Electrophysiology of BZR ligands has been reviewed from different points of view. A great effort was made to critically discuss the arguments for and against the temporarily leading hypothesis of the mechanism of action of BZR ligands, the GABA hypothesis. As has been discussed at length in the present article, an impressive body of electrophysiological and biochemical evidence suggests an enhancement of GABAergic inhibition in CNS as a mechanism of action of BZR agonists. Biochemical data even indicate a physical coupling between GABA recognition sites and BZR which, together with the effector site build-up by Cl− channels, form a supramolecular GABAA/BZR complex. By binding to a specific site on this complex, BZR agonists allosterically increase and BZR inverse agonists decrease the gating of GABA-linked Cl− channels, whereas BZR antagonists bind to the same site without an appreciable intrinsic activity and block the binding and action of both agonists as well as inverse agonists. While this model is supported by many electro- physiologial experiments performed with BZR ligands in higher nanomolar and lower micromolar concentrations, it does not explain much controversial data from animal behavior and, more importantly, is not in line with electrophysiological effects obtained with low nanomolar BZ concentrations.
The latter actions of BZR ligands in brain slices occur within a concentrations range compatible with concentrations of BZ observed in CSF fluid, which would be expected to be found in the biophase (receptor level) during anxiolytic theraphy in man. Enhanced K+ conductance seems to be a suitable candidate for this effect of BZR ligands. This direct action on neuronal membrane properties may underlie the many electrophysiological observations with extremely low systemic doses of BZR ligands in vivo which demonstrated a depressant effect on spontaneous neuronal firing in various CNS regions.
Skeletomuscular spasticity and epilepsy are two neurological disorders, where both the enhanced GABAergic inhibition and increased K+ conductance may contribute to the therapeutic effect of BZR agonists, since electro- physiological and behavioral studies strongly support GABA-dependent as well as GABA-independent action of BZR ligands elicited by low to intermediate doses of BZ necessary to evoke anticonvulsant and muscle relaxant effects. Some- what higher doses of BZR ligands, inducing sedation and sleep, lead perhaps to the only pharmacologically relevant CNS concentrations (ca. 1 μM) which might be due entirely to increased GABAergic inhibition.
At the upper limit of the concentration range used in electrophysiological studies reviewed here (10- 100 μM), BZR ligands may suppress status epilepticus and produce side effects, such as pronounced sedation and ataxia. At these concentrations BZR ligands markedly inhibit adenosine uptake, bind to micro-molar BZR and reduce the voltage-dependent CA2+ conductance.
As speculative as such a descriptive synthesis might be, it can give the reader an imaginative picture of the whole spectrum of electrophysiological effects of BZR ligands, without by itself compromising GABA hypothesis. One can, by such an account, even support the GABA hypothesis of BZ action by avoiding an exclusivity otherwise attributed to it, which (exclusivity) would in the future necessarily divide researchers into two mutually incompatible groups, i.e. those who are for and those who are against the GABA hypothesis. Of course, partial agnism found with some BZR ligands and coupled with a postulated receptor reserve may be an important argument for GABA being implicated in almost every action of BZR ligands, but this proposal cannot explain effects observed in the virtual absence of endogenous GABA, neuronal actions of BZR ligands in the lowest concentration range, as well as several behavioral observations.
The intriguing question of multiplicity of BZR mediating various pharmacological effects of BZR ligands remain unsettled, because the available proposed ligands for BZR subtypes have not yet achieved the selectivity for particular receptor subtypes which might be clearly associated with particular pharmacological actions.
An interesting issue, emerging from intrinsic effects of virtually inactive BZR antagonists observed in several electrophysiological and behavioral studies, as well as from a conceptual question of the purpose of higher bony fishes, birds and mammals, has been that of endogenous ligands naturally occupying BZR. Within the extensive research going on in this field, DBI must be regarded as the most promising candidate and, in fact, fulfils some criteria of a neuromodulator or, if it is released together with GABA, a co-transmitter. The presence of such an anxiety-inducing endogenous ligand is supported by several behavioral and biochemical observations, but it is also probable that a counterpart, an anxiolytic endogenous ligand, may be discovered in the future. Ultimately, a fine equilibrium between two opposing endogenous ligands might dynamically regulate neuronal excitability and thus be susceptible to physiological and pathological environmental influences, leading somehow either to a psychological well-being or anxiety. One can then postulate that exogenous BZR ligands, by displacing the endogenous ones, would be particularly active in states of a disequilibrium of endogenous ligands, i.e. in anxiety, insomia and eventually even epileptic phenomena.