GABAa antagonistic convulsants

Epilepsy is an example of excessive neural signaling in the central nervous system. Relative cellular and extracellular space (ECS) volume has been demonstrated to play an important role in the propensity for epileptic seizures. For example, reducing ECS volume by exposure to hypotonic medium produces hyperexcitability and enhanced epileptiform activity, whereas hyperosmolar medium reduces excitability. The hypothesis that AQP4-dependent water transport in astrocytes might modulate intrinsic brain excitability was tested by seizure susceptibility in response to the GABAa antagonist convulsant pentylenetetrazol... 

Experimentally all GABA antagonists induce convulsions. These include the genuine receptor antagonist bicuculline, which competes with GABA for its recognition site on the GABAa receptor and picrotoxin, which binds to a different site more closely related to the chloride ion channel. 

Other chemicals are agonists such as those that directly affect the y-butyric acid receptor (GABAa) receptor in neurons. Drugs such as barbiturates and benzodiazepines are agonists (activators) for this receptor and cause neuronal inhibition and sedation at therapeutic doses but coma and depression at higher doses. Conversely, antagonists (inhibitors) for this receptor such as the insecticides lindane and cyclodienes and picrotoxin inhibit neurons and may cause tremor and convulsions at toxic doses. 

Specific antagonists for GABAa receptors include the alkaloid convulsants bicuculline (Fig. 30-25)699 and picrotoxin (Fig. 22-4) and the convulsant terpenoid compound thujone (Fig. 22-3), which is present in the wormwood plant Artemesia absinthium. Thujone is present in the liqueur absinthe, which was the national drink of France in the late 19th century but, because of its toxicity, has been illegal in most countries since -1915.719... 

PTZ is a GABAa receptor antagonist that is widely used to study the susceptibility of drugs to alter convulsive threshold [reviewed in Loscher (2009)]. As a direct inhibitor of GABA systems in the brain, PTZ is itself a potent seizurogenic... 

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