What about humans?
The most obvious question to be answered relates to human behaviors: What role might the SP-NK1R system play in alcohol(Drug information on alcohol) dependency in people? You cannot perform knockout experiments in humans, but there are other ways of assessing NK1R’s role in people. There is an NK1R antagonist that functions as if it were dropped from research heaven, and it goes by the tongue-twisting name of LY686017. This antagonist is brain-penetrant, well tolerated, orally available, and, most fortunate of all, displays a high affinity for human NK1R. Several of these antagonists have been developed, including GR205171.
Since the experimental question really revolved around stress and alcoholism, it was important to establish the effects of these antagonists on stress responses in typical human populations. Sure enough, administration of GR205171 was shown to reduce social anxiety. It also inhibited measurable brain responses to social stressors, as measured by the Trier Social Stress Test (TSST).
But what about the effects in patients with alcohol dependency, especially in those with high-stress backgrounds? A group of researchers from academic and industry-related laboratories decided to find out. Enrollees in the experimental group (n = 25) had to have 3 measurable traits. First, they must have received a formal diagnosis of alcoholism and to have presented with alcohol-related problems as the primary complaint. Second, they had to score above 39 on the Spielberger Trait Anxiety Inventory, a measure that reliably detects the overt presence of anxiety and stress. Third, they had to have ingested alcohol within the past 30 days. All patients were hospitalized throughout the study; some were treated with withdrawal therapies if needed before experimental administration.
Using a combination of behavioral tests in the presence of the antagonists and even a little brain imaging, the researchers hit pay dirt. First, patients who had received LY686017 showed remarkably suppressed alcohol cravings. This was measured by the Alcohol Urge Questionnaire, which was given to each patient, and by the Clinical Global Impression Scale, a weekly inventory that was given to an impartial observer and shown to be a reliable indicator of patient behavior. As expected, the cravings declined over time.
Second, the researchers subjected the patients to a simulated real-life challenge using cues associated with high-relapse probabilities. The investigators used the TSST and an alcohol-cue challenge protocol. Patients who were treated with LY686017 showed reduced craving response, even in these more robustly tempting real-world situations, which was consistent with the results of the previous inventories. Treated patients also showed an inhibited cortisol response to the challenge compared with controls. Clearly, LY686017 had an effect in these higher-risk situations. It also had effects on stress.
Third, these patients were also assessed using functional MRI during craving experiences. The idea was to allow researchers to evaluate what was occurring in the brains of the treated patients—particularly within the insula—following a presentation of negative and positive emotional stimuli. This was done by visually presenting the patient with pictures
in the International Affective Picture System (a standardized visual cue presentation), mixed with pictures of nonalcoholic and alcohol-related beverages, during imaging.
Once again, positive results were obtained in the LY686017-treated patients. They exhibited much less activation to the negative images in brain regions associated with emotional responses to visual stimuli (such as ventral putamen, caudate nucleus, and several temporal areas). The most dramatic difference occurred in the activation of the insula, however. Treated groups showed markedly suppressed blood-oxygen-level–dependent signals compared with controls. Given the role the insula plays in addictive behaviors, this is an intriguing finding. Curiously, the group also demonstrated greater brain activation to the positive images in these same experiments.
Something interesting was clearly happening in patients whose NK1R responses had been blocked. In a word, at least in the short-term, they were getting better.
There are great reasons to be excited about these data. For the first time, the manipulation of a ligand-receptor system that is involved in mediating rewarding behaviors and stress has been shown to greatly reduce cravings for alcohol. These data were demonstrated in the most important and arguably toughest populations—stressed persons in the throes of alcohol addiction.
Among other things, the results suggest powerful new directions in the manufacture of medications that are capable of ameliorating the consumptive aspects of alcohol dependencies. Neural processes involved in behavioral stress might make terrific targets for pharmacological-based interventions and address the issue near its behavioral headwaters—alcoholic cravings.
There are, of course, cautions to be made in the interpretation of these data, including some potential genetic confounders. Some people are born with genetic backgrounds that make them potentially more sensitive to stress. There are also people born with predilections toward addictions of many kinds, including alcoholism. How these genetic backgrounds are related to each other and what that relationship has to do with the NK1R-blocking studies is not known. Indeed, alcohol dependence itself can certainly produce stress, but if you are more stress-sensitive, does that add an additional variable to these data?
The typical nature/nurture and chicken-and-egg issues need to be addressed in future experiments. Stratifying individuals as to the types of stress they experience and doing so with larger trials throughout will be required to definitively establish the relationship between NK1R, stress, and alcohol dependency.
These cautions do nothing to dampen the power of the findings or the enthusiasm for future experiments. The data illuminate the powerful role continued research with animals has in the study of behavioral issues of importance to mental health professionals who are interested in human motivations. Because of the mice data, there are now clear links between gene, cell, and behavior in this otherwise murky world of alcoholic relapse and stress in humans. Such robust findings are relatively rare in the never-ending quest to characterize the distance between genes and behaviors. Whatever else the data present, you have to admit that these tiny little mammals make quite a flashlight.