Friday, October 8, 2010

Beyond Pagoclone, Part 2

This post discusses two additional drugs that may act to improve fluency.

Pregabalin, marketed by Pfizer under the trade name Lyrica, is claimed to be a more potent successor to gabapentin. Pregabalin increases GABA levels by enhancing GAD (glutamic acid decarboxylase) activity. GAD is an enzyme that converts the excitatory neurotransmitter glutamate into the inhibitory neurotransmitter GABA. By this action, pregabalin also decreases the level glutamate and, in addition, decreases the excitatory neurotransmitter norepinephrine.

Pregabalin's therapeutic effect appears after about a week of use and is similar in effectiveness to BZs, but it is claimed that pregabalin produces more consistent therapeutic effects for anxiety symptoms. In addition, unlike BZs, it appears that pregabalin is effective over the long term without the development of tolerance, does not disrupt sleep patterns, and leads to less severe cognitive and psychomotor impairment. Its lower potential for abuse and dependence makes it preferable over BZs.

In addition to binding sites for GABA and BZs, GABA receptors also contain binding sites for various neurosteroids, which are produced naturally in the brain. . The transfer of cholesterol into glial cells is involved in the synthesis of naturally occurring neurosteroids such as allopregnenolone and tetrahydrodeoxycorticosterone. These neurosteroids, much like BZs, enhance the activity of GABA

An excitatory neurotransmitter such as dopamine acts as a gas pedal to use an automotive analogy, while GABA acts as a brake pedal. The level of neurosteroids, which act as a brake fluid, control how strongly the brakes (i.e., GABA) are actually applied. So increasing certain neurosteroid levels will increase GABA function, thus reducing dopamine function. In effect, these neurosteroids bind to and modulate the behavior of neuronal GABA receptors.

Neurosteroid drugs such as ganaxolone, an analog of allopregnanolone, which is a positive modulator of GABA-A receptors, may have advantages over other GABA-A receptor modulators, notably BZs, in that tolerance does not appear to occur with extended use.

In a previous post, we discussed the dopamine overabundance hypothesis of stuttering, which assumes excessive dopaminergic activity either because of an overabundance of dopamine receptors in the motor neuron section of the brain or because of excessive amounts of the excitatory neurotransmitter dopamine in this brain region. But if neither of these conditions is present, the problem might be that there is insufficient GABAergic activity, which would inhibit the dopaminergic activity. This leads us to a GABA insufficiency hypothesis of stuttering. In view of the discussion regarding neurosteroids in this post, we can posit a third hypothesis of stuttering--namely the neurosteroid insufficiency hypothesis of stuttering. Insufficiency of certain neurosteroids may lead to a weak GABAergic response which, in turn, results in an overly active dopamine system.

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