Blockade of alcohol's amnestic activity in humans by an alpha5 subtype benzodiazepine receptor inverse agonist.
Alcohol produces many subjective and objective effects in man including pleasure, sedation, anxiolysis, plus impaired eye movements and memory. In human volunteers we have used a newly available GABA-A/benzodiazepine receptor inverse agonist that is selective for the alpha5 subtype (a5IA) to evaluate the role of this subtype in mediating these effects of alcohol on the brain. After pre-treatment with a5IA, we found almost complete blockade of the marked impairment caused by alcohol (mean breath concentration 150mg/100ml) of word list learning and partial but non-significant reversal of subjective sedation without effects on other measures such as intoxication, liking, and slowing of eye movements. This action was not due to alterations in alcohol kinetics and so provides the first proof of concept that selectively decreasing GABA-A receptor function at a specific receptor subtype can offset some actions of alcohol in humans. It also supports growing evidence for a key role of the alpha5 subtype in memory. Inverse agonists at other GABA-A receptor subtypes may prove able to reverse other actions of alcohol, and so offer a new approach to understanding the actions of alcohol in the human brain and in the treatment of alcohol related disorders in humans.
Nutt
David J
DJ
Psychopharmacology Unit, Dorothy Hodgkin Building, University of Bristol, Whitson Street, Bristol, BS1 3NY, UK. david.j.nutt@bristol.ac.uk
Besson
Marie
M
Wilson
Susan J
SJ
Dawson
Gerard R
GR
Lingford-Hughes
Anne R
AR
D000328:Adult; D000345:Affinity Labels / Q000378:metabolism; D000438:Alcohols; D000647:Amnesia / Q000139:chemically induced* / Q000517:prevention & control*; D014151:Anti-Anxiety Agents / Q000627:therapeutic use*; D001386:Azides / Q000378:metabolism; D001569:Benzodiazepines / Q000819:agonists* / Q000378:metabolism; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D018755:GABA Agonists / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008954:Models, Biological; D009483:Neuropsychological Tests; D012720:Severity of Illness Index; D012890:Sleep / Q000187:drug effects; D013997:Time Factors; D014055:Tomography, Emission-Computed
D000345:Affinity Labels; D000438:Alcohols; D014151:Anti-Anxiety Agents; D001386:Azides; D018755:GABA Agonists; D001569:Benzodiazepines; C042957:Ro 15-4513