Benzodiazepine Neuropharmacology

Benzodiazepines (BZs) and non-benzodiazepines (also known as “Z-drugs”) are both part of a group of drugs that are known as benzodiazepine receptor agonists.  They are positive allosteric modulators of the GABA_A receptor.  They work by increasing the efficiency of a natural brain chemical, GABA, to decrease the excitability of neurons. This reduces the communication between neurons and, therefore, has a calming effect on many of the functions of the brain.

GABA controls the excitability of neurons by binding to the GABA_A receptor.  All GABA_A receptors contain an ion channel that conducts chloride ions across neuronal cell membranes and two binding sites for GABA, while a subset of GABA_A receptor complexes also contain a single binding site for BZs and Z-drugs.  A model of a BZ or Z-drug modulated GABA_A  receptor is shown in Figure 1.

The subset of GABA_A receptors that also bind BZs and z-drugs are referred to as “benzodiazepine receptors”.  The GABA_A receptor complex is composed of 5 glycoprotein subunits, each with multiple isoforms, or subtypes.  Subtypes (α_1–6, β_1–3, and γ_1–3) have been identified.  GABA_A receptors contain 2 α subunits, 2 β subunits, and 1 γ subunit. GABA_A receptors that are made up of different combinations of subunit subtypes have different properties, different distributions in the brain and different activities relative to pharmacological and clinical effects. Each receptor complex has 2 GABA-binding sites but only 1 BZD-binding site. The BZ binding site is in a specific pocket at the pairing (intersection) of the α and γ subunits. Within the α subunit of isoforms 1, 2, 3, and 5 resides a histidine residue (H101, H101, H126, and H105, respectively) that possesses a high affinity for BZs.³ Isoforms 4 and 6 of the α subunit contain an arginine residue and do not have an affinity for BZs.³ Researchers in 2013 showed that BZs bind to the pocket created by the α and γ subunits and induce a conformational change in the GABA_A receptor, allowing GABA to bind. BZs bind to the pocket created by α and γ subunits and induce a conformational change in the GABA_A receptor. This alteration, in turn, induces a conformational change in the GABA_A receptor’s chloride channel that causes an increase in the flow of chloride ions into the cell. A model of this action is shown in figure 2.

This increased chloride ion influx hyperpolarizes the neuron’s membrane potential. As a result, the difference between resting potential and threshold potential is increased and firing is less likely. Different GABA_A receptor subtypes have varying distributions within different regions of the brain and, therefore, control distinct neuronal circuits. Hence, activation of different GABA_A receptor subtypes by BZs or z-drugs may result in distinct pharmacological actions. In terms of the mechanism of action of BZs and Z-drugs, their similarities are too great to separate them into individual categories such as anxiolytic or hypnotic. For example, a hypnotic administered in low doses produces anxiety-relieving effects, whereas a benzodiazepine marketed as an anti-anxiety drug at higher doses or a short-acting Z-drug induces sleep.^[164]

Benzodiazepines and Z-drugs also interact with peripheral benzodiazepine receptors. Peripheral benzodiazepine receptors were discovered in 1992, and are also known as tryptophan-rich sensory protein (TspO) receptors or translocator protein receptors.  They are present in peripheral nervous system tissues, glial cells, in mitochondria (the cells’ energy factories) throughout the body, and to a lesser extent the central nervous system. These peripheral receptors are not structurally related or coupled to GABA_A receptors. They modulate the immune system, possibly control cellular energy processes, and are involved in the body response to injury. Benzodiazepines also function as weak adenosine reuptake inhibitors. It has been suggested that some of their anticonvulsant, anxiolytic, and muscle relaxant effects may be in part mediated by this action.