Most of us have at some point in our lives taken antihistamines–drugs that block the action of histamine (e.g., Claritin, Allegra)–to relieve allergy symptoms. And while histamine is best known for its role in the immune response, it also has many other important roles in the central nervous system.
In the brain, histamine release is important for arousal (this is why antihistamines tend to make us drowsy). It has also been implicated in regulating appetite, taste perception, learning, memory, aggressive behavior, motivation, and emotion, among others (Yoshizawa et al., 2009; see this quick summary).
Alterations in histamine signalling in the brain have been implicated in a variety of disorders, including schizophrenia (Iwabuchi et al., 2005), depression (Kano et al., 2004), and multiple sclerosis (Wikipedia has a nice summary chart; or you can read this open paper for more details, too).
Of particular interest to us here is the role of histamine in food and appetite control (see this open access review paper for a more detailed exploration). As summarized by Yoshizawa et al. (2009), it is been reported that
- increasing histamine decreases food intake (Brown, Stevens, & Hass, 2001; Masaki & Yoshimatsu, 2006)
- blocking histamine increases feeding behaviour (e.g., Orthen-Gambill and Salomon, 1992)
- histaminergic activity is increased by food intake after starvation (Oishi, Itoh, Nishibori & Saeki, 1987; Itoh, Oishi, & Saeki, 1991)
Essentially, there appears to be an inverse relationship between histamine activity and feeding: High histaminergic activity suppresses food intake whereas low histaminergic activity increased food intake. Histamine’s effect on feeding appears to be mediated through the histamine H1 receptor (more on receptors below).
There are also findings suggesting that the histamine system is more active in women than in men, particularly with regard to the histamine H1 receptor (e.g., Ghi, Orsetti, Gamalero, & Ferreti, 1999; Kasoako et al., 2005; Prell et al., 1991). In particular, previous studies have shown that women have higher densities of the H1 receptor.
Given these findings, the authors of the present study wanted to see whether the histaminergic system is perturbed in women with anorexia nervosa relative to women (and men) without AN using positron emission tomography (PET) scans, focusing specifically on the H1 receptor. The authors also hypothesized that perturbations in the histaminergic activity in AN patients would be related to the extent/severity of abnormal eating behaviours or negative emotions.
A QUICK BACKGROUND ON (HISTAMINE) NEUROTRANSMISSION
If you have some background in neurobiology, feel free to skip this section.
Neurons communicate with each other by releasing chemicals called neurotransmitters (e.g., histamine, serotonin, dopamine, etc.). These chemicals exert their action on other cells by binding to specific receptors on those cells (receptors are picky; they don’t just bind any molecule that comes their way, and they bind to some molecules more readily than others). This binding can have many effects on the cell. For example, it can make those cells more or less likely to participate in neuronal communication with other cells, or it can turn on/off genes in that cell (among other things). There are four histamine receptors, creatively called H1, H2, H3, and H4, which are involved in different pathways and activities (see this chart).
When scientists talk about changes in histaminergic activity in the brain (or serotonergic or dopaminergic, etc.), they could be talking about a variety of different things that affect the overall system. For example, changes in the density of histamine receptors on a cell membrane, changes in histamine metabolism, changes in how readily histamine will bind to its receptor, changes in how much or how often the histamine is released from a cell can all affect histaminergic activity. These changes can then affect our physiological and behavioural responses. In the case of histamine, for example, this could mean affecting the extent of allergy symptoms we experience.
To assess histaminergic activity in the brain, the authors used the [(11)C]doxepin radioligand. Radioligands are radioactively labeled drugs “that can associate with a receptor, transporter, enzyme, or any site of interest. Measuring the rate and extent of binding provides information on the number of binding sites, and their affinity and accessibility” (Source).
PET studies frequently measure something called the binding potential. The binding potential is a combined measure of receptor density (in this case, the density of H1 receptors that are able to bind to the radioligand) and the affinity of the radioligand for the receptor. In this study, the authors assessed the binding potential of [(11)C]doxepin to study the H1 receptor.
I don’t read PET studies often, so I don’t know if this is common practice, but I thought it was interesting that the authors also took into account the female subjects’ menstrual cycle: All PET scans were performed within a week after last menstruation.
The participants were 12 female patients with anorexia nervosa (restricting subtype), 12 healthy female volunteers, and 11 healthy male volunteers. The participants did not have a history of any other psychiatric illnesses. The average age of the participants was early 20s. AN patients had an average illness duration of 5.2 years (range: 3-9 years), and had an average BMI of 14.7 (versus 20.3-20.4 for the two control groups). Patients with AN had higher anxiety and depression scores compared to the controls.
SUMMARY OF MAIN FINDINGS
Confirming previous findings, the authors found that the binding potential of [(11)C]doxepin was higher in many brain regions in females than in males.
More interestingly, the binding potential of [(11)C]doxepin was higher in AN patients than in female controls in two regions: the left lenticular nucleus and the right amygdala; there were no regions where binding potential was lower in AN patients than controls.
Contrary to the researchers’ hypothesis, there were no positive correlations between the binding potential of [(11)C]doxepin and extent/severity of eating disorder behaviours, state and/or trait anxiety, and depression scores. In fact, there were several negative correlations. This means that the more severe the eating disorder behaviours, anxiety, or depression scores, the lower the binding potential (i.e., the more similar the binding potential is to female and male healthy controls).
WHAT DOES THIS MEAN?
As mentioned earlier, females have higher H1 receptor density than males. Interestingly, in rats, ovariectomy (surgical removal of the ovaries) decreases H1 receptor density and estradiol replacement reverses this decrease. In animals, food restriction increases histaminergic activity and reduces food intake. The authors suggest that maybe these differences play a role in increasing the vulnerability of women to develop AN:
Until now, CNS disturbances seen in AN were mainly considered to be secondary changes due to chronic starvation. However, in the present study, higher BP of [11C]doxepin in several brain areas was observed in normal female subjects. The risk of developing AN may be increased by not only the social background that women want to be thin because people tend to admire a thin figure but also biological vulnerability associated with central histaminergic activity.
It is an interesting thought, but for the time being, it is important to keep in mind that we really have no idea if and to what extent the differences in the histaminergic system play a role in the development of AN.
The higher binding potential in the lentiform nucleus (a region of the brain important for fine motor movement, among other things) and the amygdala (the so-called “fear center” of the brain) are also interesting. However, besides the fact that they have to be replicated by a different group, we don’t know whether this increased binding potential is the cause or result of AN; we also don’t know what it means.
The authors predicted the opposite effect based on findings in depressed subjects (who had lower binding potential). The authors put forth several possible explanations for this finding, but without knowing whether it is the cause or result of AN, and assessing only one time point (i.e., not studying the patients after they’ve recovered or at least restored their weight), it is impossible to really know what this means.
The authors mention several limitations to this study, including:
- a small sample size (I am sure this partly due to cost, PET studies are expensive to conduct),
- comparisons between many different brain regions (increasing risk for certain statistical errors),
- inability to rule out that the results are due to brain shrinkage in AN (I’m not sure why this couldn’t have been controlled for, though)
- and inability to tell whether the differences in binding potential are due to changes in receptor density or receptor affinity (remember, binding potential is a composite measure of both)
THE TAKE-HOME MESSAGE
As with a lot of things I blog about here with respect to neuroscience or genetics, the takeaway is usually: This is cool research, but we can’t really conclude much. The authors provide support for the idea that individuals with AN may have higher levels of the H1 receptor in several brain regions, but these findings need to be replicated. And if they are, we’d still need to do more research to know whether the changes we see between AN patients and healthy controls lead to or are the result of the eating disorder. The typical cause or effect problem.
The brain is complicated, eating disorders are complicated, and our ways of studying both are generally very subpar. This research is preliminary, as is our general understanding of the neurobiology of eating disorders. My goal is to illustrate how complicated the situation is, how hard to study, and how difficult to have a nicely wrapped “story.”
Also: I am not a PET researcher, so if you know more than I do and spot some mistakes in my post or would like to provide additional feedback or thoughts on the study, please do so! I would very much appreciate that.
Yoshizawa, M., Tashiro, M., Fukudo, S., Yanai, K., Utsumi, A., Kano, M., Karahasi, M., Endo, Y., Morisita, J., Sato, Y., Adachi, M., Itoh, M., & Hongo, M. (2009). Increased brain histamine H1 receptor binding in patients with anorexia nervosa. Biological Psychiatry, 65 (4), 329-335