Psychopharmacology of benzodiazepines—an update

Abstract

Benzodiazepines are one of the classes of compounds which bind at the benzodiazepine site in the central nervous system. The benzodiazepine site is phylogenetically new and modulates allostericaIly the GABA-chloride ionophore. This complex is a pentamer surrounding the chloride channel and is made up of various combinations of alpha, beta and gamma subunits. The anatomical distribution of these subunits is diverse and underlies the differential binding of a number of benzodiazepine modulators in the brain. Other compounds which act at this complex include bicuculline, musicmol, ethanol and neurosteroids. Modulation at the benzodiazepine site is bidirectional. The net result of positive modulation is facilitation of conductance and thus hyperpolarisation i.e. an inhibitory effect, while negative modulation has the inverse effects. There is considerable receptor reserve at this complex, in addition since modulators depend on the presence of GABA for their effects, supraphysiological stimulation does not occur. These factors account for the extreme safety of benzodiazepines and explain the lack of selectivity of action of full agonists, since small increases in fractional occupancy are enough to produce the full gamut of effects. The same however does not apply to partial agonists which manifest the different actions at well separated receptor occupation. Endogenous ligands have not yet been found for these sites, although benzodiazepines have been found in brains collected prior to their pharmaceutic marketing-these probably originate from vegetable foodstuffs and gut bacteria. Changes in this site can be induced by stress, convulsions and repeated administration of modulators and animals bred for different sensitivity at the benzodiazepine site manifest consistent behavioural differences. These observations have instigated a search for potential endogenous inverse agonists in human anxiety disorders and epilepsy and for endogenous agonists in metabolic encephalopathies. While thus far this has not been successful the putative isolation of endozapines in the rare condition of idiopathic recurrent stupor indicate that this may be a useful line of research. In addition the emergence of partial agonists at these sites which have fewer side effects is likely to rekindle interest in the clinical use of such compounds in a variety of neurological and psychiatric syndromes.

Pharmacology of the β‐Carboline FG‐7142, a Partial Inverse Agonist at the Benzodiazepine Allosteric Site of the GABAA Receptor: Neurochemical, Neurophysiological, and Behavioral Effects

“…Anxiety‐related effects of FG‐7142 were reversible with 1 mg lormetazepam i.v., with a time course of recovery within several minutes. Severe panic‐like responses following FG‐7142 administration in humans has led to the suggestion that further human experimentation be abandoned for ethical reasons (Malizia and Nutt 1995).…”

Drug effect on EEG connectivity assessed by linear and nonlinear couplings

“…Peak plasma concentrations are obtained between 0.5 and 2 h after intake [Greenblat and Wright,1993]. Regarding brain effects, it is widely known that benzodiazepine activity runs in a progressive continuum from anxiolytic, to sedative, hypnotic, and anesthetic effects, each well characterized by specific behavioral features [Malizia and Nutt,1995]. Benzodiazepines induce an enhancement of the inhibitory pathways through their activity on the GABA A receptor complex, favoring the entrance to chloride ions into the neurons [Haefely,1990].…”

Different Acute Tolerance Development to EEG, Psychomotor Performance and Subjective Assessment Effects after Two Intermittent Oral Doses of Alprazolam in Healthy Volunteers

“…Despite the similarities in the qualitative effects of BZDs, relevant quantitative differences in the pharmacokinetic (PK) and pharmacodynamic (PD) properties have led to their many therapeutic uses as anxiolytics, hypnotics, pre-anesthetics, anticonvulsants and muscular relaxants [2] .…”