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Fear, Anxiety and Anguish |
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ANXIETY NEUROTRANSMITTERS |
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Because GABA is the primary inhibitory neurotransmitter in the brain,
it obviously plays an important role in controlling the neuronal
hyperactivity associated with anxiety.
Since GABA agonists can induce comas, the pharmaceutical industry
has had to turn to other ligands that enhance GABA’s
effects. Benzodiazepines such
as Valium and Librium, which act as modulators for GABAa
receptors, have become some of the best anxiolytics available.
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In just the
same way that, once scientists had characterized the receptors
for opiates in the brain, they also discovered natural endogenous
morphines that bind to them, researchers have now identified
molecules produced by the body that bind to exactly the same
site on the GABAa receptor as synthetic benzodiazepines. These
endogenous benzodiazepines, or endozepines, which seem
to be produced chiefly by the glial
cells, have been partially purified in the human brain.
The term “endozepines” designates both diazepam-binding
inhibitor (DBI) and the peptides derived from it, including
triakontatetraneuropeptide (TTN) and octadecaneuroepetide (ODN). |
Despite the potential importance of endozepines as endogenous
ligands for the benzodiazepine site on GABAa receptors, very little
research has been done on the role of these peptides. Endozepines
may of course achieve some of their effects by modulating GABAa
receptors, but other effects, such as the anorexigenic effect of
ODN, might involve a separate metabotropic
receptor.
DBI may be an inverse agonist for the benzodiazepine
site on the GABAa receptor. In other words, DBI may reduce
the receptor’s chloride permeability and hence GABA’s
effectiveness, and thus would be anxiogenic. In fact, DBI is
a disconcerting molecule for neurobiologists, who have shown
far less enthusiasm about endozepines than they have about enkephalins
and endorphins. Nevertheless, these endogenous benzodiazepines,
through their modulating effects on GABA, are thought to enable
it to play a more flexible role in neurophysiological processes.
It is also thought that disturbances in their activity may play
a role in chronic anxiety.
The molecules conventionally identified
as neurotransmitters are not the only ones that may have
an effect on anxiety. Neuropeptides such
as cholecystokinin (CCK) may also be anxiogenic; the release
of this molecule may be enhanced by serotonin and norepinephrine
in the cortico-limbic system. The use of cholecystokinin
antagonists as anxiolytics is therefore being considered.
Another peptide, CRH, is a powerful
anxiogenic whose release is stimulated by stress. Neuropeptide
Y has an anxiolytic effect almost as powerful as the benzodiazepines’.
It is believed that under normal conditions, CRH and neuropeptide
Y, through their opposing effects, constitute a system
that controls the integration of stress signals in the amygdala. |
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