Alprazolam, diazepam, yohimbine, clonidine: In vivo CA(1) hippocampal norepinephrine and serotonin release profiles under chloral hydrate anesthesia

1. Although the GABA-A receptor complex has been the main focus of anti-anxiety therapy, the neural interaction in the septohippocampal circuit between GABA-A and the neurotransmitter, 5-HT, compels a study of the monoamine, 5-HT, in anxiety as well. 2. Neurochemistry for anxiety is also intimately involved with the neurotransmitter, NE. Indeed, 5-HT is a component of the dorsal ascending noradrenergic bundle and both neurotransmitters, NE and 5-HT, have been implicated in clinical depression. 3. In vivo microvoltammetric studies were performed using miniature carbon based sensors to detect NE release and concurrent 5-HT release, with 2 separate neural electrochemical signals, within CA(1) region of hippocampus, in the chloral hydrate anesthetized rat. 4. Time course studies showed that both the triazolobenzodiazepine (TBZD), alprazolam, and the benzodiazepine (BZD), diazepam, decreased hippocampal NE release. 5. The in vivo and on line neurochemical profile of hippocampal 5-HT release for alprazolam differed from that of diazepam, i.e. alprazolam increased hippocampal 5-HT release, whereas diazepam decreased hippocampal 5-HT release. 6. Time course studies showed that the az-adrenergic antagonist, yohimbine, an anxiogenic agent, increased both NE and 5-HT release in CA(1) region of hippocampus; the alpha(2)-adrenergic agonist, clonidine, decreased NE release and increased 5-HT release in the same region. 7. Neither the profile for the TBZD, alprazolam, nor that of the BZD, diazepam, mimicked the neurochemical profile for the anxiogenic agent, yohimbine; the neurochemical profile for the TBZD, alprazolam, was similar to that of the alpha(2)-adrenergic agonist, clonidine. 8. Interestingly, alprazolam's hippocampal 5-HT/NE interaction is similar to clonidine's 5-HT/NE action at alpha(2)-adrenergic autoreceptors, resulting in enhanced 5-HT release. 9. Enhanced 5-HT release in hippocampus, exhibited by the atypical TBZD, alprazolam, and not by the typical BZD, diazepam, may be an underlying mechanism for the antidepressant activity exhibited by alprazolam.