THE BRAIN FROM TOP TO BOTTOM

TOPIC:		EMOTIONS
Sub-Topic:		FEAR, ANXIETY AND ANGUISH
Level:		MOLECULAR, ADVANCED

Fear, Anxiety and Anguish

There are many neurotransmitter systems that can influence anxiety. In addition to GABA, serotonin is often cited for its high levels in certain parts of the brain associated with anxiety. Serotonin is also known for its role in obsessive-compulsive disorder and depression, both of which are closely related to anxiety. And the fact that serotonin-reuptake-inhibiting antidepressants have an effect on these conditions shows that serotonin probably plays a role in them.

The same thing goes for norepinephrine in the locus ceruleus, where excess production of this neurotransmitter is often associated with panic attacks, an acute form of anguish.

ANXIETY NEUROTRANSMITTERS

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.

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.

GABA RECEPTORS

GABA (gamma-aminobutyric acid) exerts its effects through at least three different types of receptors: the GABA-A receptor (which is the best known), and the GABA-B and GABA-C receptors.
The GABA-A and C receptors are ionotropic, while the GABA-B receptor is a metabotropic receptor that modulates the opening of potassium channels through second messengers involving a G-protein.

Each of these receptors is a macromolecular complex comprising several sub-units. For example, the GABA-A receptor is composed of 5 sub-units surrounding a channel that is preferentially permeable to chloride ions and to a lesser extent to bromide ions. The GABA receptor site appears to be located in the large extracellular domain of the beta sub-unit. These 5 sub-units have 16 known isoforms, each produced by a different gene.

In addition to the primary binding sites for GABA, the GABA-A receptor has other secondary binding sites for molecules that modulate GABA’s effects, such as benzodiazepines, barbiturates, convulsants, steroids, and alcohol.

These modulating agents alter GABA’s efficiency by inducing a change in the protein architecture of the GABA-A complex. This change modifies the size of the channel, which in turn modifies the receiving neuron’s permeability to chloride ions. Since chloride ions are negatively charged, when they enter the neuron, they hyperpolarize it.

The result is an inhibition of neuronal activity and a general anxiolytic effect.Treatment with benzodiazepines thus helps to reduce anxiety by potentiating the effect of GABA, and more specifically, by making the chloride channel open more frequently. However, in the absence of GABA at the primary site on the GABA-A receptor, the modulating molecules have no effect on the neuron’s chloride permeability.