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alpha6-subunits and a delta-subunit in place of the gamma-subunit. In contrast, the GABAB
receptor is coupled, via a G-protein, to potassium channels which mediate slow
hyperpolarisation of the post-synaptic membrane. This receptor is also found pre-synaptically
where it acts as an auto-receptor, with activation limiting further GABA release. GABA is
removed from the synaptic cleft into localised nerve terminals and glial cells by a family of
transport proteins, denoted GAT-1, GAT-2, GAT-3, and BGT-1. Thereafter, GABA is either
recycled to the readily releasable neurotransmitter pool or inactivated by the mitochondrial
enzyme GABA-transaminase.

Excitatory neurotransmission
Glutamate is the principal excitatory neurotransmitter in the mammalian brain. Following
release from glutamatergic nerve terminals, it exerts its effects on three specific subtypes of
ionotropic receptor in the postsynaptic membrane, designated according to their agonist
specificities; AMPA, kainate and NMDA. These receptors respond to glutamate binding by
increasing cation conductance resulting in neuronal depolarisation or excitation. The AMPA
and kainate receptor subtypes are permeable to sodium ions and are involved in fast excitatory
synaptic transmission. In contrast, the NMDA receptor is permeable to both sodium and
calcium ions and, owing to a voltage-dependent blockade by magnesium ions at resting
membrane potential, is only activated during periods of prolonged depolarisation, as might
be expected during epileptiform discharges. Metabotropic glutamate receptors perform a
similar function to GABAB receptors; they are G-protein coupled and act predominantly as
auto-receptors on glutamatergic terminals, limiting glutamate release. Glutamate is removed
from the synapse into nerve terminals and glial cells by a family of specific sodium-dependent
transport proteins (EAAT1–EAAT5) and is inactivated by the enzymes glutamine synthetase
(glial cells only) and glutamate dehydrogenase.

Other putative targets
Countless proteins and processes are involved in the regulation of the neuronal micro-
environment and in maintaining the delicate balance between excitation and inhibition in the
brain and, theoretically at least, represent additional or secondary targets for AED action.
These include the enzyme carbonic anhydrase and components of the synaptic vesicle release
pathway, both of which are discussed in more detail below.

Mechanisms of action of existing agents

Sodium channels. Blockade of voltage-gated sodium channels is the most common
mechanism of action among currently available AEDs. The established agents phenytoin and
carbamazepine are archetypal sodium channel blockers, a mechanism they share with the
newer drugs, lamotrigine, felbamate, topiramate, oxcarbazepine, zonisamide, rufinamide,
lacosamide, and eslicarbazepine acetate. There is also anecdotal evidence to suggest that
sodium valproate and gabapentin have inhibitory effects on neuronal sodium channels.
Voltage-gated sodium channels exist in one of three basic conformational states: resting,
open, and inactivated. During a single round of depolarisation, channels cycle through these
states in turn (resting to open, open to inactivated, inactivated to resting) and are unable to
respond to further depolarisations until sufficient numbers have returned from the inactivated
state to the resting state. Antiepileptic agents with sodium channel blocking properties have
highest affinity for the channel protein in the inactivated state and binding slows the
conformational recycling process. As a result, these drugs produce a characteristic voltage-
and frequency-dependent reduction in channel conductance, resulting in a limitation of
repetitive neuronal firing, with little effect on the generation of single action potentials.
Further complexity is added by the existence of multiple inactivation pathways. Although
most sodium channel blocking AEDs target the fast inactivation pathway, lacosamide appears
to enhance slow inactivation and there is preliminary evidence to suggest that eslicarbazepine
acetate may do likewise. The clinical implications of this distinction remain unclear but it has