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Dopamine, GABA-alpha and other receptors
Part 3 of presentation Visualizing the alcohol-dependent brain
Presentation: Professor David Nutt, Imperial College, London, UK
Visualizing the alcohol-dependent brain
Professor David Nutt, Imperial College, London, UK
Reduced dopamine receptors in addiction
Many of you who have thought about addiction will have read work suggesting that dopamine is the central neurotransmitter underpinning addiction and that dopamine dysregulation occurs as a consequence of addiction.
Here are some of the data on which that hypothesis or theory has been developed. On the left-hand side here, you see images of dopamine receptors. The hotter the image, the more radioactivity in the brain at that point and in this case the more receptors. Here you have normal controls, here you have this is a cocaine user, this is a methamphetamine user and here is an alcohol user.
You can see there is less binding to dopamine receptors in those three addictions and here we have done a kind of meta-analysis of all the studies published using this technology and you can see seven studies of alcoholics showing a net reduction in the density of receptors by about 10%, similar reduction for cocaine users, for two studies about 8% reduction in methamphetamine users and really no significant reduction in nicotine users.
So it’s quite likely that reductions in dopamine receptor underpin aspects of addiction and possibly they relate to the failure of people to restrain their behaviour when they become cued or triggered by drugs and drug cues, so that’s an interesting approach.
Unfortunately it hasn’t led to any new treatments because whatever we do to the dopamine system, we don’t actually improve addiction.
Role of GABA-alpha receptor subtypes
Now the GABA system is slightly more complicated. What you see here are four images of different subtypes of the GABA receptor. There are six major subtypes but only four of them seem to be relevant to the sort of things we do with drugs like benzodiazepines or alcohol.
You can see that these subtypes are expressed in different parts of the brain and from animal studies we are able to generate quite credible theories as to what these receptors do.
For instance, this is the Alpha-1 subtype of receptor, it’s in the cortex and that’s where zolpidem works to put you to sleep and it’s also in the cerebellum and we think that the effects of alcohol to produce sedation and unsteadiness, ataxia, are mediated through activating those receptors either directly or indirectly.
The Alpha-2 and the Alpha-3 receptors have a very different distribution and they seem to have a role in the anxiolytic effect of drugs and possibly also some of the more relaxing pleasurable effects of drugs like alcohol.
And then the Alpha-5 receptors down at the bottom here, they are massively located in the hippocampus, at least in the rat.
We know from animal studies they are involved in memory function in the rat and we are now in the position to ask the question, are they involved in other things, in humans?
PET tracers for GABA-A receptors
Here you see two separate images from two different tracers. The tracer on the left, flumazenil binds to all four of the receptors. The tracer on the right, Ro15-4513 binds largely to the Alpha-5 subtype and you can see the Alpha-5 subtype has a very different distribution. There is none in visual cortex, there’s loads of these in visual cortex. It binds to the nucleus accumbens, to the anterior cingulate cortex and the hippocampus, so it binds to the areas of the brain where we think emotions and addictive behaviours emerge from.
The GABA-A receptor and alcohol
What’s GABA got to do with alcohol? Let me just briefly explain how the GABA receptor works. The receptor is a complex mixture of five proteins that come together like a bracelet to sit in the cell membrane and they have a hole in the middle and through that hole, chloride ions travel. When GABA, the natural transmitter which calms the brain, stimulates its receptor the hole in the middle gets bigger and that’s the calming effect of GABA.
When you take alcohol, it potentiates the effects of GABA so you get more inhibition which is why alcohol dampens down brain activity and puts people to sleep and also disinhibits people.
Over time, the receptors change. Because there are different subunits, the brain neurons can express different subtypes which have less effect of alcohol or GABA and so the process of tolerance is some kind of switch in the expression of those subunits.
Reduced GABA-A receptor number and benzodiazepine sensitivity in alcohol dependence
We can see that. Here’s an early study done by Anne Lingford-Hughes who is now working with me. This is a study she did quite a few years ago using a flumazenil-like tracer showing significant reductions in the density of these GABA receptors across the frontal cortex of the brain.
We were able to show subsequently that this reduction in these receptors seems to explain the cross-tolerance to midazolam, a benzodiazepine. This form of cross-tolerance is very well recognised by anaesthetists who often find it very difficult to sedate people with alcoholism because they are tolerant to any GABA acting drug.
[11C]-Ro15-4513 binding in the nucleus accumbens is reduced in alcohol dependence
More recently we’ve asked the question about the specific receptors in the nucleus accumbens, so here is a nice three-dimensional image of the brain showing this very high density of these receptors in the nucleus accumbens here.
You can see on the left-hand side of this slide that in alcoholics there is less of these receptors and these receptors will calm the brain down, so what we believe now is that the deficiency of these inhibitory receptors in the nucleus accumbens is maybe a significant contributory factor to loss of control of people with alcohol dependence. In fact we have shown the same thing, unpublished as yet, with heroin users so we think there may be a general problem of inhibitory control in the nucleus accumbens in addiction and for the first time using this tracer we can image it.