Hypnotics and anxiolytics

Physiology

γ-Aminobutyric acid (GABA) is the main inhibitory neurotransmitter within the CNS and acts via two different receptor subtypes, GABAA and GABAB:

• GABAA – this receptor is a ligand-gated Cl− ion channel. It consists of five subunits (2α, β, δ and γ – each having a number of variants) arranged to form a central ion channel. GABA binds to and activates GABAA receptors and increases the opening frequency of its Cl− channel, augmenting Cl− conductance and thereby hyperpolarizing the neuronal membrane. Cl− ion conductance is potentiated by the binding of BDZs to the α subunit of the activated receptor complex. GABAA receptors are essentially (but not exclusively) postsynaptic and are widely distributed throughout the CNS.

• GABAB – this receptor is metabotropic (i.e. acts via a G-protein and second messengers), and when stimulated it increases K+ conductance, thereby hyperpolarizing the neuronal membrane. GABAB receptors are located both presynaptically on nerve terminals and postsynaptically in many regions of the brain, as well as in the dorsal horn of the spinal cord. Baclofen acts only via GABAB receptors to reduce spasticity.

BDZs modulate the effects of GABA at GABAA receptors. The specific α-subunit type determines the BDZ pharmacology – anxiolytic or sedative. Two BDZ receptor subtypes have been identified: BZ1, found in the spinal cord and cerebellum – responsible for anxiolysis; and BZ2, found in the spinal cord, hippocAMPus and cerebral cortex – responsible for sedative and anticonvulsant activity.