Anticipations of Dopamine

Dopamine is famous for two things: 1. When it is depleted from the substantia nigra, it can cause Parkinson's disease 2. It is popularly thought of as the "pleasure neurotransmitter". It is also well known for being involved in schizophrenia.

Two new studies cast an interesting light on dopamine's variable effects -- depending upon the individual's genetic complement:

Highly creative person's have dompamine systems similar to schizophrenics.

"The study shows that highly creative people who did well on the divergent tests had a lower density of D2 receptors in the thalamus than less creative people," says Dr Ullén. "Schizophrenics are also known to have low D2 density in this part of the brain, suggesting a cause of the link between mental illness and creativity."

The thalamus serves as a kind of relay centre, filtering information before it reaches areas of the cortex, which is responsible, amongst other things, for cognition and reasoning.
"Fewer D2 receptors in the thalamus probably means a lower degree of signal filtering, and thus a higher flow of information from the thalamus," says Dr Ullén, and explains that this could a possible mechanism behind the ability of healthy highly creative people to see numerous uncommon connections in a problem-solving situation and the bizarre associations found in the mentally ill. _SD

This suggests that creative people are born and not made. But creativity is also a skill that can be improved in virtually anyone with practise. The higher realms of creativity may be reserved, however, for those with a combination of very high IQ and a genetic predisposition to creativity via brain structure.

Another fascinating finding relating to dopamine: Some people are genetically predisposed to have a strong dopamine response to drinking alcohol.

Using human positron emission tomography (PET), an imaging technique that allowed the researchers to analyze dopamine activity in the brain, they compared dopamine release in two groups of people that had been given a dose of alcohol. The groups consisted of those who carried a copy of the gene for the 118G mu-opioid receptor variant, and those who carried only genes for the more common 118A variant. They found that only people with the 118G variant had a dopamine response to alcohol -- no such response happened in subjects with the 118A receptor variant. _SD

The authors of the study suggest that persons with the 118G mu-opioid receptor variant may experience an enhanced pleasurable reaction to alcohol, predisposing to a greater risk of addiction.

Dopamine is not really a pleasure neurotransmitter -- it is more of an "anticipation of pleasure" neurotransmitter. It helps motivate the animal or person in pursuit of anticipated pleasure. Thus the connection of dopamine to addictions.

Another interesting line of research on the dopamine system involves the use of apomorphine to "kick-start" the dopamine system in vegetative patients.

One reason Fridman chose apomorphine was that it reaches dopamine receptors directly, even if the body's own ability to make the neurotransmitter is damaged. Apomorphine also binds to many types of dopamine receptors. Some other drugs, such as levodopa (L-dopa), are actually precursors—they are converted into dopamine by the body rather than acting directly on the receptors, so if that conversion mechanism were impaired they would be less helpful. Other drugs, such as amantadine, boost cellular production of dopamine, but if those cells are damaged or less active then they can only be boosted so far. Yet others only bind to certain dopamine receptors. _SciAm

Dopamine and Reward Seeking Behavior PDF

The dopamine reward circuit

The Dopamine System (short learning videos)

Dopamine by itself does not control behaviour. The neurotransmitter acts within the complex anatomy, physiology, biochemistry, and genetics of each individual brain. But humans tend to think in narratives, assigning each neurotransmitter its particular "role" to play, as if it were an independent actor.

Humans are constrained by such metaphorical thoughtways, and are often led down dead end streets of investigation. Perhaps the greatest challenge in learning about the universe around us, is rising above our own limitations in as many ways as we can.

Dopamine Drives Risk Taking and Status Seeking

The neurotransmitter dopamine plays a vital role in determining an individual's level of drive and ambition, as well as thrill seeking behaviours.  Two recent studies look at important behavioural effects of the monoamine neuro-molecule.

Our need for stimulation and dopamine's action upon the brain are connected, which explains why people who constantly crave stimulation are in danger of addictive behaviour such as drug abuse and gambling. _SD

People have typically viewed the benefits that accrue with social status primarily from the perspective of external rewards. A new paper in the February 1st issue of Biological Psychiatry, published by Elsevier suggests that there are internal rewards as well.

Dr. Martinez and colleagues found that increased social status and increased social support correlated with the density of dopamine D2/D3 receptors in the striatum, a region of the brain that plays a central role in reward and motivation, where dopamine plays a critical role in both of these behavioral processes. _Eurekalert

Both studies were collaborative, representing the work of neuroscientists from several research centers in Europe, Japan, and the US. The research is quite intriguing, as it suggests that dopamine may be a source of exquisite internal conflict -- between the drive to take risks, and the drive to achieve and hold high status. Of course, in a material world, the two drives can also work together.

Many individuals experience the urge to engage in new activities every day, and that's perfectly understandable. However, some are looking for more than that, experiences that will take their senses to a whole-new level. Other than extreme sports and gambling, there isn't very much else that can fulfill that and be legal. Psychologists have been aware of this type of behavior for years, but science has failed to pin down an underlying hormonal activity that triggers it, until now. The international group of scientists in charge of the recent study came from the University of Copenhagen, the University of Aarhus, and the University of Tokyo, in Japan. _Softpedia

Interestingly, patients who take dopamine replacement and dopamine-sparing treatments for Parkinson's Disease also often manifest strong tendencies to take risks -- including pathological gambling.

I wonder how one would program such drives into an artificial intelligence.

Fascinating Look Into the War on Mental Depression Fascinating Look Into the War on Mental Depression

Northwestern University researcher Eva Redei recently presented her research on the underlying causes of depression at the Neuroscience 2009 in Chicago. The sophistication of the research is impressive, and suggests the promise of hugely important advances in the study of human cognition and mental illness in the relatively near future.

Redei used microarray technology to isolate and identify the specific genes related to depression in these animals. She examined the genes in the brain regions -- the hippocampus and amygdala -- commonly associated with depression in rats and humans.

Then she took four genetically different strains of rats and exposed them to chronic stress for two weeks. Afterwards, she identified the genes that had consistently increased or decreased in response to the stress in all four strains in the same brain regions.

Redei now had one set of depression-related genes that came out of an animal model of depression and one set of stress-related genes that came our of her chronic stress study.

Next she compared the two sets of genes to see if there were any similarities. "If the 'stress causes depression theory' was correct, there should have been a significant overlap between these two sets of genes," she said. "There weren't."

Out of a total of over 30,000 genes on the microarray, she discovered approximately 254 genes related to stress and 1275 genes related to depression, with an overlap of only five genes between the two.

"This overlap is insignificant, a very small percentage," Redei said. "This finding is clear evidence that at least in an animal model, chronic stress does not cause the same molecular changes as depression does." _SD

Redei claims to have shown that modern methods of treating depression are misconceived -- since they are aimed more at stress than at the real cause of depression. She also claims to have demonstrated that depression is caused by something significantly more profound than an imbalance of neurotransmitters. Redei believes that her findings point to potentially more powerful and effective treatments for depression.

I have not read the full study, so I cannot comment on Redei's claims. But I do admit to being impressed by the powerful genetic and bioinformatic methods used to tease out the differences between the genetics of stress and the genetics of depression. These tools can be used to solve many genetic problems that have been the source of heated philosophical arguments for centuries. But powerful and exotic tools do not guarantee valid results. Logical and philosophical rigour must be combined with a creative and adventurous spirit.

Redei suggests that the "real" problem of depression originates in the developmental stages of neurons, and may have to be solved at the same level. There is some evidence that some neurotransmitters can trigger neurogenesis via stem cell migration and differentiation. Better therapies for selective neurogenesis may well find their way into psychiatric treatment for depression. It is likely that deep brain stimulation, for example, and other electromagnetic stimulation techniques, will be found to stimulate neurogenesis at least indirectly.

For the animal depression model, Redei was apparently using a strain of rats that has been bred for decades to mimic physical and physiological human symptoms and signs of depression. The rats are said to be "the most depressed rats in the world." If so, they should be helpful in screening new therapies for depression.

It is not surprising that some therapies will work for depression and others will not.

Why Do Antidepressants Take 6 Weeks to Work?

Until fairly recently, psychiatrists and neuropharmacologists have been puzzled by the several-week delay in onset of antidepressant efficacy of commonly prescribed mood elevators. It shouldn't take that long to boost neurotransmitter levels. But straight from central casting, the neural stem cell made its appearance in the science annals, and it was found that some antidepressants stimulate the differentiation of neural stem cells to mature nerve cells. Voila! New neurons--a feat once thought impossible!--from neural stem cells, with a little help from pharmacology. Recent work from the University of Texas supports that hypothesis.

...Antidepressants act very quickly to increase levels of natural compounds, called neurotransmitters, which nerve cells use to communicate. It takes several weeks to several months, however, for the patients who respond to such treatments to feel less depressed. Dr. Parada said this implies that some other long-term mechanism is also at work.

...Matching the timeframe for medicated patients to feel less depressed, it takes several weeks for new nerve cells to grow, Dr. Parada said. This parallel effect, he said, may mean that antidepressants need to stimulate growth of new cells in the dentate gyrus in order to achieve their full effect. _Sciencedaily

Antidepressants stimulate the production of new nerve cells in the hippocampus, and appear to protect nerve cells from apoptosis, at least in animal studies. The time delay for the mood elevation from antidepressants appears to be caused by the time to differentiation and integration of new neurons.

All this time, psychiatrists have been engaging in regenerative neuromedicine, and did not even realise it. Now that we have a better idea of what we are doing, perhaps we can learn to do it better?

Dopamine--Polymer Implant Stimulates Rapid Nerve Growth

Scientists at Georgia Tech have discovered how to stimulate rapid nerve growth in tissue culture, using a polymer with dopamine impregnated into it. This method may offer hope for nerve regeneration in patients with Parkinson's, Alzheimer's, and other neuro-degenerative conditions.

Because neural circuits use electrical signals often conducted by neurotransmitters (chemical messengers) to communicate between the brain and the rest of the body, he (Ya Dong Wang) could build neurotransmitters into the material used to repair a broken circuit. The neurotransmitters could coax the neurons in the damaged nerves to regrow and reconnect with their target organ.

Strange though his idea might have seemed to others in his field, Wang, an assistant professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University, discovered that he could integrate dopamine, a type of neurotransmitter, into a polymer to stimulate nerve tissues to send out new connections. The discovery is the first step toward the eventual goal of implanting the new polymer into patients suffering from neurological disorders, such as Alzheimer's, Parkinson’s or epilepsy, to help repair damaged nerves. The findings were published online the week of Oct. 30 in the Proceedings of the National Academy of Sciences (PNAS).

“We showed that you could use a neurotransmitter as a building block of a polymer,” said Wang. “Once integrated into the polymer, the transmitter can still elicit a specific response from nerve tissues.”

The “designer” polymer was recognized by the neurons when used on a small piece of nerve tissue and stimulated extensive neural growth. The implanted polymer didn’t cause any tissue scarring or nerve degeneration, allowing the nerve to grow in a hostile environment post injury.

When ready for clinical use, the polymer would be implanted at the damaged site to promote nerve regeneration. As the nerve tissue reforms, the polymer degrades.

Read more at Source.

This is an interesting experiment, illustrating that there are still many new uses to which commonplace biochemicals can be put. The combination of dopamine with an unnamed polymer apparently has effects no one predicted. How many other everyday biochemicals, when combined with polymers, nanostructures, or other modifying agents, have the capacity to perform similar useful functions? Time will tell.

Killing Neurons with Excitement

We know that much of the damage from strokes comes from an overload of glutamate, an excitatory neurotransmitter. Neurodegenerative changes in Alzheimer's Disease is probably also due to glutamate overexcitation, at least in part. Now scientists are beginning to tease apart the mechanism of excitative neurotoxicity. This news release give more information:

For neurons, overexcitement is deadly. To avoid this, brain cells must sop up unneeded neurotransmitters from the synapse through membrane-bound transporters. If these transporters fail, neurons and other brain cells get excited to death-- a phenomenon that may contribute to brain damage during stroke and Alzheimer's disease.

Indeed, brain deterioration after stroke is associated with elevated levels of glutamate -- the major excitatory neurotransmitter in the mammalian central nervous system (CNS) -- in the plasma and cerebral spinal fluid. One possible explanation for this glutamate build-up, reported online on March 6th in The Journal of Experimental Medicine, is a mutation in the gene encoding the glutamate transporter protein EAAT2.

This mutation --- a single nucleotide change in the promoter region of the EAAT2 gene -- was equally prevalent in healthy individuals and stroke patients. But among stroke patients, those with the mutated allele had higher plasma levels of glutamate and were more likely to suffer from post-stroke neurological problems than those with the normal allele.

The mutation changed a binding site for the activating transcription factor AP-2 into a binding site for the repressor GCF2 -- a swap that inhibited promoter activity in transfected rat brain cells. Whether the mutant promoter decreases EAAT2 expression in the human brain, as would be predicted, remains to be tested.

Little by little, gene by gene, protein by protein, science is learning why humans suffer the way they do. And little by little science is finding ways to do something about it.

Beyond Smart Drugs: Getting Smarter

Aubrey de Grey's SENS approach to gerontology may very well help us to live longer, perhaps much longer. Then what? Humans really do need to become smarter. Present levels of human intelligence are just about good enough to get us all killed. To go beyond what was discussed in the posting Smart Drugs, I would like to look toward longer term prospects for boosting intelligence--permanently.

Returning briefly to neuroscientist Michael Gazzaniga in his Oct 2005 SCIAM articleSmarter On Drugs, we see the real essence of the problem. Smart drugs temporarily augment the brains we have, but they do not make them better. To do that, we have to go further:

We have isolated one gene involved in intelligence, and others will follow. We know which parts of the brain are influenced by particular genes and which parts correlate with high IQ. We also know some of the neurochemicals involved in learning and memory. With such knowledge, we will gain understanding of what needs to be manipulated to increase intelligence in people who were not blessed with brilliance in their genomes or further increase the intelligence of those who were. Gene therapy could insert, delete, turn on or turn off genes that we find to be associated with intelligence.

We know about the Human Genome Project, and we understand that it is the foundation for much bigger things. We have heard about the International Hapmap Project, and we may have a vague idea of the possibilities that will be generated because of it. Diseases and other human attributes possess significant genetic components. We need to know what they are.

But we must think more broadly than mere genes. Genes are only part of the story. The better understanding of proteins, or proteomics, holds many of the keys we are looking for. In addition, non-coding RNA is a critical piece of the puzzle. The entire control structure of each cell is a highly complex internetwork of feedback systems. If you add the feedback systems of neighboring cells and tissues, then take into account signals coming to the cell from the blood, lymph, nerve terminals, and other meta-control systems--and you begin to see the problem.

We were talking about how to become more intelligent, using the genes. But now we understand that it can never be just the genes. It has to include the entire biological environment of the nervous system, and the entire organism.

But, wait. The organism is not hermetically sealed. The organism has inputs from the outside, and outputs to the outside. We know that growing organisms have to be given adequate nutrition, physical exercise, and mental stimuli to develop normally. They also need emotional nurturing. From Intelligence Testing Blog, we learn from Kevin that even video games may contribute to cognitive enhancement in young children. But what about the mature, developed organism--human? Assuming he is getting optimal nutrition, exercise, mental challenge, and emotional support? What else can be done?

OK, I talked about ampakines, donezepil, and modafinil here. If you are living on the edge of your mental capacity, it might be worth it to you, to try to get your hands on some donezepil. Modafinil should be treated gently, since everyone needs ample sleep, and with modafinil the temptation is to skimp on sleep to get more done, potentially abusing the body in the process. Ampakines are not available yet, but will be relatively soon. These are temporary approaches.

While we are waiting for researchers to understand the genetics, proteomics, and epigenetics of intelligence, there may be more permanent actions we can take to augment our mental capacity.

Assuming your nutrition is indeed optimal, your physical activity regular, your mental stimulation productive, and your emotional supports satisfying--what else can you do?

Neurofeedback is a technology that has been largely ignored by the public and news media, but is an approach that holds enormous potential for mental growth, even for mature and normal human mind/brains. It is still experimental in terms of stimulating mental growth for normal brains, but it is safe and non-invasive.

People with phobias, such as math phobia, are preventing themselves from progressing in the direction of their phobia. Such persons can certainly be helped by neurofeedback and other behavioural approaches.

There are many commercial programs, such as this one, that tries to capitalise on the human desire to improve oneself. This is another group that seems to be taking an even more advanced approach to developing mind improving technology. And while Daniel Amen may be rightly criticised by his peers for jumping too quickly into imaging technology to diagnose common everyday conditions, there is no doubt that Amen is at the leading edge of the curve, and may have the last laugh after all.

Taking nutritional supplements may not be a bad idea, either. In addition to the multivitamins, the extra vitamin C and E, and the minerals, taking curcumin, lipoic acid, and precursors for neurotransmitters might be helpful for many, particulary those with depression, fatigue, or ADD. This is not medical advice, but merely a suggestion for something that might be looked into.

Long life and increased intelligence are not the final goal. To reach the final goal, you must also include enlightenment, and wisdom. Using both sides of the brain to the fullest extent. Mysticism and holism are only part of wisdom. Wisdom also includes the ability to look at the details with exquisite clarity, and being able to place them into dynamic context.

We have some distance yet to travel, many things to learn. There is no reason not to use the footstools, ladders, and knotted ropes dangling above us.