Brain serotonin 2A receptor binding: Relations to body mass index, tobacco and alcohol use
Introduction
Serotonergic neurotransmission in the brain is involved in the inhibitory control of behavior. Evidence for this notion comes from different lines of research as reviewed below. Depletion of the monoamine neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) in animals consistently leads to an impulsive behavioral pattern with increased responding for conditioned reinforcers (Fletcher, 1996, Fletcher and Korth, 1999, Sills and Greenshaw, 1999) and manipulations that decrease brain 5-HT neurotransmission have been shown to elevate self-administration of food (Saller and Stricker, 1976, Waldbillig and Bartness, 1981) and alcohol (Lyness and Smith, 1992, Ciccocioppo, 1999, Ciccocioppo and Angeletti, 1999) as well as the attentional salience of tobacco smoking (Hitsman et al., 2007). On the other hand, manipulations that increase 5-HT levels (eg by administrating SSRI) inhibit intake of both food, alcohol, and nicotine in both animals and humans (Olausson and Engel, 2002, Halford and Harrold, 2005, Johnson, 2008).
Overweight and obesity are conditions defined as abnormal or excessive accumulation of fat that may impair health. According to the latest data from World Health Organization (WHO 2006), on a global scale approximately 1.6 billion adults are overweight, and at least 400 million of them are obese. Body mass index (BMI), defined as the weight in kilograms divided by the square of the height in meters (kg/m2), is used as a convenient measure for the nutrition state of an individual and is known to generally correlate well with other anthropometric measures such as waist circumference (Molarius and Seidell, 1998). BMI of more than 25 kg/m2 is defined as overweight, and a BMI over 30 kg/m2 as obese. Overweight is an important risk factor for developing a variety of disorders, including type-2 diabetes, cardio-vascular diseases, and certain types of cancer.
The involvement of 5-HT in the regulation of food intake and body weight is well established: Administration of agents that are either toxic to 5-HT neurons (e.g. 5,7-dihydroxytryptamine, 5,7-DHT) or prevent 5-HT synthesis (e.g. parachlorophenylanine, pCPA) increase food intake in rats with a subsequent increase in body weight (Saller and Stricker, 1976, Waldbillig and Bartness, 1981). Conversely, increased central 5-HT levels following administration of the 5-HT precursor 5-hydroxytryptophan (5-HTP) or of the 5-HT releasing agent fenfluramine significantly decrease food intake (Clineschmidt, 1973, Barrett and McSharry, 1975, Blundell and Leshem, 1975, Duhault and Boulanger, 1975). Both experimentally and clinically, administration of the 5-HT releasing agent fenfluramine, the selective serotonin reuptake inhibitor (SSRI) fluoxetine, the serotonin and norepinephrine reuptake inhibitor (SNRI) sibutramine, the 5-HT1B/2C agonist mCPP, and the 5-HT1B/1D agonist sumatriptan all lead to a reduced food intake and subsequent weight loss (Halford et al., 2005). In further support of a central role of serotonin in the regulation of food intake, selective activation of 5-HT1B, 5-HT2A and 5-HT2C receptors leads to hypophagia in various animal models (Dourish, 1995, Bickerdike and Vickers, 1999).
Different lines of evidence suggest that the 5-HT2A receptor has a specific role in the regulation of body weight. G/G carriers of the A(− 1438)G promoter polymorphism of the 5-HT2A receptor gene have increased body mass and predominantly abdominal distribution of body fat (Rosmond et al., 2002). Some studies argue that A carriers of the same polymorphism are at higher risk of developing anorexia nervosa but these results are more mixed (Ricca et al., 2002). In vivo imaging studies using Positron Emission Tomography (PET) and Single Photon Emission Computed Tomography (SPECT) have suggested that both anorexia nervosa patients and patients recovered from regular anorexia nervosa and bulimia-type anorexia nervosa display decreased cerebral 5-HT2A receptor binding (Kaye et al., 2005). Moreover, obesity-prone mice exposed to high-fat diet were found to have increased 5-HT2A/2C receptor density in comparison to obesity-resistant mice fed on the same diet (Huang et al., 2004). Finally, in a sample of 52 healthy, largely normal-weighted subjects, we have previously identified a positive correlation between BMI and 5-HT2A receptor binding in the left superior temporal cortex, left medial inferior temporal cortex, right dorsal lateral prefrontal cortex, and right sensory motor cortex (p < 0.0125) (Adams et al., 2004). We now investigated if this serendipitous observation could be replicated in a larger, independent sample including overweight and obese people.
The purpose of the present study was to test in healthy human subjects whether BMI, alcohol consumption, and tobacco smoking were associated with changes in the cerebral 5-HT2A receptor binding using 18F-altanserin-PET. We also explored possible associations between the 5-HT2A A(− 1438)G promoter polymorphism and BMI.
Section snippets
Participants and interviews
We included 136 adult human subjects (51 females, with a mean age of 40.5 ± 18.6 years, and a mean BMI of 25.2 ± 4.3 kg/m2) in the study. Fourteen of the subjects had BMI above 30 and were thus classified as obese.
Written informed consent was obtained according to the declaration of Helsinki II, and the study had been approved by the Copenhagen Ethics Committee ((KF) 02-058/99, (KF) 12-122/99, (KF) 12-113/00, (KF) 12-152/01, (KF) 01-001/02, (KF) 11-061/03, (KF) 12-142/03, (KF) 01-124/04, (KF)
MR/PET co-registration
PET and MR images were co-registered using a Matlab (Mathworks Inc., Natick, MA, USA) based program (Willendrup et al., 2004) where PET and MR images are brought to fit through manual translation and rotation of the PET image with subsequent visual inspection in three planes (Adams et al., 2004).
Volumes of interest (VOIs)
VOIs were automatically delineated on each individual's transaxial MRI slices in a strictly user-independent fashion (Svarer et al., 2005). With this approach, a template set of 10 MRIs is automatically
Results
The overweight individuals (BMI > 25 kg/m2, n = 57) did not differ from normal-weighted subjects (BMI ≤ 25 kg/m2, n = 79) in fP (0.040 ± 0.019 vs. 0.040 ± 0.017%, p = 0.88), injected cold dose of altanserin (0.09 ± 0.07 vs. 0.09 ± 0.07 nmol/kg bodyweight, p = 0.99), global SCL score (0.21 ± 0.22 vs. 0.19 ± 0.18, p = 0.57), or neuroticism score (70 ± 17 vs. 72 ± 20, p = 0.72). The overweight subjects were older (46.4 ± 18.6 vs. 35.8 ± 16.9 years, p = 0.001) and had a higher plasma content of metabolized fraction of the radiotracer
Discussion
We found a positive correlation between BMI and in vivo cerebral 5-HT2A receptor binding. We hereby replicate and extend the preliminary observation of a positive correlation between BMI and 5-HT2A receptor binding in some brain regions (Adams et al., 2004), also in an independent sample. The relationship between BMI and global brain 5-HT2A receptor binding was also confirmed in a voxel-based analysis.
Some possible sources of errors or confounds will be considered below. An obvious source of
Conclusion
We identified a positive correlation between cerebral cortex 5-HT2A receptor binding and BMI. Whether the 5-HT2A receptor has a direct role in the regulation of appetite and eating behavior or whether the finding is due to a compensatory upregulation of the receptor secondary to other dysfunction(s) in the serotonergic transmitter system, such as low baseline serotonin levels, remains to be resolved. We saw no association between past or current alcohol consumption or tobacco smoking and
Acknowledgments
The Danish Medical Research Council, H:S (Copenhagen Hospital Cooperation) Research Council, Copenhagen University Hospital, and The Lundbeck Foundation provided financial support for the study.
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