89
6
ping with the binding site of the endogenous receptor agonist GABA (Bormann 2000).
They are therefore classified as allosteric modulators. Barbiturate derivatives are employed
in anaesthetics, as sedatives and in hypnosis. They have been used as anti- epileptic drugs.
Their disadvantages include the induction of dependence due to changes in the function
of inter-neuronal AMPA receptors in the ventral tegmentum of the brain. Other important problems are sedative side effects and especially the danger of accidental (or suicidal)
overdosing, which is essentially lethal. Marilyn Monroe allegedly was a victim of barbiturates. Barbiturates bind to an allosteric site on GABA channels in the second small intracellular loop. At low doses this increases the action of GABA. However, at higher dose the
channel opens even in the absence of GABA (Olsen 2015).
Benzodiazepines, the so-called tranquillizers, replaced barbiturates in the late 1960s of
the last century. They also enhance the activity of GABA. The first benzodiazepine synthesized was chlordiazepoxide produced by Roche under the trade name of Librium, and
later diazepam was introduced under the trade name of Valium. The East German Valium
equivalent was called Faustan.
A true GABA-agonist is muscimol. It binds to the same site as GABA and opens the
chloride channel. In this way, it activates the inhibitory centre of the CNS and increases
the serotonin concentration. It acts as a mild sedative and has psychoactivity. The prodrug
for muscimol is ibotenic acid, which is found in some forest fungi such as Amanita pantherina and Amanita muscaria. By decarboxylation of ibotenic acid, e.g. when the mushrooms are dried, muscimol is formed. Changes in visual perception (distortion of sizes
and shapes) and auditory hallucinations are observed after ingestion of dried Amanita
fungi. In more sensitive people or at higher doses, dissociative reactions and loss of the
ability to communicate are also common (Johnston 2014).
GABA-active plant products include sesquiterpenes, for instance, valerenic acid, a
constitute of the essential oil of valerian (Valeriana officinalis). Like synthetic barbiturates,
it is an allosteric positive modulator of GABA-gated channels (Luger et al. 2015). By contrast, the sesquiterpene anisatin, the polyacetylene cicutoxin and the monoterpene ketone
thujone are GABA channel blocker (Hold et al. 2000). Thujone, at high concentrations,
can induce epileptic convolutions. Antagonists of GABA signalling can be used as antidotes, e.g. for barbiturate poisoning. These include bicuculline and picrotoxin.
6.4 Glycine Receptor: Strychnine and Tutin
The glycine receptor (GlyR) is another important pentameric chloride channel in spinal
cord and brain stem neurons. It is involved in motor control and pain perception and
especially in fast inhibitory neurotransmission. Most prominently, it mediates a fast feedback inhibition in motoneurons during activation of muscle contraction (. Fig. 6.2).
Strychnine, produced by bark and seeds of Strychnos nux-vomica, and tutin from plants of
the Coriaria genus both act as antagonists for glycine and block the feedback inhibition of
motoneurons, leading to spastic muscle contractions and convulsions. Eventually, cramping of respiratory muscles can cause death. Thirty to 120 mg of strychnine are deadly to
humans. Tetanus toxin works in the same pathway. It blocks SNARE-degradation at these
inhibitory synapses and thus inhibits the release of glycine (and GABA) with similar
effects on muscle contraction as strychnine. Strychnine, however, in addition to GlyR,
binds NAcR and 5HT 3 -ion channels and has little specificity but high affinity for these
receptors (Brams et al. 2011).
6.4 · Glycine Receptor: Strychnine and Tutin
6
ping with the binding site of the endogenous receptor agonist GABA (Bormann 2000).
They are therefore classified as allosteric modulators. Barbiturate derivatives are employed
in anaesthetics, as sedatives and in hypnosis. They have been used as anti- epileptic drugs.
Their disadvantages include the induction of dependence due to changes in the function
of inter-neuronal AMPA receptors in the ventral tegmentum of the brain. Other important problems are sedative side effects and especially the danger of accidental (or suicidal)
overdosing, which is essentially lethal. Marilyn Monroe allegedly was a victim of barbiturates. Barbiturates bind to an allosteric site on GABA channels in the second small intracellular loop. At low doses this increases the action of GABA. However, at higher dose the
channel opens even in the absence of GABA (Olsen 2015).
Benzodiazepines, the so-called tranquillizers, replaced barbiturates in the late 1960s of
the last century. They also enhance the activity of GABA. The first benzodiazepine synthesized was chlordiazepoxide produced by Roche under the trade name of Librium, and
later diazepam was introduced under the trade name of Valium. The East German Valium
equivalent was called Faustan.
A true GABA-agonist is muscimol. It binds to the same site as GABA and opens the
chloride channel. In this way, it activates the inhibitory centre of the CNS and increases
the serotonin concentration. It acts as a mild sedative and has psychoactivity. The prodrug
for muscimol is ibotenic acid, which is found in some forest fungi such as Amanita pantherina and Amanita muscaria. By decarboxylation of ibotenic acid, e.g. when the mushrooms are dried, muscimol is formed. Changes in visual perception (distortion of sizes
and shapes) and auditory hallucinations are observed after ingestion of dried Amanita
fungi. In more sensitive people or at higher doses, dissociative reactions and loss of the
ability to communicate are also common (Johnston 2014).
GABA-active plant products include sesquiterpenes, for instance, valerenic acid, a
constitute of the essential oil of valerian (Valeriana officinalis). Like synthetic barbiturates,
it is an allosteric positive modulator of GABA-gated channels (Luger et al. 2015). By contrast, the sesquiterpene anisatin, the polyacetylene cicutoxin and the monoterpene ketone
thujone are GABA channel blocker (Hold et al. 2000). Thujone, at high concentrations,
can induce epileptic convolutions. Antagonists of GABA signalling can be used as antidotes, e.g. for barbiturate poisoning. These include bicuculline and picrotoxin.
6.4 Glycine Receptor: Strychnine and Tutin
The glycine receptor (GlyR) is another important pentameric chloride channel in spinal
cord and brain stem neurons. It is involved in motor control and pain perception and
especially in fast inhibitory neurotransmission. Most prominently, it mediates a fast feedback inhibition in motoneurons during activation of muscle contraction (. Fig. 6.2).
Strychnine, produced by bark and seeds of Strychnos nux-vomica, and tutin from plants of
the Coriaria genus both act as antagonists for glycine and block the feedback inhibition of
motoneurons, leading to spastic muscle contractions and convulsions. Eventually, cramping of respiratory muscles can cause death. Thirty to 120 mg of strychnine are deadly to
humans. Tetanus toxin works in the same pathway. It blocks SNARE-degradation at these
inhibitory synapses and thus inhibits the release of glycine (and GABA) with similar
effects on muscle contraction as strychnine. Strychnine, however, in addition to GlyR,
binds NAcR and 5HT 3 -ion channels and has little specificity but high affinity for these
receptors (Brams et al. 2011).
6.4 · Glycine Receptor: Strychnine and Tutin