Are pleasure circuits really activated in natural
behaviors? When a recording
electrode is implanted in the ventral tegmental area (VTA), a key region in the pleasure circuit of a rat, this reveals a burst of neuronal
activity when the rat begins to eat.
Furthermore, when biochemical probes that can measure dopamine levels
are implanted into the target regions of VTA neurons, eating is found to
trigger a surge of released dopamine.
Interestingly, VTA activity and dopamine release were most strongly
stimulated by consumption of sweet and highly caloric foods. When drugs that flood the brain with
dopamine, like cocaine or amphetamine, are given chronically, rats eat less and
consequently gain less weight.
Loss of appetite is also produced when drugs that mimic dopamine are
given (these are called dopamine receptor agonists.) Conversely, drugs that block dopamine receptors increase
appetite, energy intake (total calories consumed) and cause weight gain. When rats are starved, the background
levels of dopamine in the nucleus accumbens are reduced, coincident with an
increase in appetite. Thus, it appears that rats are motivated to eat, and specifically
to eat sweet and energy-dense foods, through activation of the VTA dopamine
pleasure circuit.
These results
paint a picture in which food and addictive drugs activate overlapping pleasure circuitry in the brain. There are well-known behavioral
interactions between food and addictive drugs that are likely to result from
this behavioral overlap. For example, starved rats show enhanced motivation for
either addictive drugs like cocaine or amphetamine or direct electrical
stimulation of the medial forebrain bundle (they will press a lever faster and
longer to receive these pleasures.)
What does this suggest about obesity? Is obesity, at
least in a subset of cases, a kind of food addiction? Emmanuel Pothos and colleagues at Tufts
University School of Medicine approached this problem by breeding rats for
several generations, crossing high weight gainers to other high weight gainers
and low weight gainers to other low weight gainers in order to create
obesity-prone and obesity-resistant strains. When allowed free access to standard laboratory rat chow for
15 weeks, the obesity-prone rats ate significantly more food and gained an
average of 22% more weight, compared with their obesity-resistant cousins. Pothos (and many others) have
hypothesized that obesity-prone rats have blunted dopamine signaling in their
midbrain pleasure circuits and that this causes them to eat more in an attempt
to achieve a certain target level of dopamine signaling shared by all rats. Indeed when dopamine levels in the
nucleus accumbens were measured, the obesity-prone rats showed a significant
reduction, in both baseline dopamine levels and in the dopamine surge evoked by
electrical stimulation of the VTA.
Is this reduced dopamine function something the obesity prone rats are
born with or do they acquire it as they grow up? Studies on obesity-prone rat pups found similar attenuation
of dopamine signaling, suggesting the former. These findings support
the idea that obesity-prone rats must eat more to achieve the same
set-point of pleasure achieved by smaller meals in obesity-resistant rats.
Now obese rats
are interesting for their own sake, but how well do these ideas carry over to
humans? Is there even evidence for
a genetic component to obesity in humans or is it all environmental? It’s not a simple story. There’s not a single gene for obesity
(actually, about 0.01% of all cases of obesity can be traced to single gene
mutations, but you get my drift.)
While human obesity is complex and is strongly influenced by sociocultural
factors, individual life-history and food availability, there is a significant genetic component in obesity. Estimates from twin studies indicate
that 50 – 70% of the variability in body mass index can be attributed to
genetic differences. This is a
crucial point as obese people are stigmatized by the widespread belief that the
decision to overeat is completely under voluntary control. The same belief applies to
predisposition for drug/alcohol addiction, which is estimated to be 40 – 60% genetically
based. The comedian Mitch Hedberg riffed, “Alcoholism is a disease,
but it's the only one you can get yelled at for having. ‘Goddamn it, Otto,
you’re an alcoholic. Goddamn it,
Otto, you have lupus.’ One of those
two doesn't sound right.”
Does the
genetic component of obesity result from overeating or from normal eating
coupled with a slow metabolism?
In most cases it appears as if overeating is key. Can we reasonably
extrapolate from the aforementioned rat studies-- might a blunted dopamine reward
circuit stimulate compensatory overeating in humans? Like rats, eating in humans is associated with dopamine
release in VTA target zones, including the dorsal striatum. The nice thing about human studies is
that we can talk to the subjects afterwards and ask them how they felt. This revealed that not only was eating
associated with dopamine release, but that the degree of dopamine release could
be used to predict how pleasurable the subject rated the experience of
eating. Different foods produced
different levels of dopamine release and this correlated with the reported
pleasure of eating. Also, as subjects continued to eat and became full, the
amount of dopamine released in the dorsal striatum was reduced. Not surprising: the first bites of meal
give the most pleasure when you’re hungry.
Again, like
rats, humans who take drugs that increase basal dopamine signaling show reduced
appetite, reduced caloric intake and weight gain whereas drugs that reduce
dopamine signaling produce the opposite effects. So far, so good.
Another important observation is that, on average, dopamine receptor
density is reduced in the VTA target regions of obese subjects as compared with
lean subjects (this can be measured in a brain scanner). But the key question remains: do obese
individuals show reduced dopaminergic activation of VTA target areas in
response to food? Is a blunted
pleasure response to food involved in obesity?
A recent study
by Eric Stice and co-workers at the University of Oregon placed obese and lean
subjects, all young women, in a brain scanner while giving them sips of
chocolate milkshake through a plastic tube. Chocolate is an unusually good activator of brain pleasure
centers and it’s a lot easier to run a flexible straw into the mouth of a head-fixed
subject in the brain scanner than, say, proffering a corned beef sandwich or a
plate of risotto. The main finding
was that the obese subjects showed significantly less activation of the dorsal
striatum in response to milkshake sips when compared with the lean subjects,
thereby supporting the blunted pleasure hypothesis.
In addition,
these milkshake-sipping young women also agreed to DNA testing for a common
genetic variant, called the TaqIA A1 allele, which results in a reduction in
the density of dopamine receptors in the pleasure circuit (particularly a type
of dopamine receptor called D2).
Carriers of the A1 allele showed the greatest reduction in
milkshake-evoked dorsal striatum activation. When follow-up examination were performed a year later, A1
carriers also showed significantly greater weight gain than non-carriers. So, do some obese people overeat to try
to compensate for low-functioning pleasure circuitry? That’s likely to be part of the explanation, but there may
be another twist. “If you look at the brain response when people are about
to get the milkshake, obese
individuals show greater
activation of the reward circuitry, not less,” Stice says. “So, ironically,
they expect more reward but seem to experience less.” [Interview on National Public Radio, October 16, 2008] This increased craving coupled with
decreased pleasure may be a general problem for many forms of compulsive and
addictive behavior, not just overeating.
In fact, carriers of the TaqIA A1 allele are not only more likely to be
obese, they are more likely to struggle with drug/alcohol abuse as well.