Pentylenetetrazol, also known as pentylenetetrazole, leptazol, metrazol, pentetrazol (
INN), pentamethylenetetrazol, Corazol, Cardiazol, Deumacard, or PTZ, is a drug formerly used as a circulatory and respiratory stimulant. High doses cause
convulsions, as discovered by Hungarian-American neurologist and psychiatrist
Ladislas J. Meduna in 1934. It has been used in convulsive therapy, and was found to be effective—primarily for depression—but side effects such as uncontrolled
seizures were difficult to avoid.[1] In 1939, pentylenetetrazol was replaced by
electroconvulsive therapy, which is easier to administer, as the preferred method for inducing seizures in England's mental hospitals. In the US, its approval by the
Food and Drug Administration was revoked in 1982.[2] It is used in Italy as a cardio-respiratory stimulant in combination with
codeine in a
cough suppressant drug.[3]
Mechanism
The mechanism of pentylenetetrazol is not well understood, and it may have multiple
mechanisms of action. In 1984, Squires et al. published a report analyzing pentylenetetrazol and several structurally related convulsant drugs. They found that in vivo convulsant potency was strongly correlated to in vitro affinity to the
picrotoxin binding site on the
GABA-A receptor complex. Many GABA-A ligands, such as the sedatives
diazepam and
phenobarbital, are effective
anticonvulsants, but presumably pentylenetetrazol has the opposite effect when it binds to the GABA-A receptor.[4]
Several studies have focused on the way pentylenetetrazol influences neuronal ion channels. A 1987 study found that pentylenetetrazol increases calcium influx and sodium influx, both of which depolarize the neuron. Because these effects were antagonized by calcium channel blockers, pentylenetetrazol apparently acts at calcium channels, and it causes them to lose selectivity and conduct sodium ions, as well.[5]
Research
Pentylenetetrazol has been used experimentally to study seizure phenomena and to identify pharmaceuticals that may control seizure susceptibility. For instance, researchers can induce
status epilepticus in animal models. Pentylenetetrazol is also a prototypical
anxiogenic drug and has been extensively used in animal models of
anxiety. Pentylenetetrazol produces a reliable
discriminative stimulus, which is largely mediated by the
GABAA receptor. Several classes of compounds can modulate the pentylenetetrazol discriminative stimulus, including
5-HT1A,
5-HT3,
NMDA,
glycine, and
L-type calcium channelligands.[6]
^Squires RF, Saederup E, Crawley JN, Skolnick P, Paul SM (1984). "Convulsant potencies of tetrazoles are highly correlated with actions on GABA / benzodiazepine / picrotoxin receptor complexes in brain". Life Sci. 35 (14): 1439–44.
doi:
10.1016/0024-3205(84)90159-0.
PMID6090836.
^Papp A, Fehér O, Erdélyi L (1987). "The ionic mechanism of the pentylenetetrazol convulsions". Acta Biol. Hung. 38 (3–4): 349–61.
PMID3503442.
^Jung ME, Lal H, Gatch MB (2002). "The discriminative stimulus effects of pentylenetetrazol as a model of anxiety: recent developments". Neurosci. Biobehav. Rev. 26 (4): 429–39.
doi:
10.1016/S0149-7634(02)00010-6.
PMID12204190.
S2CID26055062.