Wednesday, July 26, 2006

Medicine: drunken mice and serotonin

From Nature Neuroscience:

We all know that consumption of alcohol can lead to changes in mood, cognition and motor behaviour, but how ethanol affects neuronal function is not so well understood. A new study shows that ethanol inhibits clearance of the neurotransmitter serotonin (5-HT) from the extracellular fluid in the mouse hippocampus, and that, surprisingly, this occurs through a mechanism that is independent of the serotonin transporter (5-HTT).
Beyond just being interesting for the exact cellular mechanisms of alcohol intoxication (which have amazingly eluded researchers for the most part), it's dually interesting that increasing serotonin concentrations with more alcohol produces a CNS depressive effect, which seems paradoxical in the light of SSRIs. Further in the the study, fluvoxamine was found to have similar effects acutely on the hippocampal serotonergic neurons. Of course, being an SSRI probably has nothing to do with being an antidepressant in the short run.

The serotonin transporter doesn't tell us the whole story, but does offer at least some clue as to part of the genetic basis of alcoholism, as the ability to clear 5HT (which attributes at least somewhat to intoxicating effects) gives a mechanism for subjective differences in experience. The study does not address changes in regulation of the 5HTT chronically with alcohol abuse, but we could speculate that, most importantly, there could be genetic differences predisposing some to more maladaptive physiology.

But the 5HT transporter isn't the whole story, as a hippocampal NE-T might contribute. Imagine that, no clean mechanisms.
This work clearly establishes that blocking the removal of 5-HT underlies, at least in part, the effects of ethanol in the brain. It remains to be determined exactly how ethanol inhibits 5-HT removal from the extracellular fluid. The noradrenaline transporter, which also transports serotonin and is expressed in the hippocampus, is one candidate site of action. However, more work will be required to confirm a role for this transporter in the influence of alcohol on neuronal function and behaviour. These findings could help to explain the positive association between a polymorphism in the promoter region of human 5-HTT, which confers low-expression of 5-HTT, and alcoholism.
With alcoholism, our primitive understanding has continued to limit our therapeutic approaches to a problem that, intuitively, an outsider would expect wouldn't be all that terribly difficult to hash out.

My undergrad research PI sent me the article, making me nostalgic for my invertebrate neurotransmitter research days. Sigh.

(Note: the other Sparks GM with the ophthy article from 1967 obviously isn't me)

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