Monday, November 17, 2008

Dopamine and obesity

Dopamine is a neurotransmitter that's well-known for its involvement in several notable medical and behavioral problems, such as Parkinson's disease and drug addiction. But it is connected with many other issues of medical and psychological importance.

Perhaps the main reason that dopamine is so interesting is that it plays a big role in the brain's pleasure and reward systems. And therefore it is inevitably involved in reward-motivated behaviors of all kinds, from gambling, investing, substance abuse, and sex, to – eating. After all, isn't a high percentage of behavior motivated by rewards? There are other motivations for particular behaviors – fear and physiological needs, for example – but reward covers an awful lot of it.

Consequently, problems in the reward system can lead to excesses in some behaviors (e. g., gambling, eating), and perhaps also deficiencies in other behaviors (e. g. loss of interest in normal pleasures, as might accompany depression).

And because of the importance of dopamine in the reward system, problems with dopamine signaling can lead to problems in the reward system, with predictable consequences.

In the research we're going to look at, dopamine signaling is impaired in the presence of a particular allele associated with the D2 receptor for dopamine (known as DRD2). The conclusion is reached via the observation of decreased activity, as mesured by fMRI, in a brain region called the dorsal striatum. It is known that the variant allele causes a lower density of D2 receptors in this region.

The bottom line of the research is that individuals with this variant allele tend to have impaired ability to enjoy rewards from foods that most people like, such as chocolate. As a result, such individuals are disposed to consume more food in order to achieve an acceptable level of satiation of reward.

It might be thought, instead, that since the desirable foods produce less reward in individuals with the variant allele, they might consume less, due to reduced interest. However, that's not how the reward system seems to work. It seems to require achievement of a certain signal level in order to reach satiation and thus decrease the motivated behavior.

This is similar to the way signaling works with another hormone connected with eating, namely leptin. Normally, leptin levels rise when food is consumed. There are receptors for leptin in the ventromedial nucleus of the hypothalamus, a region that is responsible for appetite. There leptin inhibits the activity of neurons that contain neuropeptide Y (NPY).

A connection has been found between obesity and insensitivity to leptin, much as diabetes results from decreased sensitivity to the hormone insulin. Preseumably, individuals with reduced sensitivity to leptin don't know when to stop eating. Much the same state of affairs seems to exist in individuals with the allele (which is a DNA restriction enzyme called TaqIA) that affects DRD2 receptor density in the dorsal striatum.

Obesity, Abnormal 'Reward Circuitry' In Brain Linked: Gene Tied To Dopamine Signaling Also Implicated In Overeating (10/16/08)
Using brain imaging and chocolate milkshakes, scientists have found that women with weakened "reward circuitry" in their brains are at increased risk of weight gain over time and potential obesity. The risk increases even more for women who also have a gene associated with compromised dopamine signaling in the brain.

The results, drawn from two studies using functional magnetic resonance imaging (fMRI) at the University of Oregon's Lewis Center for Neuroimaging, appear in the Oct. 17 issue of the journal Science. The first-of-its-kind approach unveiled blunted activation in the brain's dorsal stratium when subjects were given milkshakes, which may reflect less-than-normal dopamine output.

Here's the research paper, with abstract:

Relation Between Obesity and Blunted Striatal Response to Food Is Moderated by TaqIA A1 Allele
The dorsal striatum plays a role in consummatory food reward, and striatal dopamine receptors are reduced in obese individuals, relative to lean individuals, which suggests that the striatum and dopaminergic signaling in the striatum may contribute to the development of obesity. Thus, we tested whether striatal activation in response to food intake is related to current and future increases in body mass and whether these relations are moderated by the presence of the A1 allele of the TaqIA restriction fragment length polymorphism, which is associated with dopamine D2 receptor (DRD2) gene binding in the striatum and compromised striatal dopamine signaling. Cross-sectional and prospective data from two functional magnetic resonance imaging studies support these hypotheses, which implies that individuals may overeat to compensate for a hypofunctioning dorsal striatum, particularly those with genetic polymorphisms thought to attenuate dopamine signaling in this region.

The idea that problems with dopamine signaling might be related to overeating and obesity isn't new. The following research announced in July involved rats rather than humans and considered other dopamine insufficiency mechanisms, but the basic conclusions are the same:

Obesity Predisposition Traced To The Brain's Reward System (7/29/08)
The tendency toward obesity is directly related to the brain system that is involved in food reward and addictive behaviors, according to a new study. Researchers at Tufts University School of Medicine (TUSM) and colleagues have demonstrated a link between a predisposition to obesity and defective dopamine signaling in the mesolimbic system in rats.

The mesolimbic system is a system of neurons in the brain that secretes dopamine, a neurotransmitter or chemical messenger, which mediates emotion and pleasure. The release of the neurotransmitter dopamine in the mesolimbic system is traditionally associated with euphoria and considered to be the major neurochemical signature of drug addiction. ...

Pothos says, "These findings have important implications in our understanding of the obesity epidemic. The notion that decreased dopamine signaling leads to increased feeding is compatible with the finding from human studies that obese individuals have reduced central dopamine receptors." He speculates that an attenuated dopamine signal may interfere with satiation, leading to overeating.

Paper abstract:

Evidence for defective mesolimbic dopamine exocytosis in obesity-prone rats
In electrophysiology studies, electrically evoked dopamine release in slice preparations was significantly attenuated in OP [obesity-prone] rats, not only in the nucleus accumbens but also in additional terminal sites of dopamine neurons such as the accumbens shell, dorsal striatum, and medial prefrontal cortex, suggesting that there may be a widespread dysfunction in mechanisms regulating dopamine release in this obesity model. Moreover, dopamine impairment in OP rats was apparent at birth and associated with changes in expression of several factors regulating dopamine synthesis and release: vesicular monoamine transporter-2, tyrosine hydroxylase, dopamine transporter, and dopamine receptor-2 short-form. Taken together, these results suggest that an attenuated central dopamine system would reduce the hedonic response associated with feeding and induce compensatory hyperphagia, leading to obesity.

News reports of the human dopamine results:
E. Stice, S. Spoor, C. Bohon, D. M. Small (2008). Relation Between Obesity and Blunted Striatal Response to Food Is Moderated by TaqIA A1 Allele Science, 322 (5900), 449-452 DOI: 10.1126/science.1161550

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Tuesday, November 11, 2008

BDNF and depression

Back in March I wrote a little bit about the convoluted relationships among stress, learning, and memory (here). About the same time, I wrote about the relationship between memory and an important neural growth factor, BDNF (here).

It seems that BDNF is an important bridge connecting the topics of memory, stress, and depression. Back in March I also started to write more about how BDNF is linked to depression, but I got sidetracked. So the rest of this message is what I started to write about that connection, which is why the research covered is from March or earlier.

But before turning to that, it should be noted that there is more to say about the relationship between BDNF and stress, which I'll put off a little longer. There's also more to say about the relationship between BDNF and antidepressant drugs, some of which is more recent than March. I'll put that off too.

So let's just get into the older stuff about BDNF and depression, to start the ball rolling again.

Research has shown that one way in which BDNF is linked to depression is through the neurotransmitter serotonin – whose connection to mood, depression, anxiety, etc. is pretty well known (think Prozac).

In particular, BDNF seems to affect expression of the gene for the serotonin transporter (SERT). (The gene itself is called SLC6A4, which stands for "solute carrier family 6, member 4".) SERT is a cell membrane protein that transports serotonin from the synapse between neurons back into the neuron from whence it came – enabling "serotonin reuptake". Some forms of the gene for SERT seem to predispose individuals who carry it to mood disorder.

Here are some reports of recent research on BDNF, which give an idea of the variety of effects it has within the nervous system. (The summaries included here are mine.)

The yin and yang of genes for mood disorders (3/12/08)
This research studied conditions under which a variant of the gene for SERT (i. e. SLC6A4) predisposes the carrier to mood disorders. Apparently there are also at least two variants of the gene for BDNF. An individual with one form of BDNF is particularly susceptible to the deleterious form of the SERT gene, but with the other form of BDNF, an individual is completely protected against it.

Brain Chemistry Ties Anxiety And Alcoholism (3/4/08)
Production of BDNF is known to be stimulated by exposure to alcohol. The researchers in this study, whose leader author is Subhash Pandey, also knew from previous experiments that reduced levels of BDNF in the amygdalas of normal laboratory rats led to increased anxiety in the rats, followed by increased consumption of alcohol. The question was what happened due to deficiency of BDNF that increased anxiety, and how did consumption of alcohol reverse this effect by restoring BDNF.

It is also known that BDNF stimulate the production of another protein, Arc. If Arc could be suppressed in the amygdala even in the presence of normal levels of BDNF, and the rats experienced increased anxiety anyhow, this would show that it is probably a deficiency of Arc rather than of BDNF that is responsible for the anxiety. And indeed, when Arc was suppressed in spite or normal BDNF, the rats had higher anxiety. They also consumed more alcohol. But when Arc levels returned to normal, the anxiety returned to normal, and alcohol consumption did too.

The question then came down to how a deficiency of Arc increased anxiety. It was found that temporarily reduced levels of Arc resulted in reduced numbers of dendritic spines of neurons in the amygdala. Since axons of other neurons form synapses with dendritic spines, there will be fewer synapses when there are fewer spines. At the same time, anxiety also increased. Conversely, when levels of Arc returned to normal, either naturally or as a result of higher levels of BDNF due to alcohol consumption, the number of spines increased, and anxiety decreased. Once Arc had increased normally, alcohol consumption decreased too.

Earlier results: Brain Chemical Plays Critical Role In Drinking And Anxiety (8/8/06) – when expression of BDNF (which is regulated by CREB) is blocked, anxiety and alcohol consumption in rats increases.

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Sunday, December 17, 2006

Is pot a gateway drug?

Apparently not:

No 'Smoking' Gun: Research Indicates Teen Marijuana Use Does Not Predict Drug, Alcohol Abuse
Marijuana is not a “gateway” drug that predicts or eventually leads to substance abuse, suggests a 12-year University of Pittsburgh study. Moreover, the study’s findings call into question the long-held belief that has shaped prevention efforts and governmental policy for six decades and caused many a parent to panic upon discovering a bag of pot in their child’s bedroom.

Of course, as we just noted here, cannabis doesn't do any good for your memory.

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Saturday, October 14, 2006


We just mentioned caffeine here, in relation to the mood-enhancing effects of fast thinking.

So along comes a little more information about the connections.

Probing Question: Is caffeine harmful to your health?

The basic answer seems to be "no", when the stuff is used in moderation. Just as interesting are the details of how it works:
How does caffeine achieve its most sought-after effect of counteracting fatigue? To understand that, we first have to understand the chemistry of fatigue itself. Like all cells in the body, brain cells access fuel through an energy-storage nucleotide called ATP. ATP -- adenosine triphosphate -- loses one of its three phosphate molecules with each burst of energy it releases, eventually becoming a single adenosine molecule. The longer a person is awake, the more adenosine will accumulate on special adenosine receptors in the brain, signaling it to slow its activity.

Enter caffeine. Acting as a wolf in sheep's clothing, caffeine is molecularly similar enough to adenosine to fit into its receptors, blocking adenosine from getting through -- yet it is distinct enough not to be "read" by the brain as instructions to take a nap.

Without adenosine's calming effect, the brain's neurons fire more rapidly and the body reads this increased activity as an emergency requiring the release of the "flight or fight" chemical: adrenalin [AKA: epinephrine]. The result? You feel excited, alert, mentally quick, ready for anything.

Of course, if there actually is a lot of adenosine in the brain, that's a sign it may be running on a nearly empty tank. Probably not a good idea to continue this too long without replenishing the fuel supply.

Another thing to watch out for: If you take caffeine while pulling an all-nighter to finish that important assignment, you may not be able to come back and have a good nap after the work is turned in:

Negative Effects Of Caffeine Are Stronger On Daytime Sleep Than On Nocturnal Sleep
A new study at the Université de Montréal has concluded that people drinking coffee to get through a night shift or a night of studying will strongly hurt their recovery sleep the next day.


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Sunday, October 08, 2006

How fast thinking makes us happy, energized and self-confident

Recent psychological research claims to have found evidence for what the title of this piece says: merely speeding up our thought processes is enough to make us feel better mentally.

I don't know about you, but I don't find this very surprising. I feel a lot more like a tortise than a hare before I've had my first dose of caffeine for the day. But I generally get into a higher gear right after that, and my mood becomes a whole lot better too.

It's hard to deny the mood-enhancing effects of caffeine when you look at the stock price of a company like Starbucks. According to Wikipedia,
By the time of its initial public offering on the stock market in 1992, Starbucks had grown to 165 outlets. In April 2003, Starbucks added nearly that many new outlets in a single day by completing the purchase of Seattle's Best Coffee and Torrefazione Italia from AFC Enterprises, bringing the total number of Starbucks-operated locations worldwide to more than 6,400.

The company probably wouldn't have enjoyed such success, even at the prices they charge, if they didn't make a whole lot of people feel good.

But psychologists can reproduce the effect in the lab, without any chemical additives:

Study explores 'manic' thinking
How fast thinking makes us happy, energized and self-confident

Fast thinking, or "racing thoughts," is most commonly known as a symptom of the clinical psychiatric disorder of mania (and of the manic part of bipolar disorder or "manic-depression"). But, according to Princeton University psychologist Emily Pronin, most healthy people also have experienced racing thoughts at some point in time--perhaps when they are excited about a new idea they have just learned, or when they are brainstorming with a group of people, or even when they lie in bed unable to fall asleep. Pronin and her Harvard colleague Daniel Wegner decided to explore whether inducing people to think fast might lead them to feel some of the other experiences also associated with the manic experience.

It would be most intresting to know a lot more about the neurochemistry involved here. No doubt it's related to "runner's high", endorphins, higher levels of epinephrine (which is closely related to the neurotransmitter norepinephrine), and that sort of thing.


At all events, in times like these, it's always good to have some happy news.


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Monday, December 19, 2005

Why caffeine works

Coffee's effects revealed in brain scans
Coffee improves short-term memory and speeds up reaction times by acting on the brain’s prefrontal cortex, according to a new study.

Researchers used functional magnetic resonance imaging (fMRI) to determine how coffee activates different areas of the brain in 15 volunteers.

“Caffeine modulates a higher brain function through its effects on distinct areas of the brain,” explains Florian Koppelstätter, who carried out the research with colleagues at the Medical University at Innsbruck, Austria.

What areas specifically?
“The group all showed activation of the working memory part of the brain," Koppelstätter explains. "But those who received caffeine had significantly greater activation in parts of the prefrontal lobe, known as the anterior cingulate and the anterior cingulate gyrus. These areas are involved in 'executive memory', attention, concentration, planning and monitoring."

There must be more to the effect of caffeine than that. Most of us know, for instance, that a common symptom of withdrawal from caffeine is headaches. What's with that? Adenosine recoptors?
Caffeine is known to influence adenosine receptors which are found throughout the brain on nerve cells and blood vessels. It is thought that the drug inhibits these receptors and that this excites the nerve cells in the brain. “This may be the mechanism involved,” suggests Koppelstätter.

Another story on this: The tall and the short of why caffeine works
Press release: Coffee Jump-starts Short-term Memory

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Saturday, December 03, 2005

Did More Endorphins Make Us Human?

We may be getting closer to understanding some of the evolutionary changes that occurred between humans and our last common ancestor with chimpanzees. Surprisingly, it could involve changes in gene regulation, rather than in genes themselves. And even more surprisingly, one of the genes involved seems to be one for an opium-like protein.

"Perception" gene tracked humanity's evolution, scientists say

BLOOMINGTON, Ind. -- A gene thought to influence perception and susceptibility to drug dependence is expressed more readily in human beings than in other primates, and this difference coincides with the evolution of our species, say scientists at Indiana University Bloomington and three other academic institutions. Their report appears in the December issue of Public Library of Science Biology.

The gene encodes prodynorphin, an opium-like protein implicated in the anticipation and experience of pain, social attachment and bonding, as well as learning and memory.

"Humans have the ability to turn on this gene more easily and more intensely than other primates," said IU Bloomington computational biologist Matthew Hahn, who did the brunt of the population genetics work for the paper. "Given its function, we believe regulation of this gene was likely important in the evolution of modern humans' mental capacity."

Another news story on this: Did More Endorphins Make Us Human? (may require registration)