Developmental pharmacology of benzodiazepines under normal and pathological conditions.

Benzodiazepines are allosteric agonists of GABAA receptors (GABAAR), pentameric ligand-gated Cl(-) channels, which serve both an important neurodevelopmental role but are also the principal inhibitory system in the brain. However, their subunit composition, channel properties, and function, as well as their region-specific expression patterns, change through development. These processes have been extensively studied in rodents and to some extent confirmed in higher species. Specifically, GABAARs acquire faster kinetics with age and their pharmacology changes rendering them more sensitive to drugs that have higher affinity for α1 subunit-containing GABAARs, such as benzodiazepines, but also, their inhibitory function becomes more potent as they shift from having depolarising to hyperpolarising responses due to a shift in Cl(-) gradient and cation chloride cotransporter expression. Concerns have been raised about possible pro-apoptotic and paradoxical effects of benzodiazepines in the neonatal normal rat brain, although it is unclear, as yet, whether this extends to brains exposed to seizures. Growing evidence indicates that the pharmacology and physiology of GABAARs may be altered in the brain of rats or humans with seizures or epilepsy, or different aetiologies that predispose to epilepsy. These changes follow different paths, depending on sex, age, region, cell type, aetiology, or time-point specific factors. Identification of dynamic biomarkers that could enable these changes in vivo to be monitored would greatly facilitate the selection of more effective agonists with fewer side effects.