Posted by Shawn. T. on April 18, 2003, at 0:04:59
In reply to Re: Please help with my list of promising future drugs, posted by bretbe on April 17, 2003, at 0:26:19
I looked more deeply into the relationship between Lamictal and GABA. One report has found that Lamictal increases cerebral GABA levels by 25% after four weeks (see http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11839834&dopt=Abstract ). Another has found no change in plasma GABA levels with Lamictal (see http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12691776&dopt=Abstract ). However, two other reports have found that Lamictal decreases GABA- mediated synaptic transmission (see http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11955522&dopt=Abstract ).
I think it's difficult to judge exactly how Lamictal affects GABA- mediated effects in the brain after chronic treatment. I hesitate to suggest that Lamictal is an anti-GABAergic drug; that just doesn't fit well with the profile of an anticonvulsant. The relationship between Lamictal and GABA is definitely complex, so making a sure judgment is difficult. On the other hand, Lamictal's actions on glutamate release are well understood and accepted. Drugs that block the effects of glutamate at NMDA and perhaps other types of glutamate receptors are known to cause hyperactivity. I think the connections among Lamictal, decreased glutamate release, and activation are rather clear; conclusions involving GABA are not.
There is a possible link between GABA and depression in some subtypes of depression (see http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11253954&dopt=Abstract). I did find one report of a connection between recurrent unipolar depression and a variation of the GABA-A receptor alpha 5 subunit gene. I'm really not that familiar with the relationship between depression and GABA, so I can't really give you a good overview of the topic. I can say that your intuition is probably correct.
Valproic acid likely increases GABAergic transmission by reducing the expression of GAT-1 and GAT-3 GABA transporter proteins; it's currently unknown how the drug causes this effect. That means that valproic acid might reduce the reuptake of GABA into neuron terminals, but no one knows if this occurs in humans at normal doses. I'm personally really interested in how valproic acid works in bipolar disorder; I doubt that its GABAergic effects play much of a role.
Shawn
poster:Shawn. T.
thread:219077
URL: http://www.dr-bob.org/babble/20030417/msgs/220276.html