Nice but, unfortunately, dopamine is probably going to be ceased to be credited with `happy feelings` in the not so far future as a paradigm shift is building showing that it`s probably more related to salient phenomena. Evidence actually started building up straight after it was initially named as the `reward hormone` etc but the media went off on one, as did scientists.kay wrote:Found this article yesterday: In Search of Better Antidepressants
A new study from researchers at MIT and Stanford University pinpoints brain cells that appear to be critically involved in depression, offering a possible target for new, more effective antidepressants.
By stimulating these cells to deliver dopamine to other parts of the brain, the researchers were able to immediately eliminate symptoms of depression in mice. They also induced depression in normal mice by shutting off the dopamine source.
The findings could help researchers develop antidepressants that are more precisely targeted, says Kay Tye, an assistant professor of brain and cognitive sciences at MIT and one of the lead authors of a paper on the work appearing in the Dec. 12 online edition of Nature.
“The first step to achieving a new era of therapy is identifying targets like these,” says Tye, who is a member of MIT’s Picower Institute for Learning and Memory. “The fact that this target exists, I really hope it motivates drug companies to revitalize their neuroscience research groups.”
Tye performed much of the research as a postdoc in the lab of Stanford professor Karl Deisseroth, the senior author of the paper. Other lead authors are Stanford research assistant Julie Mirzabekov and Stanford postdoc Melissa Warden.
Finding targets
Depression affects an estimated one in 10 Americans, many of whom receive drugs that boost the brain chemical serotonin. However, these drugs (which include Prozac) require four to six weeks to have any effect. This suggests, Tye says, that serotonin may not be part of the brain system most responsible for depression-related symptoms.
“If serotonin was directly underlying the antidepressant effects of Prozac, then the very first day you take Prozac you should feel the effects, because that’s what it’s targeting immediately,” she says. “The fact that it takes so long for the drug to work makes me think that the immediate effect of the drug itself is not having an antidepressant effect. When you have the drug in your system for a long time, the brain adapts, and the adaptation might actually be what is underlying the antidepressant effects of these drugs.”
Finding more specific targets, rather than dousing the whole brain in chemicals, is key to developing better therapies, Tye says.
The researchers decided to investigate the dopamine system because it is known to play a major role in reward, motivation and pleasure. People suffering from depression often lack motivation, so dopamine has been considered a prime suspect in the disease. “Depressed patients will move around less, they have trouble getting out of bed, they don’t enjoy things that they used to enjoy,” Tye says.
Additionally, Parkinson’s disease patients, who suffer from dramatically reduced dopamine levels that severely impair their movements, often experience depression before the complete onset of Parkinson’s symptoms.
Dopamine control
For this study, the researchers used a relatively new technology known as optogenetics to selectively inhibit or stimulate dopamine-releasing neurons in the ventral tegmental area (VTA), which is a primary source of the brain’s dopamine for reward and motivation.
Optogenetics allows scientists to control neurons’ activity by genetically engineering them to express a light-sensitive protein that regulates the flow of ions in and out of the cell. Exposing these neurons to light turns them on or off nearly instantaneously. This offers a much more precise way of manipulating brain circuits than drugs, which can influence neighboring neurons and take more time to exert their effects.
In the first part of the study, the researchers turned off VTA dopamine-releasing neurons in normal mice. This immediately provoked depression-like symptoms, including a decline in motivation and the inability to feel pleasure.
Next, the researchers tested what would happen if they turned on VTA neurons in mice showing symptoms of depression. To generate depressive behavior, these mice were exposed to some type of mild stress twice a day for 10 weeks. Stressors included disruptions in circadian rhythms, social isolation, overcrowding or changes in temperature.
In humans, depression is often induced by similar patterns of low-grade but constant stress, Tye says.
This chronic mild stress is very different from severe acute stress, which can lead to post-traumatic stress disorder, Tye says. “It’s more like a wearing away, where you don’t really feel like you’re in control. You never know what’s going to happen. You just feel helpless as all these frustrating or annoying things happen.”
When the researchers caused the VTA neurons in these mice to fire in bursts, flooding their brains with dopamine, the mice returned to normal behavior patterns within about 10 seconds.
Neurons in the VTA send dopamine to many different parts of the brain, but the researchers found that dopamine signals sent to the nucleus accumbens, known to play roles in reward, pleasure, fear and addiction, appear to have the most important role in controlling depression.
‘A bird’s-eye view’
James Bibb, an associate professor of psychiatry at the University of Texas Southwestern Medical Center, says the new study represents a “tour de force of cutting-edge neuroscience.”
“This gives us a completely new bird’s-eye view of the critical synapses that will need to be targeted to more effectively treat mood disorders,” says Bibb, who was not part of the research team. “Antidepressants represent the largest share of the mental-illness drug market and drug developers may very well use this information to come up with new and greatly needed treatments for those [who] suffer from major depressive disorder.”
In her current research, Tye is looking for more new targets for antidepressants, both in the dopamine circuit studied in this paper and in other parts of the brain. She is also interested in examining how stress experienced early in life can influence health later on.
Source: http://today.uconn.edu/blog/2012/11/uco ... e-anymore/UConn Today wrote:To John Salamone, professor of psychology and longtime researcher of the brain chemical dopamine, scientific research can be very slow-moving.
“It takes a long time for things to change in science,” he says. “It’s like pulling on the steering wheel of an ocean liner, then waiting for the huge ship to slowly turn.”
Salamone, a UConn Board of Trustees Distinguished Professor, has spent most of his career battling a particular long-held scientific idea: the popular notion that high levels of brain dopamine are related to experiences of pleasure. As increasing numbers of studies show, he says, the famous neurotransmitter is not responsible for pleasure, but has to do with motivation.
He summarizes and comments on the evidence for this shift in thinking in a Nov. 8 review in the Cell Press journal Neuron.
In the early 1980’s, explains Salamone, the National Institute on Drug Abuse put out a call for research on the neurological basis for drug abuse and addiction.
The research that ensued built support for the idea that when the brain produced elevated amounts of dopamine, it was accompanied by perceptions of pleasure. The chemical quickly became known for this relationship, which was thought to be important for responding to drugs and other motivational substances, such as food.
The chemical, which was formerly only thought to play a small role in movement, became over the subsequent decades among the most well-known and important in the brain. It turned out to be so important that it found its way into popular culture, with dozens of self-help books and websites explaining its relationship to feelings of happiness and reward.
But over time, Salamone’s studies and those of others started revealing problems. In animals, dopamine levels can spike after stress, such as losing a fight with another animal. Soldiers dealing with post-traumatic stress disorder also show activity in dopamine-rich parts of the brain when hearing recorded gunshots and other combat sounds.
“Low levels of dopamine make people and other animals less likely to work for things, so it has more to do with motivation and cost/benefit analyses than pleasure itself.”
So if dopamine was really the pleasure element, then why all this association with negative experiences?
Salamone’s research over the past 15 years has attempted to find an answer to that question. His work involves artificially raising or lowering dopamine levels in animals, then giving them a choice between two rewards with different value, which can be obtained through different amounts of work.
For example, what will a rat do when on one end of a corridor there’s a pile of food, but on the other end there’s a pile of food twice as big with a small fence to jump over on the way?
As Salamone’s studies have showed, animals with lowered levels of dopamine almost always choose the easy, low-value reward, while animals with normal levels don’t mind exerting the effort to jump the fence for the high-value reward.
Other studies in humans have corroborated these results, such as research with depressed patients.
“Often, depressed people say they don’t want to go out with their friends,” says Salamone. But it’s not that they don’t experience pleasure, he says – if their friends were around, many depressed people could have fun.
“Low levels of dopamine make people and other animals less likely to work for things, so it has more to do with motivation and cost/benefit analyses than pleasure itself,” he explains.
In essence, says Salamone, this is how amphetamines work, which increase dopamine levels and help people motivate to focus on tasks at hand.
“When you give people amphetamines, you see them putting more effort into things,” he says.
The big implications of this change in understanding come at the level of overlapping motivational symptoms of depression with those seen in other disorders such as schizophrenia, multiple sclerosis, and Parkinson’s disease. Symptoms of fatigue may be related to low levels of dopamine or changes in other parts of the same brain circuitry.
On the one hand, this lack of perceived energy is maladaptive, because it reduces the tendency to interact with the environment. But, Salamone says, it could also reflect the body’s attempt to save energy in a crisis.
He points out that new ideas in science are traditionally met with criticism. But after all the mounting evidence, he says he’s no longer regarded as “a crazy rebel,” but simply someone who thought differently.
“Science is not a collection of facts. It’s a process,” he says. “First we thought dopamine was involved only in movement. Then that faded and we thought it was pleasure. Now we’ve gone beyond that data on pleasure.”
Although he has thought about writing a popular-press book, he’s not sure he really wants to go to the public and “debunk” the dopamine hypothesis of pleasure and reward. But if he ever does, one thing is for sure.
“I can sum up all this work with one phrase, which would make a great book title,” he says. “Dopamine: it’s not about pleasure anymore.”
Salamone’s work has been funded by the National Institute of Mental Health, a division of the National Institutes of Health, and by the National Institute on Drug Abuse. His co-author is Mercè Correa of the Universitat Jaume I in Spain.
This could also rework the actual nature of depression: is it an anhedonic phenomena, a lack of motivation, or is mainstream science just missing out the actual life of a person and just using simple chemistry models as a cheap replacement?
