effect frequency.

Animals↗
PubMed1994

Influence of gonadal hormones on sexual differences in sensitivity to methamphetamine-induced neurotoxicity.

The administration of high doses of methamphetamine to mice causes long-lasting depletions of striatal dopamine to a greater extent in males than in females. Likewise, the incidence of Parkinson's disease is higher in males than in females. The present study investigated the roles of estrogen and testosterone in mediating the dopamine depletion induced by methamphetamine. Male and female mice received four cumulative SC doses of methamphetamine (10 mg/kg) at two hour intervals and were sacrificed two weeks later for HPLC analysis of striatal monoamines. Intact male mice were found to have a 76% dopamine depletion, which was significantly greater than the 37% depletion exhibited by the intact female mice. Neither removal of the ovaries nor removal of the testes one month prior to the methamphetamine treatment significantly changed the magnitude of the methamphetamine-induced dopamine depletion. Thus, the reduced sensitivity of female mice to methamphetamine may be independent of physiological gonadal hormones.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1994

Ethanol consumption following acute treatment with methysergide, fluoxetine, fenfluramine, and their combination.

Methysergide (MS), a postsynaptic serotonin antagonist, was administered acutely in three experiments in relation to water or 5% ethanol solution intake of 24-hr, water-deprived male Sprague-Dawley rats. In the first experiment, MS significantly increased the consumption of ethanol at doses of 0.25, 2.0, and 4.0 mg/kg. Water intake was significantly increased by MS at the 2.0 mg/kg dose. In the second experiment, which was different from the first one in that MS was administered during the dark cycle, ethanol solution intake was again significantly increased at all three levels. In the third experiment, fenfluramine (FFL) and fluoxetine (FLU) were administered acutely (at 8 mg/kg) after MS (0.25 mg/kg) followed by measuring water or ethanol solution intake. FFL and FLU significantly decreased intake of both water and ethanol solution, a process that was significantly reversed by MS; to a greater degree for FLU (74%) than for FFL (57%). The successful use of MS in increasing ethanol intake in these studies may be due to the low doses used in comparison with earlier unsuccessful attempts. The procedure of treating 24-hr, water-deprived rats with acute doses of pre- and postsynaptic serotonin agonists and antagonists appears to be a useful model for further elucidation of their interaction in ethanol consummatory behavior.

Alcohol Drinking↗
PubMed1993

Sexual differences in sensitivity to methamphetamine toxicity.

Male and female mice were treated with methamphetamine (10.0 mg/kg/injection for four injections) and sacrificed two weeks later. It was observed that the methamphetamine treatment caused depletions in striatal dopamine which were significantly greater in males (74%) than in females (56%). These results indicate that estrogen may have a protective effect against methamphetamine-induced dopamine depletions and may relate to the fact that males are more likely to incur Parkinson's disease than females.

Animals↗
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↗