Mesolimbic dopamine turnover effects of benzodiazepines do not correlate with sedative and muscle-relaxant potencies.

Benzodiazepines are known to decrease the dopamine turnover in the mesolimbic dopaminergic system in stimulated rather than in basal conditions. Stimulation of dopamine turnover can be achieved by administration of the dopamine antagonist haloperidol. In the present paper, we tested the hypothesis that the effect of the benzodiazepines on the mesolimbic dopamine turnover is mediated by the benzodiazepine receptor, comparing the minimal potency of inhibition of the stimulated dopamine turnover with the ED50 values for the sedative and muscle-relaxant actions of the compounds. Five compounds were studied: desmethyldiazepam, lorazepam, flunitrazepam, triazolam and brotizolam. In contrast to the other compounds, lorazepam appeared to have no effect on the haloperidol-induced increase in DOPAC concentration. The relative potency of the benzodiazepines for this effect on the haloperidol-induced DOPAC increase is very different from that on sedation and muscle relaxation, suggesting that the effect on the mesolimbic dopamine turnover is not mediated by the classical benzodiazepine receptor. Since the background of this study was the relation between the dopaminergic effects and the development of psychotic symptoms during benzodiazepine withdrawal, this different pattern of the benzodiazepines is suggested to be an indication that benzodiazepines may differ qualitatively in the development of withdrawal symptoms after long-term treatment.

Validation of spontaneous morphine withdrawal symptoms in rats.

Spontaneous morphine withdrawal has been studied in rats after induction of dependence using administration of morphine via the food (+/- 160 mg/kg/day on the basis of body weight). In the present paper, the decrease of the nocturnal locomotor activity and of food intake were validated as real morphine withdrawal symptoms. During the withdrawal phase, morphine was readministered either by subcutaneous injection of morphine or admixed in the food. Subcutaneous administration resulted in short-lasting enhancements (of 50%) of the locomotor activity (peak effects) followed by a decrease of 50%, while food intake and loss of body weight were hardly affected. Administration via the food resulted in a dose-dependent reduction of the decrease of the nocturnal locomotor activity, the decrease in food intake and the loss of body weight. Chronic naloxone infusion (0.03 or 0.1 mg/kg/hr) via osmotic minipumps appeared to have similar effects on locomotor activity, food intake and body weight, compared with spontaneous withdrawal of morphine. However, the recovery to normal values appeared to occur faster after naloxone infusion. It is concluded that the observed withdrawal symptoms, i.e. decrease of the locomotor activity, decrease of food intake and loss of body weight, can be interpreted as real withdrawal symptoms not caused by additional manipulations occurring in the course of the experiments.