The possible involvement of GABA mechanisms in the action of benzodiazepines on central catecholamine neurons.

With the use of quantitative microspectrofluorometry, it has been shown that diazepam (10 mg/kg) and chlordiazepoxide (10 mg/kg) reduce DA turnover in the tuberculum olfactorium, nuc. accumbens, the DA islands of the entorhinal cortex, and caput of nuc. caudatus, whereas DA turnover is increased in the lateral external layer of the median eminence after 10 mg/kg of diazepam. It is of considerable interest that with a dose of 1 mg/kg of diazepam a reduction of DA turnover can still be observed in the tuberculum olfactorium and nuc. accumbens but not in the nuc. caudatus, due to a high variability of the response in this area. A similar trend is also found with chlordiazepoxide. Thus, changes in limbic DA turnover are observed in doses close to the minimal effective dose (0.6 mg/kg) needed to release punished behavior and to cause anticonvulsive effects, and may therefore be related to these actions of diazepam. For various reasons it is speculated that an increased GABA receptor activity on the DA cell bodies and their dendrites could mainly be involved in causing the reduction of DA turnover observed after benzodiazepines by diminishing the firing rate in the ascending DA pathways, particularly the mesolimbic DA pathways. Evidence for a change of GABA turnover by diazepam has also been found. It is also suggested that the reduction of cortical NE turnover found after benzodiazepines can partly involve an increased GABA receptor activity on the locus ceruleus cells, although the activation of E receptors on these cells cannot be excluded. These effects on locus ceruleus may be partly responsible for the sedation found after benzodiazepines. Diazepam (1 mg/kg) mimics both clonidine and GABA-ergic drugs in reducing blood pressure and slowing respiration rate, but the effects are blocked by picrotoxin but not by piperoxane, an E receptor-blocking agent. In agreement with the view that blockade of the stress-induced increases of NE turnover by benzodiazepines may be related to their antianxiety actions, it was found that the increase in NE turnover elicited by yohimbine, a drug that causes anxiety in man, is blocked by diazepam.