In article <7hvq5d$7fu at sjx-ixn9.ix.netcom.com> F. Frank LeFever,
flefever at ix.netcom.com writes:
>I think the most likely explanation for the reports of sedation due to
>oral GABA, and one which should never be underestimated, is "placebo
>effect"; perhaps acting synergistically with selective recall,
>selective reporting, etc.
I agree with this. GABA doesn't cross membranes per se, although it can
be actively transported by a variety of carriers, or leak through
epithelial junctions or through certain osmoregulatory anion channels.
But that's all beside the point. The fact is that GABA uptake in the
brain is so powerful that if you bath apply 1 mM GABA (a lot more than
you would expect from an oral dose) onto the surface of a hippocampal
slice (in which issues of access to the tissue are unimportant), you
evoke very little GABA response in the neurons because most of it gets
taken up before it can do anything. On the other hand, if you perform the
same experiment with muscimol (a GABA-A receptor agonist that is not a
substrate of the GABA transporters), or use GABA in the presence of
uptake blockers, you get a humungous response. The tissue is therefore
responsive, but it has built-in mechanisms for making sure that GABA has
only very local effects right around the synapses where it is released.
So I find it dubious that there would be a direct sedative effect of
taking GABA orally, for the very reasons mentioned in the original post.
Having said that, there are drugs (benzodiazepines, barbiturates) that
can be taken orally, cross the BBB, get to the brain, and strongly
potentiate GABAergic transmission to cause sedation or anesthesia. These
drugs aren't GABA agonists, but rather are "positive allosteric
modulators" of the GABA-A receptor. Also, there are specially designed
GABA-A receptor agonists (e.g. THIP, paper by Cheng and Brunner about ten
years ago I think) that do cross the BBB, and have been used to induce
clinical anesthesia in humans by intravenous injection.