The Doctor Weighs In

By Dov Michaeli MD, Ph.D

Alcoholism is a major public health problem. This we all know. But did you know that as alcoholism evolves, stress systems in the brain play an increasing role in motivating continued alcohol use and relapse. In other words, someone who is a moderate drinker will drink more if subjected to stress. And that, in turn would increase her sensitivity to stress, which would result in yet an additional increase in alcohol consumption, which in turn… you get the picture.

The stress response

Deficiency of a stress response is life threatening. For instance, in response to stress blood pressure goes up, heart rate increases and more blood is pumped into the brain and skeletal muscles. On the other hand, less blood is pumped into the GI tract or the kidneys. What’s the physiological rationale? Just imagine you are about to be mugged by a gun totting robber—a common American stress. You would like to assess the risk and think of an appropriate response, and then run as fast as you can to save your life, or stand your ground and fight, and maybe die a hero. Or if you are philosophically inclined, you might muse about the second amendment and its role in your predicament. All these considerations go through your mind at lightning speed, which requires blood supply and the energy (oxygen and glucose) that it provides. Either way, the last thing your body needs during this emergency is to waste precious blood supply and energy on digesting your last meal, or making urine.

The usual suspect for hormonal response to stress is the stress hormone cortisol. This hormone is released into the circulation after a rise in the level of another brain hormone called Corticotrophin Releasing Hormone (CRH). And rise in cortisol level in the blood will cause all the effects we have described.

The stress of alcoholism

Since the demonstration that alcoholism can result from repeated bouts of stress and drinking, several experimental drugs were tested to see if one could break the vicious cycle by inhibiting release of CRH. Alas, not much success.

Apparently, the CRH/cortisol system is not the only one alerting our body that it is subjected to stress and causing it to physiologically adapt quickly. Another brain hormone system, substance P (SP) and its receptor neurokinin 1 receptor (NK1R) is highly expressed in brain areas involved in stress responses and drug reward, including the hypothalamus, amygdala, and nucleus accumbens. In rodents, psychological stressors induce release of SP in the amygdala, whereas genetic deletion or pharmacological blockade of NK1R inhibits the associated behavioral responses. Interestingly, SP is also involved in the transmission of pain from the peripheral nervous system to the brain. And the expression of SP/NK1R system is especially high in the vomiting center in the brain stem. Food for thought.

In a paper published in the latest Science issue ( March 14, 2008 ) a group of scientists from the National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health , tested the hypothesis that the NK1/NK1R system is largely responsible stress-induced alcoholism. They went about it in two ways. First, they “knocked out” (inactivated) the gene that codes for NK1R in mice, so in effect they created mice that lack this system of stress response. They then subjected wild type (normal) mice and mice deficient in NK1R to escalating concentrations of alcohol, starting at 3% and ending with 15% over 60 days. Lo and behold, they created what amounts to holier than thou mice: the wild type mice consumed an average of 10g/kg body weight, whereas the “knocked out” mice consumed only 6g/kg. They also showed an increased sensitivity to the sedative effects of alcohol. In other words, they drank little, and they couldn’t “hold their liquor” very well. Party poopers.

What about us, humans?

In a randomized controlled experimental study, recently detoxified alcoholic inpatients were treated with an NK1R antagonist (LY686017; n = 25) or placebo (n = 25). LY686017 suppressed spontaneous alcohol cravings, improved overall well-being, blunted cravings induced by a challenge procedure, and attenuated concomitant cortisol responses. Brain functional magnetic resonance imaging responses to affective stimuli likewise suggested beneficial LY686017 effects.

Small population, so it’s too early to pop the champagne. But the results are truly impressive, and as the authors state with typical scholarly restraint: “Thus, as assessed by these surrogate markers of efficacy, NK1R antagonism warrants further investigation as a treatment in alcoholism”.

Judging from results of treatments of other psychiatric conditions, a combination of drug and behavioral therapy is likely to prove more effective than drug alone. So, no—we are not likely to see AA go out of business any time soon. But the ready availability of effective drugs may make the excuse of scoundrels who “check in for rehabilitation” a lot less believable.