An inhibitory role for brain serotonin-containing systems in the locomotor effects of d-amphetamine

Abstract

Locomotor activity induced by d-amphetamine was found to be potentiated by food deprivation, a tryptophan-free diet, p-chlorophenylalanine and drugs proposed to antagonize serotonin receptors in brain. Administration of L-tryptophan 1 hour prior to d-amphetamine injection was found to antagonize the enhanced response to d-amphetamine in starved rats and in rats which had tryptophan removed from their diet. However, tryptophan did not block the potentiated response to d-amphetamine in animals pretreated with p-chlorophenylalanine. These findings suggested that the antagonism of d-amphetamine-induced activity by tryptophan in starved rats and rats fed a tryptophan-free diet was not due to a nonspecific depressant effect of the amino acid. Since accumulation of d-amphetamine and its metabolites was not affected by any of the treatments which enhanced its activity, it seems unlikely that an alteration in the metabolism of d-amphetamine can explain these findings. The present work provides additional support for the view that serotonergic fibers play an important role in the actions of d-amphetamine.

FIG. 1

Effects of 48-hour food deprivation, l-tryptophan and 5-HTP on d-amphetamine-induced motor activity. Activity response to 2 mg/kg of d-amphetamine sulfate in normal diet (solid bar) and 48-hour food deprived (striped bars) animals. Some animals deprived of food received 25 or 100 mg/kg of l-tryptophan (TRY) or 25 or 75 mg/kg of 5-HTP i.p. 1 hour before administration of d-amphetamine. When given 1 ml/kg of saline instead of d-amphetamine, normal diet animals recorded 638 ± 77 counts; and 48-hour food-deprived animals, 577 ± 90 counts. Values represent the average activity counts accumulated over a 3-hour period by 6 to 21 animals. Vertical bars represent the S.E.M. *P < .05. **P < .001 when compared with normal diet. †P < .02. ††P < .01 when compared with control.

FIG. 2

Effect of tryptophan-free diet on d-amphetamine-induced motor activity: time-course effect of the tryptophan-free diet on the locomotor response to 2.0 mg/kg of d-amphetamine sulfate. Zero day of treatment represents the control response to d-amphetamine. Values represent the mean ± S.E.M. of at least eight animals. Solid portion of bars represents the activity accumulated for 3 hours after injection of saline. *P < .05. **P < .01 when compared with control response to d-amphetamine.

FIG. 3

Reversal of tryptophan-free diet potentiation of d-amphetamine by l-tryptophan administration. Animals fed the tryptophan-free diet for 0, 1, 2 or 14 days received 100, 25, 25 and 100 mg/kg of l-tryptophan, respectively, 1 hour before administration of d-amphetamine. The data for “No l-tryptophan” are reproduced from figure 2 for comparison. Values represent the mean ± S.E.M. of at least eight animals. #P < .05. †P < .01 when compared with the no tryptophan treatment.

FIG. 4

Effects of PCPA, 5-HTP and l-tryptophan (TRY) on the locomotor activity stimulated by 3.0 mg/kg of d-amphetamine. Some animals received 75 mg/kg of 5-HTP or 100 mg/kg of TRY i.p. 1 hour prior to d-amphetamine administration. PCPA-pretreated animals received 150 mg/kg by oral intubation 48 and 24 hours before d-amphetamine. Control and PCPA animals given saline instead of d-amphetamine averaged 694 ± 52 and 950 ± 197 counts/180 min, respectively. Values represent the mean ± S.E.M. of at least eight animals recorded over a 3-hour period. *P < .01. **P < .001 when compared with control. †P < .001 when compared with PCPA treatment group. #P < .02 when compared with tryptophan alone.

FIG. 5

The effect of serotonin receptor blocking agents on the locomotor activity induced by 2.0 mg/kg of d-amphetamine sulfate. Methysergide and cyproheptadine were administered i.p. 1 hour before the injection of d-amphetamine. Values represent the mean ± S.E.M. of at least eight animals. *P < .05. **P < .01 when compared with saline.