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.

Differential effects of monoaminergic agonists on alcohol intake in rats fed a tryptophan-enhanced diet.

The goal of the present study was to determine if enhancement of tryptophan levels in a nutritionally balanced liquid diet would affect alcohol intake in a two-bottle choice procedure. Furthermore. the monoaminergic agonists amphetamine, phentermine (dopaminergic- and noradrenergic-releasing drugs), and fenfluramine (a serotonin releaser) were administered to determine if these drugs reduced alcohol intake in animals fed the tryptophan-enhanced diet compared to those fed an alcohol-containing diet without added tryptophan. Amphetamine 0.5 and 2 mg/kg and phentermine 4 mg/kg selectively reduced alcohol intake in animals fed the tryptophan-enhanced diet; higher doses also reduced alcohol intake in animals fed the control alcohol diet. Three hours after drug administration, phentermine 2 and 4 mg/kg produced increases in consumption of the nonalcoholic diet in animals fed the control diet without affecting consumption in animals fed the tryptophan-enhanced diet. Finally, animals in the tryptophan-enhanced group gained less weight than those animals fed an identical diet without the added tryptophan. Neurochemical analysis revealed that the tryptophan-fed groups showed increased 5-HIAA concentrations and serotonin turnover in the striatum. hypothalamus, and frontal cortex compared to animals fed the control diet. The tryptophan-alcohol group also showed almost double the tryptophan levels in the hypothalamus compared to the tryptophan-isocaloric group. These results indicate that, whereas increasing tryptophan levels by itself was not sufficient to alter consumption of an alcohol-containing diet, the administration of monoaminergic agonists significantly interacted with tryptophan in a dose-dependent manner to reduce intake of an alcohol-containing diet without reducing intake of an isocaloric diet.

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.

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.