Benzodiazepines: how they provide their anxiolytic and hypnotic effects.

The main actions of benzodiazepines (hypnotic, anxiolytic, anticonvulsant, myorelaxant and amnesic) confer a therapeutic value in a wide range of conditions. Since the discovery and the development of the first tranquilizer, Librium, by Roche in the mid-1950s, benzodiazepines have become one of the most widely prescribed drugs in the world. Most famously, Valium, first marketed in 1963, is prescribed for anxiety and panic disorders. In 2011, 14.6 million prescriptions were made in the US alone. The leading successor to Valium, Xanax, was developed by Pfizer and is prescribed for anxiety. Xanax now outsells all other psychiatric drugs on the market in the US, with 47.7 million prescriptions made in the US in 2011.

Benzodiazepines are also used as hypnotics for insomnia, epilepsy (mainly clonazepam and clobazam), anaesthesia (midazolam), some motor disorders and occasionally in acute psychoses.

How benzodiazepines work in the brain:

Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mammalian central nervous system. Benzodiazepines work by increasing the efficiency of the natural brain chemical GABA, to decrease the excitability of neurons and subsequently, reduce the communication between neurons. This has a calming effect on many of the functions of the brain.

GABA participates in the regulation of neuronal excitability through interaction with specific membrane proteins, the GABAA receptors.The GABAA receptor is a complex made up of five proteins and is located in the synapses of neurons. GABAA receptors contain an ion channel that conducts chloride ions across the neuronal cell membranes. Chloride ions are negative and when the GABAA receptor conducts chloride ions through its pore, this results in the hyperpolarization of the neuron. In other words, negative ions cause a decrease in the electrical potential of the cell they are entering. This causes an inhibitory effect on neurotransmission by diminishing the chance of a successful action potential occurring.

All cells in animal body tissues are electrically polarized, i.e. they maintain a voltage difference across the cell membrane. This is known as the membrane potential. Typically, a neuron’s resting potential (i.e. when it is not firing) is around -70 millivolts (mV). Neurotransmitters provide synaptic inputs to a neuron, causing the membrane to either depolarize (bringing the membrane potential towards and above 0) or hyperpolarize (bringing the membrane potential further down). Where the neurons is depolarized or hyperpolarized depends on what ions enter the cell – positive ions cause the membrane potential to rise, whereas negative ions cause the membrane potential to fall. Action potentials are triggered when enough depolarization accumulates to bring the membrane potential up to the threshold, typically -55mV. When an action potential is triggered, the membrane potential abruptly shoots upward, often reaching as high as +100 mV.

Upon activation, the GABAA receptor selectively conducts negative chloride ions through its pore, resulting in hyperpolarization of the neuron. This causes an inhibitory effect on neurotransmission by diminishing the chance of a successful action potential occurring.

GABA is released from the presynaptic neuron and diffuses across the synaptic cleft, where two molecules of GABA bind to a GABAA receptor. This causes chloride ions to enter the postsynaptic cell. The negative ions serve to hyperpolarize the cell, decreasing the likelihood of firing of the postsynaptic neuron.

Schematic diagram of the (α1)2(β2)2(γ2) GABAA receptor complex that depicts the five-protein subunits that form the receptor, the chloride (Cl-) ion channel pore at the center, the two GABA active binding sites at the α1 and β2 interfaces and the benzodiazepine (BZD) allosteric binding site at the α1 and γ2 interface.

All GABAA receptors contain two binding sites for the neurotransmitter GABA, while a subset of GABAA receptors also contain a single binding site for benzodiazepines (variation is conferred by different combinations of protein subunits). Binding of a benzodiazepine promotes binding of GABA, which in turn increases the conduction of chloride ions across the cell membrane. As such, benzodiazepines reduce brain activity and induce hypnotic, tranquilizing effects on the individual. Benzodiazepines are prescribed for a broad range of problems, including anxiety, insomnia and epilepsy. Their usefulness, however, is limited by a broad range of side effects such as amnesia, tolerance development and abuse potential.

For further introductory notes on drugs and receptors, see here.

1 thought on “Benzodiazepines: how they provide their anxiolytic and hypnotic effects.

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