Pentylenetetrazol (PTZ), also known aspentylenetetrazole,pentetrazol (INN), andpentamethylenetetrazol, is adrug formerly used as a circulatory and respiratory stimulant. High doses causeconvulsions, as discovered by Hungarian-American neurologist and psychiatristLadislas J. Meduna in 1934. It has been used in convulsive therapy, and was found to be effective in treating depression, but side effects such as uncontrolledseizures were difficult to avoid.[1] In 1939, pentylenetetrazol was replaced byelectroconvulsive therapy, which is easier to administer, as the preferred method for inducing seizures in England's mental hospitals. In the US, Pentylenetetrazol's approval by theFood and Drug Administration (FDA) was revoked in 1982.[2] It is used in Italy as a cardio-respiratory stimulant in combination withdihydrocodeine in acough suppressant drug.[3]
The mechanism of pentylenetetrazol is not well understood, and it may have multiplemechanisms of action. In 1984, Squires et al. published a report analyzing pentylenetetrazol and several structurally related convulsant drugs. They found thatin vivo convulsant potency was strongly correlated toin vitro affinity to thepicrotoxin binding site on theGABAA receptor complex. Many GABAA receptor ligands, such asdiazepam andphenobarbital, are effectiveanticonvulsants, but pentylenetetrazol presumably has the opposite effect when it binds to the GABAA receptor.[5]
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 bycalcium channel blockers, pentylenetetrazol apparently acts atcalcium channels, and it causes them to lose selectivity and conduct sodium ions, as well.[6]
Pentylenetetrazol has been used experimentally to study seizure phenomena and to identify pharmaceuticals that may control seizure susceptibility. For instance, researchers can inducestatus epilepticus in animal models. Pentylenetetrazol is also a prototypicalanxiogenic drug and has been extensively used in animal models ofanxiety. Pentylenetetrazol produces a reliablediscriminative stimulus, which is largely mediated by theGABAA receptor. Several classes of compounds can modulate the pentylenetetrazol discriminative stimulus, including5-HT1A,5-HT3,NMDA,glycine, andL-type calcium channelligands.[7]
^Durant C, Christmas D, Nutt D (2009). "The Pharmacology of Anxiety".Current Topics in Behavioral Neurosciences. Vol. 2. Berlin, Heidelberg: Springer Berlin Heidelberg. pp. 303–330.doi:10.1007/7854_2009_8.ISBN978-3-642-02911-0.ISSN1866-3370.PMID21309115.Preliminary evidence that reducing GABAergic transmission induces anxiety came from the early use of pentylenetetrazol (PTZ) a convulsant drug used to induce seizures in the treatment of severe psychiatric disorders before the discovery of ECT. During its use dose titration was difficult, in many cases too little was given and no seizure was caused. This, however, produced a severely anxious state, leading to patients feeling 'as if they were going to die', and trying (often successfully) to escape from the clinic. Memory of this anxiety was extremely strong resulting in resistance to return to therapy and it was later shown that PTZ acts as an antagonist GABAA receptor.
^Squires RF, Saederup E, Crawley JN, Skolnick P, Paul SM (October 1984). "Convulsant potencies of tetrazoles are highly correlated with actions on GABA/benzodiazepine/picrotoxin receptor complexes in brain".Life Sciences.35 (14):1439–1444.doi:10.1016/0024-3205(84)90159-0.PMID6090836.
^Papp A, Fehér O, Erdélyi L (1987). "The ionic mechanism of the pentylenetetrazol convulsions".Acta Biologica Hungarica.38 (3–4):349–361.PMID3503442.
^Jung ME, Lal H, Gatch MB (June 2002). "The discriminative stimulus effects of pentylenetetrazol as a model of anxiety: recent developments".Neuroscience and Biobehavioral Reviews.26 (4):429–439.doi:10.1016/S0149-7634(02)00010-6.PMID12204190.S2CID26055062.
^Takahashi T, Noriaki S, Matsumura M, Li C, Takahashi K, Nishino S (3 October 2018). "Advances in pharmaceutical treatment options for narcolepsy".Expert Opinion on Orphan Drugs.6 (10):597–610.doi:10.1080/21678707.2018.1521267.ISSN2167-8707.
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