October 2008

Several months ago, I commented on a study that showed that there was an increased incidence of depression in patients taking a drug used to treat nicotine addition.  The study concluded that because nicotine and the endogenous neurotransmitter, acetylcholine, act to stimulate the brain’s own reward circuitry drugs which block this pathway would reduce the level of reward experienced by the subject during their normal life experiences.  Dopamine is an important neurotransmitter in the reward pathway and many activities that we enjoy activate this dopamine pathway.  One of these pleasurable and rewarding activities is eating. 


A recent study (http://www.sciencemag.org/cgi/content/full/322/5900/449) has further substantiated the role of dopamine in endogenous reward pathways and the results of this study suggest that deficiencies in the reward pathway might contribute to obesity.   The investigators used functional magnetic resonance imaging (fMRI) to measure blood flow in specific brain regions of human subjects.  Increases in blood flow indicate an increase in nerve activity in that area of the brain.  This study focused on the dorsal striatum which is a component of the endogenous reward pathway.  Dopamine is an important neurotransmitter in the dorsal striatum and dopamine stimulates D2 type dopamine receptors in this brain area.  The authors studied two groups of female subjects.  The first was a group of female college students while the second group was composed of adolescent females; the authors obtained genetic information about most of the women in the second group.  Body mass index (BMI) was calculated for all subjects in both groups. 


Subjects were shown pictures of a chocolate milkshake and then they were given a chocolate milkshake to drink.   During exposure to these stimuli fMRI scans of the ventral striatum were obtained.  The authors found that there was a negative correlation between BMI and activity in the ventral striatum when the subjects consumed the chocolate milkshake.  The authors interpreted these data to mean that the heavier subjects experienced less reward from consuming the chocolate milkshake compared to leaner subjects.  What was very interesting was that the subjects that experienced the least activation of the ventral striatum had a genetic polymorphism associated with low D2 receptor expression. 


Previous twin studies have shown that there is a genetic link for obesity.  This study suggests that at least in some subjects, reduced D2 dopamine receptor activity in the reward pathway may be associated with reduced levels of eating induced reward.  This would lead these individuals to consume more food in order to achieve some level of reward and this would predispose these subject to overeating.  Perhaps drugs which can activate the endogenous reward pathway, particularly the ventral striatum, might be useful in enhancing the reward associated with food intake and this might limit the size of meal needed to experience reward and therefore discourage overeating.    

The irritable bowel syndrome (IBS) is a common disorder that affects more than 60 million Americans (http://www.nlm.nih.gov/medlineplus/irritablebowelsyndrome.html). IBS is about twice as common in women compared to men. IBS is a gastrointestinal disorder in which patients experience chronic disruptions in bowel habit (diarrhea, constipation or both diarrhea and constipation) and abdominal pain. Psychological stress worsens these symptoms. The causes of IBS are not clear but it is likely that it is a multifactorial disorder involving changes in neural and hormonal signaling, local changes in the gut wall leading to inflammation and psychosocial factors.

There is good scientific evidence that the neurotransmitter/hormone, serotonin (aka 5-hydroxytryptamine, 5-HT) is a major player in causing IBS symptoms. This conclusion is based in part on the known effectiveness against IBS symptoms of some drugs which either block or stimulate serotonin receptors. However, serotonergic drugs have also caused adverse consequences for a small percentage of patients receiving these medications resulting in voluntary withdrawal of the drugs from the market by the manufacturers. This situation has left IBS patients wanting for effective drug treatments of their symptoms.

The gastrointestinal tract is home to a native population of bacteria which are an important contributor to normal gastrointestinal health and function. However, disruption in the balance of different types of bacteria or the total number of bacteria in the gut can cause gastrointestinal upset including, bloating, discomfort and altered motor function leading to constipation or diarrhea. These are all symptoms of IBS. A number of investigators have proposed that IBS symptoms, in a subset of patients, are caused by a disruption in the normal bacterial population in the gut. The results of a study reported at a recent meeting of the American College of Gastroenterology (http://www.gi.org/) support this conclusion (http://www.bloomberg.com/apps/news?pid=newsarchive&sid=a57cw8_0CHaA). In this study, IBS patients with diarrhea as their most prominent symptom received the antibiotic, rifaximin (http://www.forbes.com/feeds/ap/2008/10/06/ap5513260.html). Just over 50% of the patients receiving the drug reported that they experienced “adequate relief” from their symptoms. Interestingly, about 40% of the patients receiving placebo (a drug free pill) also reported adequate relief of symptoms. This study highlights two important points. Firstly, the effectiveness of the antibiotic suggests that disturbances in the normal bacterial population of the gut can contribute to IBS symptoms in a subset of patients. Secondly, the large placebo effect observed in this study is typical of clinical drug trials targeting IBS. The high placebo response raises the bar for a new drug when its effects are compared to those observed in the placebo-treated group. In the end, the results of this study provide some hope that new drug treatments will be available for IBS patients. However, additional research on the causes of IBS is needed in order to develop new safe and effective IBS drugs.

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