Neurological Correlates

“Alcohol is the source of, and answer to, all life’s problems” Homer Simpson

What’s up with alcoholic relapse?

Blocking brain receptors related to stress is showing promise in both reducing craving, as well as inducing a protective factor against relapse: happiness.

Blocking stress is a promising path, but a thorny one: you don’t want to substitute one addiction for another. So, lately, a stress-related circuit involving the neurokinin 1 receptor is being studied. In abstinent alcoholics, blocking the NK1 receptor reduced alcohol craving. And, (and this is what I think is interesting) — it allowed abstinent alcoholics to feel happiness.

From “Triggering Addiction,” by Markus Heilig, in: The Scientist, December 2008:

.. . Over the course of many years, following regular periods of binge drinking, a person’s relationship to alcohol will change as they move into a state of alcohol dependence. Rather than seeking alcohol for the experience of pleasure or reward, a person begins to seek alcohol as a relief from stressors, and stays intoxicated over protracted periods. It is at this point in the process that we begin to see long-term changes in the brain, and the person meets the criteria for alcoholism. . . .

This suggests that long term neuro-adaptations occur in the alcohol-addicted brain which provide a very different motivation for relapse than the pleasure-seeking response of those who have that genetic susceptibility. In the absence of alcohol, the individual will now find himself in a negative emotional state, which in the short term can be relieved by renewed intake of alcohol. The big question is what underlying biology is driving this shift into what George Koob has labeled “the dark side of addiction.”

So here’s the study: abstinent alcoholics were given a substance that blocks the neurokinin 1 receptor, or a placebo. Those on drug were substantially less tempted to relapse (given the triggering social stimulus).

That’s good news. But, it gets better: those on drug responded to pleasant pictures with pleasure.  Abstintent alcoholics given placebo did not show the “reward circuit” lighting up with pleasant pictures, illustrating the inability to feel pleasure.

Interestingly, this is consistent with a previous study reporting lower relapse rates for abstinent alcoholics who naturally feel happiness at pleasant stimuli. In essence, it looks like blocking stress releases a protective factor against relapse – happiness.

When was the last time any abstinent alcoholic you know actually displayed pleasure when they weren’t faking? All of the abstinent alcoholics in my orbit are, when without an audience, predominantly incapable of being happy except upon contemplation of a third party impending demise.  If anything, a happy pill for abstinent alcoholics would treat my anxiety about being around them.

Here’s the  brain scan of abstinent alcoholics on drug or placebo

From D.T. George et al., “Neurokinin 1 receptor antagonism as a possible therapy for alcoholism,” Science, 319:1536-9, 2008

Notice the putamen (lower right image): it lights up on drug — but not placebo –  with happy images.

Are the putamen NK1 receptors (or, maybe Substance P) the problem with the absence of happiness? Blocking NK1 receptors not only dialed down the negative responses but dialed up the positive ones. Now, in the absence of alcohol, there is not only fear and loathing — there can be happiness and joy.

Although normal social drinkers are motivated by brain reward-circuits, alcoholic relapse is largely due to stress.  Here are the brain scans of alcoholics who crave a drink (from ifferential Brain Activity in Alcoholics and Social Drinkers to Alcohol Cues: Relationship to Craving, Hugh Myrick, Raymond F Anton, Xingbao Li, Scott Henderson, David Drobes, Konstantin Voronin and Mark S George, Neuropsychopharmacology 29: 393–402 (2004)):

NIAAA collects data on  psychiatric comorbidities among current and former alcoholics, as well as lifelong abstainers. Here are some stats that caught my eye:

Relapse to relieve stress makes sense to me. People under stress are humorless and gruff, with hair-trigger out-of-proportion responses. Sound familiar?  “Dry drunk” traits consist of:

• Exaggerated self-importance and pomposity
• Grandiose behavior
• A rigid, judgmental outlook
• Impatience
• Childish behavior
• Irresponsible behavior
• Irrational rationalization
• Projection
• Overreaction

(For Backgrounders, See this NIAAA review for stress and alcoholism. For a Ph.D. dissertation, see “Alcohol, Alcoholism, and the Neural Correlates of Emotion,” by JM Gilman (submitted for a Ph.D. at Brown University) (the link goes to the incomplete cached version).  Here’s a recent brain scan study of alcoholic emotional responses to images with and without alcohol cues; alcohol cues modulate negative responses .

So, should everyone take an NK1 receptor antagonist to get happy?

The putamen (which lights up on drug with happy pictures, see above) is relatively packed with NK1 receptors. Moreover, it is packed with the kind of NK1 receptors that cause stress. NK1 receptors come in a full-length version, and then shorter forms.  Substance P , the neuropeptide suspected of binding to NK1 receptor and causing stress, binds and activates the full length version (having an  extra 96 amino acids at the C-terminus).The putamen has the long form  (at least as detected by its RNA transcripts, here).   (Probably the NK1 receptor “short form” (lacking the c-terminal 96 extra amino acids) has different activities, which is an interesting strategy for a really small peptide — Substance P is 11 amino acids long. If a short peptide with a variety of activities binds to receptors of all different forms, it relies on the different receptor forms to differentiate the biological activitiy. In contrast, where there is only one very specific biological activity, there is sometimes only one specific receptor and  a  big huge protein with a specific shape and charge. I’d put Factor VIII in that category, and maybe some of the other blood proteins. Most are in the middle somewhere.) No wonder the putamen lights up when the NK1 receptors are blocked.  Neurotransmitters relating to “reward” or satisfaction are released (see here and here).

Substance P, its blocking molecules, and various tachykinin (NK1) receptor antagonists, agonists and the rest come and go, largely because Substance P biological activity needs more study before a therapeutic drug discovery program really makes sense. Here’s a great summary from a few years ago on the state of Substance P-based meds. The NK1 receptor antagonist used in the George et al. study is a Lilly compound described in USP 7179804. (Lilly had some problems using homeless alcoholics in their clinical trials, let’s hope that’s cleaned up). Useful information: Pfizer has maropitant in its vet-med division, and  dogs taking maropitant, a selective neurokinin 1 receptor antagonist,  don’t get car sick.

Regardless of whether NK1 receptor antagonists are “druggable” for a label indication for preventing alcoholic relapse, the study demonstrates that cutting anxiety and upping happiness go a long way toward treating chronic addiction.

So, would abstinent alcoholics actually be motivated to take a pill which reduces cravings and increases happiness? Or do they like being in pain?

Homer Simpson points out that drinking is the source of, and answer to, all life’s problems. President Bush explains, “I’m a faith-based guy. . . Sometimes, to help change a person’s behavior, you have to change their heart. Government’s not really good at that.”

Maybe both Homer Simpson and George W. Bush are correct: alcohol is the source of and the answer to all life’s problems, and to be free of this repetitive loop, you need a change of heart – with an NK1 receptor antagonist.