Pentylenetetrazol
Encyclopedia
Pentylenetetrazol also known as metrazol, pentetrazol, pentamethylenetetrazol, Cardiazol or PTZ, is a drug used as a circulatory and respiratory stimulant. High doses cause convulsions, as discovered by the Hungarian-American neurologist and psychiatrist Ladislas J. Meduna
in 1934. It has been used in convulsive therapy, but was never considered to be effective, and side-effects such as seizure
s were difficult to avoid. Its approval by the FDA
was revoked in 1982.
. The mechanism
of the epileptogenic action of pentylenetetrazol at the cellular neuronal level is still unclear. Electrophysiological
studies have shown it acts at cell membrane
level decreasing the recovery time between action potential
s 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.
. 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 channel
ligands.
Recently, Stanford University researchers have renewed interest in PTZ as a candidate for pharmacological treatment of Down syndrome
. Published in the April 2007 issue of Nature Neuroscience
, their brief communication outlined an experiment designed to test the underlying theory proposed to explain the purported efficacy of GABAA
antagonists in restoring the declarative memory
deficits associated with the mouse model of human Down Syndrome. Ts65Dn mice injected with a 2-week regiment of either of two compounds picrotoxin
or bilobalide
(both GABA antagonists) showed marked improvements in both exploration and recognition of novel objects over controls injected with only saline. These results were duplicated in a second experiment with mice fed either plain milk or a combination of milk and a non-epileptogenic dose of PTZ daily for 17 days. PTZ-fed mice achieved novel object task scores comparable to wild-type (normal) mice. These improvements persisted at least 1 to 2 months after the treatment regiment. Not surprisingly these compounds' efficacies were accompanied by the normalization of Long-term potentiation
in the dentate gyrus
one month after the end of treatment, further suggesting persistent drug-mediated improvements in learning and memory.
The finding of pentylenetetrazol's effectiveness in treating a mouse model of Down syndrome has led to it being explored as a means of correcting other learning deficiencies. Specifically, hamsters denied their natural circadian rhythm
(though not denied sleep) had their memory restored to near-normal levels when treated with pentylenetetrazol.
as the preferred method for inducing seizures in England's mental hospitals.
Ladislas J. Meduna
Ladislas J. Meduna was a Hungarian neurologist and neuropathologist noted for his development of shock treatment for persons suffering from schizophrenia.Meduna was born to a well-to-do family in Budapest, Hungary, in 1896...
in 1934. It has been used in convulsive therapy, but was never considered to be effective, and side-effects such as seizure
Seizure
An epileptic seizure, occasionally referred to as a fit, is defined as a transient symptom of "abnormal excessive or synchronous neuronal activity in the brain". The outward effect can be as dramatic as a wild thrashing movement or as mild as a brief loss of awareness...
s were difficult to avoid. Its approval by the FDA
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
was revoked in 1982.
Mechanism
Pentylenetetrazol is considered a GABA antagonistGABA antagonist
GABA antagonists are drugs which inhibit the action of GABA. In general these drugs produce stimulant and convulsant effects, and are mainly used for counteracting overdose of sedative drugs....
. The mechanism
Mechanism of action
In pharmacology, the term mechanism of action refers to the specific biochemical interaction through which a drug substance produces its pharmacological effect...
of the epileptogenic action of pentylenetetrazol at the cellular neuronal level is still unclear. Electrophysiological
Electrophysiology
Electrophysiology is the study of the electrical properties of biological cells and tissues. It involves measurements of voltage change or electric current on a wide variety of scales from single ion channel proteins to whole organs like the heart...
studies have shown it acts at cell membrane
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...
level decreasing the recovery time between action potential
Action potential
In physiology, an action potential is a short-lasting event in which the electrical membrane potential of a cell rapidly rises and falls, following a consistent trajectory. Action potentials occur in several types of animal cells, called excitable cells, which include neurons, muscle cells, and...
s by increasing potassium
Potassium
Potassium is the chemical element with the symbol K and atomic number 19. Elemental potassium is a soft silvery-white alkali metal that oxidizes rapidly in air and is very reactive with water, generating sufficient heat to ignite the hydrogen emitted in the reaction.Potassium and sodium are...
permeability
Semipermeable membrane
A semipermeable membrane, also termed a selectively permeable membrane, a partially permeable membrane or a differentially permeable membrane, is a membrane that will allow certain molecules or ions to pass through it by diffusion and occasionally specialized "facilitated diffusion".The rate of...
of the axon
Axon
An axon is a long, slender projection of a nerve cell, or neuron, that conducts electrical impulses away from the neuron's cell body or soma....
. Other studies have implicated an increase in membrane currents of several other ions, such as sodium
Sodium
Sodium is a chemical element with the symbol Na and atomic number 11. It is a soft, silvery-white, highly reactive metal and is a member of the alkali metals; its only stable isotope is 23Na. It is an abundant element that exists in numerous minerals, most commonly as sodium chloride...
and calcium
Calcium
Calcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust...
, leading to an overall increase in excitability of the neuron membrane.
Uses
Pentylenetetrazol has been used experimentally to study seizure phenomenon and to identify pharmaceuticals that may control seizure susceptibility. Pentylenetetrazol is also a prototypical anxiogenic drug and, has been extensively utilized in animal models of anxietyAnxiety
Anxiety is a psychological and physiological state characterized by somatic, emotional, cognitive, and behavioral components. The root meaning of the word anxiety is 'to vex or trouble'; in either presence or absence of psychological stress, anxiety can create feelings of fear, worry, uneasiness,...
. Pentylenetetrazol produces a reliable discriminative stimulus which is largely mediated by the GABAA
GABA A receptor
The GABAA receptor is an ionotropic receptor and ligand-gated ion channel. Its endogenous ligand is γ-aminobutyric acid , the major inhibitory neurotransmitter in the central nervous system. Upon activation, the GABAA receptor selectively conducts Cl- through its pore, resulting in...
receptor. Several classes of compounds can modulate the pentylenetetrazol discriminative stimulus including 5-HT1A, 5-HT3, NMDA
NMDA
N-Methyl-D-aspartic acid or N-Methyl-D-aspartate is an amino acid derivative which acts as a specific agonist at the NMDA receptor mimicking the action of glutamate, the neurotransmitter which normally acts at that receptor...
, glycine
Glycine
Glycine is an organic compound with the formula NH2CH2COOH. Having a hydrogen substituent as its 'side chain', glycine is the smallest of the 20 amino acids commonly found in proteins. Its codons are GGU, GGC, GGA, GGG cf. the genetic code.Glycine is a colourless, sweet-tasting crystalline solid...
, and L-type calcium channel
L-type calcium channel
The L-type calcium channel is a type of voltage-dependent calcium channel. "L" stands for long-lasting referring to the length of activation. Like the others of this class, the α1 subunit is the one that determines most of the channel's properties....
ligands.
Recently, Stanford University researchers have renewed interest in PTZ as a candidate for pharmacological treatment of Down syndrome
Down syndrome
Down syndrome, or Down's syndrome, trisomy 21, is a chromosomal condition caused by the presence of all or part of an extra 21st chromosome. It is named after John Langdon Down, the British physician who described the syndrome in 1866. The condition was clinically described earlier in the 19th...
. Published in the April 2007 issue of Nature Neuroscience
Nature Neuroscience
Nature Neuroscience is a monthly scientific journal published by Nature Publishing Group. Its focus is original research papers relating specifically to neuroscience and was established in May 1998. According to the Journal Citation Reports, Nature Neuroscience has a 2009 impact factor of 14.345,...
, their brief communication outlined an experiment designed to test the underlying theory proposed to explain the purported efficacy of GABAA
GABA A receptor
The GABAA receptor is an ionotropic receptor and ligand-gated ion channel. Its endogenous ligand is γ-aminobutyric acid , the major inhibitory neurotransmitter in the central nervous system. Upon activation, the GABAA receptor selectively conducts Cl- through its pore, resulting in...
antagonists in restoring the declarative memory
Declarative memory
Declarative memory is one of two types of long term human memory. It refers to memories which can be consciously recalled such as facts and knowledge. Its counterpart is known as non-declarative or Procedural memory, which refers to unconscious memories such as skills...
deficits associated with the mouse model of human Down Syndrome. Ts65Dn mice injected with a 2-week regiment of either of two compounds picrotoxin
Picrotoxin
Picrotoxin, also known as cocculin, is a poisonous crystalline plant compound, first isolated by Pierre Boullay in 1812. The name "picrotoxin" is a combination of the Greek words "picros" and "toxicon" ....
or bilobalide
Bilobalide
Bilobalide is a biologically active terpenic trilactone present in Ginkgo biloba.-Chemistry:Bilobalide is a main constituent of the terpenoids found in Ginkgo leaves. It also exists in minor amounts in the roots. It is a sesquiterpenoid, i.e. it has a 15-carbon skeleton...
(both GABA antagonists) showed marked improvements in both exploration and recognition of novel objects over controls injected with only saline. These results were duplicated in a second experiment with mice fed either plain milk or a combination of milk and a non-epileptogenic dose of PTZ daily for 17 days. PTZ-fed mice achieved novel object task scores comparable to wild-type (normal) mice. These improvements persisted at least 1 to 2 months after the treatment regiment. Not surprisingly these compounds' efficacies were accompanied by the normalization of Long-term potentiation
Long-term potentiation
In neuroscience, long-term potentiation is a long-lasting enhancement in signal transmission between two neurons that results from stimulating them synchronously. It is one of several phenomena underlying synaptic plasticity, the ability of chemical synapses to change their strength...
in the dentate gyrus
Dentate gyrus
The dentate gyrus is part of the hippocampal formation. It is thought to contribute to new memories as well as other functional roles. It is notable as being one of a select few brain structures currently known to have high rates of neurogenesis in adult rats, .The dentate gyrus cells receive...
one month after the end of treatment, further suggesting persistent drug-mediated improvements in learning and memory.
The finding of pentylenetetrazol's effectiveness in treating a mouse model of Down syndrome has led to it being explored as a means of correcting other learning deficiencies. Specifically, hamsters denied their natural circadian rhythm
Circadian rhythm
A circadian rhythm, popularly referred to as body clock, is an endogenously driven , roughly 24-hour cycle in biochemical, physiological, or behavioural processes. Circadian rhythms have been widely observed in plants, animals, fungi and cyanobacteria...
(though not denied sleep) had their memory restored to near-normal levels when treated with pentylenetetrazol.
Alternatives
In 1939, pentylenetetrazol was replaced by electroconvulsive therapyElectroconvulsive therapy
Electroconvulsive therapy , formerly known as electroshock, is a psychiatric treatment in which seizures are electrically induced in anesthetized patients for therapeutic effect. Its mode of action is unknown...
as the preferred method for inducing seizures in England's mental hospitals.