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.

Benzodiazepines preferentially affect mesolimbic dopamine turnover in rats.

Withdrawal of benzodiazepines in man may induce hallucinatory symptoms and can evoke delusional depressions, which can be treated with dopamine-antagonistic drugs. Withdrawal of benzodiazepines in rats induces a strong hyperactivity during daytime, leaving the nighttime activity relatively undisturbed. This hyperactivity may be related to an enhanced dopaminergic activity in the mesolimbic area, especially in the nucleus accumbens. Mesolimbic dopaminergic activity may be specifically involved in the development of benzodiazepine withdrawal. Acute administration of benzodiazepines in otherwise non-treated rats, has been described not to affect the dopamine-turnover in the nucleus accumbens, measured by synthesis inhibition. However, activation by administration of haloperidol (feedback activation) can be suppressed by benzodiazepines effectively. Five different benzodiazepines viz. desmethyldiazepam (DMD), lorazepam (LRZ), brotizolam (BTZ), triazolam (TRZ) and flunitrazepam (FNZ) have been compared with respect to their acute effects. Using a 3-fold increase in dopamine turnover (determined by measuring the DOPAC-concentration), benzodiazepines were capable to reduce this increase maximally for 70-80% in the nucleus accumbens. The results point to a selective effect of benzodiazepines in the nucleus accumbens. The increase induced by haloperidol in the corpus striatum was found to be much less sensitive to benzodiazepines. In contrast to the other compounds lorazepam appeared to have no effect on haloperidol-induced increase in DOPAC concentration. Flunitrazepam and brotizolam did affect not only the haloperidol-induced DOPAC increase but also the basal DOPAC concentrations. Linear dose-response curves could not be obtained for the compounds, but minimal effective doses could be assessed. Flunitrazepam and triazolam appeared to be the most active compounds.(ABSTRACT TRUNCATED AT 250 WORDS)

Du 24565, a quipazine derivative, a potent selective serotonin uptake inhibitor.

Du 24565, 6-nitro,2-(1-piperazinyl)quinoline, is a potent and selective inhibitor of the synaptosomal uptake of serotonin (5-HT). At concentrations at least 10(3)-fold higher it affects the uptake of norepinephrine (NA) and dopamine (DA), The IC50 values are: 5-HT: 4 x 10(-8) M; NA: 6 x 10(-5) M and DA: 4 x 10(-5) M. Uptake of 5-HT by rat blood platelets is also strongly inhibited (Ki approximately 5 x 10(-8) M); the inhibition is probably noncompetitive. In vivo, DU 24565 is active at low oral doses: the 5-HT depletion in rat brain caused by p-chloroamphetamine is antagonized by DU 24565 (oral ED50 0.7 mg/kg). The decrease in the 5-HT content caused by 4, alpha-dimethyl-m-tyramine (H 77/77) is antagonized by DU 24565 at 1 mg/kg orally, without any effect on the depletion of catecholamines. 5-HT turnover, measured by the probenecid method, is reduced by the same dose of DU 24565. Other tests confirmed the activity and selectivity of DU 24565: it potentiated the behavioural affects of the 5-HT precursor 5-hydroxytryptophan (5-HTP) in mice (ED50 1.5 mg/kg orally); it potentiated the temperature increases caused by 5-HTP in the rabbit; it had low activity or no effect at all in NA potentiation tests. This new compound is more potent and selective than the known 5-HT uptake inhibitors. It is a potential antidepressant and can be useful as a pharmacological tool to study the role of 5-HT in the central nervous system.