Metrazol

Metrazol is the commercial trademark of pentetrazol, pentamethylenetetrazol, or pentylenetetrazol (PTZ), a drug used as a circulatory and respiratory stimulant (another commercial name is Cardiazol). Larger doses cause convulsions, thus it has been used in shock therapy, as discovered by the Hungarian-American neurologist and psychiatrist Ladislas J. Meduna in 1934. It was never considered to be effective, and side-effects such as seizures are difficult to avoid. Its approval by FDA was revoked in 1982.

It is considered a non-competitive GABA antagonist. The mechanism of the epileptogenic action of PTZ at the cellular neuronal level is still unclear. Electrophysiological studies have shown it acts at cell membrane level decreasing the recovery time between action potentials by increasing potassium permeability of the axon. Other studies have implicated an increase in membrane currents of several other ions, such as sodium and calcium, leading to an overall increase in excitability of the neuron membrane.

Pentylenetetrazole has been used experimentally to study seizure phenomenon and to identify pharmaceuticals that may control seizure susceptibility. PTZ is also a prototypical anxiogenic drug and, has been extensively utilized in animal models of anxiety. PTZ produces a reliable discriminative stimulus which is largely mediated by the GABAA receptor. Several classes of compounds can modulate the PTZ discriminative stimulus including 5-HT1A, 5-HT3, NMDA, glycine, and L-type calcium channel ligands.

Recently, it has been shown that pentetrazol at non-epileptic doses, along with two other compounds (Picrotoxin and bilobalide) can restore the cognitive function (learning and memory) of a mouse model of Down syndrome by inhibiting GABAA receptor without inducing seizures. These results caused renewed interest in pentetrazol as a potential drug candidate for Down syndrome, although clinical trials are probably still a couple of years away.

In 1939, Metrazol (also known as Cardiazol) was replaced by Electroconvulsive therapy as the preferred method for inducing seizures in England's mental hospitals.