Role of various neurotransmitter systems in the phenomenon of amphetamine-induced reverse tolerance.

The potential role of various neurotransmitter systems was investigated in the phenomenon of amphetamine-induced reverse tolerance. CF-1 mice were treated daily with amphetamine to produce reverse tolerance to the stereotypic effects of the drug. After amphetamine withdrawal, the enhanced responsiveness characteristic of reverse tolerance persisted for at least 28 days. Associated with reverse tolerance were changes in the glutamate, GABA and serotonin systems, as measured by a decrease in convulsive threshold to N-methyl-DL-aspartate (NMDLA), an increase in convulsive threshold to bicuculline, and an increase responsiveness to 5-hydroxytryptophan in the head-twitch test. In contrast, no changes were observed in the thresholds to arecoline-, strychnine- or aminophylline-induced convulsions. The changes in the NMDLA and Bicuculline convulsive thresholds, like reverse tolerance itself, were persistent after amphetamine withdrawal; in contrast, the functional responsiveness of the serotonin system returned to normal within 15 days. Daily pretreatment with the dopaminergic blocker haloperidol or with the N-methyl-D-aspartate antagonists MK-801 or ketamine blocked the development of the reverse tolerance. Pretreatment with haloperidol, MK-801 or ketamine also prevented the changes in convulsive threshold to NMDLA and bicuculline. Pretreatment with the GABAergic drug diazepam or the serotonin antagonist cyproheptadine had no effect on the development of reverse tolerance or changes in the NMDLA or Bicuculline convulsive thresholds. The results from these studies illustrate that the development of reverse tolerance to amphetamine involves not only the dopaminergic but also the glutamatergic system.