Posted by Quintal on August 17, 2007, at 21:28:34
In reply to Re: Beta-carbolines and benzos, posted by linkadge on August 16, 2007, at 14:03:11
>I had read something from a book called "Drugs and the Brain" by solomon H snyder. He was describing the limited clinical experience with beta carbolines. It was describing the intense anxiety that beta carbolines could produce (not sure about dose) and how the benzo's could act as a direct antidote.
Did he say that beta-carbolines are benzodiazepine receptor antagonists, or that benzos would be useful for treating beta-carboline induced anxiety?
>The beta carbolines remind me of isatin. Have you read about isatin?
No, I hadn't heard of it, but your post back in January came up when I Googled it. Do beta-carbolines actually reduce GABA? I'll look and see what I can find.
>Its interesting because there is some evidence to suggest that combining certain agonists with antagonists can prevent or reduce tollerance.
Here I found a study which says beta-carbolines are benzodiazepine inverse agonists:
__________________________________________________1: ScientificWorldJournal. 2007 Feb 19;7:204-23.Click here to read Links
From the behavioral pharmacology of beta-carbolines to seizures, anxiety, and memory.
Venault P, Chapouthier G.Vulnérabilité, Adaptation et Psychopathologie, CNRS UMR 7593, Hôpital Pitié-Salpêtrière, 91 Bd de l'Hôpital, 75634 Paris cedex 13, France. venault@ext.jussieu.fr
A number of beta-carbolines are inverse agonists of the GABA-A receptor complex, acting on the benzodiazepine site. They show convulsive properties when administered at high doses, anxiogenic properties at moderate doses, and learning-enhancing effects at low doses. These data suggest a possible physiological relationship, through the GABA-A receptor channel, between memory processes, anxiety, and ultimately, in pathological states, epileptic seizures. This relationship seems to be confirmed partially by experiments on mouse strains selected for their resistance (BR) and sensitivity (BS) to a single convulsive dose of a beta-carboline. These two strains also show differences in anxiety and learning abilities. However, some opposite results found while observing the behavior of the two strains suggest that in addition to pharmacologically induced anxiety, there is spontaneous anxiety, no doubt involving other brain mechanisms.
PMID: 17334612 [PubMed - indexed for MEDLINE]
__________________________________________________So they're not a direct antidote as such, rather beta-carbolines would compete with benzodiazepines at the benzodiazepine receptors. But still, they seem a useful way to temporarily reverse benzo-induced cognitive impairment and memory problems. It would be interesting to see what effects they might have on tolerance by modulating the sensitivity of the benzodiazepine receptors. I'm wondering if beta-carbolines might be helpful or harmful in that situation where the benzodiazepine receptors are locked in the inverse agonist configuration?
__________________________________________________Although the underlying mechanisms of benzodiazepine dependence are still not entirely understood, research in animals points to the clinical potential for the benzodiazepine antagonist flumazenil (Ro 15-1788) to reverse benzodiazepine dependence and tolerance and prevent withdrawal (Whitwam, 1988). Administration of flumazenil reverses tolerance and dependence to benzodiazepines (Gonsalves and Gallager, 1985) but precipitates recognizable withdrawal symptoms . However, if given during chronic treatment flumazenil can, by similarly reversing tolerance, prevent subsequent withdrawal syndromes in primates (Gallager, Heninger and Heninger, 1986) and in rats (Baldwin, Hitchcott and File, 1990). One explanation for this is the antagonism and depletion of an endogenous benzodiazepine receptor ligand with inverse agonist and thus anxiogenic activity by the antagonist flumazenil (Baldwin, Hitchcott and File, 1990). However, levels of the proposed 'anxiety peptide' ligand associated with diazepam binding inhibitor (DBI) were not found to be increased by the administration of diazepam in rats (Ball et al., 1987). An alternative explanation is that chronic agonist use causes a persistent conformational change and thus a shift in benzodiazepine receptor efficacy in the direction of inverse agonist function (Little, Nutt and Taylor, 1987) and that flumazenil resets the receptor's sensitivity (Nutt and Costello, 1988). In binding to the benzodiazepine receptor flumazenil may alter the coupling of the elements of the GABA/benzodiazepine macromolecular complex modified by benzodiazepine binding, thus restoring the GABA recognition site to its pre-drug affinity (Gonsalves and Gallager, 1985).
http://www.bcnc.org.uk/flumazenil.html
__________________________________________________Maybe a steady flow of exogenous benzodiazepine inverse agonist might help suppress endogenous overproduction and maintain balance? The problem with this though, is that a constant supply of inverse agonist would cause a constant state of anxiety, rendering the benzodiazepine ineffective. I mean, if you need to take an inverse agonist all day to counteract the cognitive impairment, would it not make more sense to take a short-acting benzo in the evening or at night?
Q
poster:Quintal
thread:776629
URL: http://www.dr-bob.org/babble/20070815/msgs/776857.html