Dysregulation of brain reward systems in obesity: measuring endogenous dopamine levels by acute dopamine depletion

Obesity (BMI >= 30 kg/m2) is a growing problem in the Netherlands because of
its morbidity and rising prevalence. One of the most important factors in the
pathophysiology of obesity is overeating of high-caloric foods.

Overeating shares similarities with addiction: compulsive behavior, loss of
control of intake, and craving. In this context, it has been suggested that
food and drugs of abuse may activate the same brain reward systems. The
mesolimbic dopaminergic projection from the ventral tegmental area (VTA) to the
ventral striatum is most frequently implicated in reward function although
other forebrain dopamine projections and other brain structures are certainly
involved as well. There is a large body of evidence to suggest that dopamine is
one of the neurotransmitters linking factors that contribute to overeating.
Several types of food induce dopamine release in a part of the ventral striatum
(nucleus accumbens) in rodents. In humans, it has also been demonstrated that
eating a meal induces a dopamine release in the striatum . It has been
postulated that the ability of drugs of abuse and food to increase dopamine is
crucial for their reinforcing effects.

Several models have been developed to conceptualize the biochemical and
psychometric changes observed in addiction. Koob and Le Moal proposed a model
for brain changes that occur during the development of addiction. The proposed
allostasis model is based primarily on findings from animal research. Evidence
is growing, however, that a state of allostasis may exist in human addiction
and possibly obesity. An important element of the model is a hypoactivated
mesolimbic reward system. Several human studies found confirmation for this
concept in addiction by demonstrating reduced expression of the striatal
dopamine-D2 receptor (D2R). Similarly, decreased striatal D2R availability has
been demonstrated in obese subjects. The expression of the striatal D2R plays
an important role in motivational aspects of drug use, as it might do for food
intake.

In addiction research, confirmation for the hypoactivated mesolimbic reward
system has also been found by demonstrating decreased baseline dopamine levels
in cocaine addicts and a blunted dopamine release on amphetamine. Whether these
changes in the dopamine system are also the case in obesity has not been
demonstrated yet. In this study, we want to test whether baseline dopamine
levels are decreased in obesity by imaging striatal D2Rs before and after
dopamine depletion. Additionally, we will test whether these levels are linked
to craving for food.

The primary goal of the proposed study is to investigate striatal D2R levels
and eating behavior before and after dopamine depletion in order to build
knowledge on the interactions between the brain reward system and overeating
behaviour.
This will be done to gain more insight in the aetiology of obesity.

In 15 female obese subjects and 15 age matched female control subjects, the
availability of D2R in the striatum will be measured with a 123I-IBZM SPECT
scan before and after dopamine depletion. For these scans the subjects will
visit the AMC twice within 2 weeks. Dopamine depletion will be achieved by
administering AMPT, which temporarily block dopamine production, to the
subjects 24 hours before the second scan. Eating behavior will be measured at
the first visit with questionnaires, neuropsychological computer tasks and an
interview.

- dopamine depletion by 2-day AMPT administration
- gastric banding procedure (only for obese subjects)

The burden for the subjects consists of exposure to each of the following: 2x
visit in fasten state to the AMC, 2x IBZM SPECT scan, 1x MRI scan, 1x 2-day
treatment with AMPT, 2x venapunction and urine sample, 2x completing
questionnaires, 1x neuropsychological computer tasks and interview.
The risks for both obese and control subjects are: radiation (within the WHO
criteria for research in humans) and possible side effects of AMPT.