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Drug-Induced Psychosis: How to Avoid Star Gazing in Schizophrenia Research by Looking at More Obvious Sources of Light

They administered dextroamphetamine by mouth on days 1, 3, and 5 to 10 healthy volunteers, and measured the effect on striatal dopamine release before exposure, then the day of first exposure, then 2 weeks later after the third dose, using the PET/[11C] raclopride technique. Each dose of amphetamine caused greater dopamine release in the ventral striatum together with greater behavioral responses. Indeed, 1 year later there was a greater psychomotor response and greater increase dopamine release compared to the initial dose, in the ventral striatum, progressively extending to the dorsal caudate and putamen (Boileau et al., 2006). Such findings have led to the “dopamine sensitization” hypothesis of schizophrenia which postulates that a sensitized dopamine system is responsible for the genesis of psychotic symptoms (Peleg-Raibstein et al., 2009).

How Meth Destroys The Body | The Meth Epidemic | FRONTLINE | PBS

"There [are] a whole variety of reasons to try methamphetamine," explains Dr. Richard Rawson, associate director of UCLA's Integrated Substance Abuse Programs. "[H]owever, once they take the drug … their reasons are pretty much the same: They like how it affects their brain[s]." Meth users have described this feeling as a sudden rush of pleasure lasting for several minutes, followed by a euphoric high that lasts between six and 12 hours, and it is the result of drug causing the brain to release excessive amounts of the chemical dopamine, a neurotransmitter that controls pleasure. All drugs of abuse cause the release of dopamine, even alcohol and nicotine, explains Rawson, "[But] methamphetamine produces the mother of all dopamine releases." For example, in lab experiments done on animals, sex causes dopamine levels to jump from 100 to 200 units, and cocaine causes them to spike to 350 units. "[With] methamphetamine you get a release from the base level to about 1,250 units, something that's about 12 times as much of a release of dopamine as you get from food and sex and other pleasurable activities," Rawson says. "This really doesn't occur from any normally rewarding activity. That's one of the reasons why people, when they take methamphetamine, report having this euphoric [feeling] that's unlike anything they've ever experienced." Then, when the drug wears off, users experience profound depression and feel the need to keep taking the drug to avoid the crash.

Link between hallucinations and dopamine not such a mystery, finds study -- ScienceDaily

"Our brain uses prior experiences to generate sensory expectations that help fill in the gaps when sounds or images are distorted or unclear," said Guillermo Horga, MD, PhD, assistant professor of clinical psychiatry at CUIMC and a research psychiatrist at NYSPI. "In individuals with schizophrenia, this process appears to be altered, leading to extreme perceptual distortions, such as hearing voices that are not there. Furthermore, while such hallucinations are often successfully treated by antipsychotic drugs that block the neurotransmitter dopamine in a brain structure known as the striatum, the reason for this has been a mystery since this neurotransmitter and brain region are not typically associated with sensory processing." The researchers designed an experiment that induces an auditory illusion in both healthy participants and participants with schizophrenia. They examined how building up or breaking down sensory expectations can modify the strength of this illusion. They also measured dopamine release before and after administering a drug that stimulates the release of dopamine. Patients with hallucinations tended to perceive sounds in a way that was more similar to what they had been cued to expect, even when sensory expectations were less reliable and illusions weakened in healthy participants. This tendency to inflexibly hear what was expected was worsened after giving a dopamine-releasing drug, and more pronounced in participants with elevated dopamine release, and more apparent in participants with a smaller dorsal anterior cingulate (a brain region previously shown to track reliability of environmental cues).

Body movements just need a 'puff' of dopamine to get started: A new study in mice suggests that a burst of dopamine levels at the beginning of a movement only, as opposed to all the time, is what gets us going; this may have important implications for treating Parkinson's disease -- ScienceDaily

Experts have long worked to understand why the absence of these so-called dopaminergic neurons (and therefore, the lack of dopamine) leads to the motor dysfunctions that are the hallmarks Parkinson's, such as stiffness, slow movements and tremors. The more widely accepted explanation has been that, in order to move normally, our brain constantly needs a certain level of dopamine -- something that Parkinson's patients progressively lose. However, as psychiatrist and neuroscientist Joaquim Alves da Silva, first author of the new study, explains, people with Parkinson's disease actually "do not have a global motor problem." As incredible as it may seem, they can even ride a bicycle -- a rather complex motor task -- if pushed at the right time. The motor problems that Parkinson's patients experience are more specific, and this was the observation that motivated the new study. "The patients' problem is in the difficulty to initiate movement and in the slowness of movement," adds Alves da Silva. In fact, as these authors now showed in mice not afflicted by Parkinson's disease, for a movement to unfold correctly it only takes a "puff" of dopamine -- or more precisely, a peak of dopaminergic cell activity -- right before the movements starts. In other words, dopamine (or, in this case, the activity of the cells that produce it) is just a "trigger" for voluntary movements. "Our most important result is that we showed, for the first time, that the change in neural activity is necessary to promote movement," says Alves da Silva. "And also for the first time, we showed that the dopamine peak that precedes movement initiation does not only regulate initiation, but also regulates movement vigor."

Low Dopamine Levels During Withdrawal Promote Relapse to Smoking

“This study is an elegant example of yet another way that addiction ‘hijacks’ the reward system. The phasic release of dopamine triggers us to seek things that, in theory, help us to adapt to our environment,” commented Dr. John Krystal, editor of Biological Psychiatry. “However, in addiction the phasic release of dopamine is heightened and it triggers the pursuit of abused substances. This disturbance of dopamine function would, conceivably, make it that much harder to avoid seeking drugs of abuse.”

Key psychiatric drug target comes into focus: Team determines first high-resolution structure of dopamine receptor -- ScienceDaily

One way or another, many psychiatric drugs work by binding to receptor molecules in the brain that are sensitive to the neurotransmitter dopamine, a chemical signal that is central to how our experiences shape our behavior. But because scientists still don't understand the differences between the many kinds of dopamine receptors present on brain cells, most of these drugs are "messy," binding to multiple different dopamine receptor molecules and leading to serious side effects ranging from movement disorders to pathological gambling.

Surprising discovery about how neurons talk to each other -- ScienceDaily

The team then demonstrated that the increase in acidity was driven by a transport channel in the cell's surface, which allowed an influx of negatively charged glutamate ions to enter the neuron, thus increasing its acidity. Genetically removing the transporter in fruit flies and mice made the animals less responsive to amphetamine, a drug that exerts its effect by stimulating dopamine release from neurons. "In this case, glutamate is not acting as a neurotransmitter. Instead it is functioning primarily as a source of negative charge, which is being used by these vesicles in a really clever way to manipulate vesicle acidity and therefore change their dopamine content," Freyberg said. "This calls into question the whole textbook model of vesicles as having fixed amounts of single neurotransmitters. It appears that these vesicles contain both dopamine and glutamate, and dynamically modify their content to match the conditions of the cell as needed."

Sleep, dopamine and memory

The study shows that increasing sleep, with either a sleep-promoting drug or by genetic stimulation of the neural sleep circuit, decreases signaling activity by dopamine, while at the same time enhancing memory retention. Conversely, increasing arousal stimulates dopamine signaling and accelerates forgetting. This signal activity isn’t constant but is tied directly to the animal’s arousal level. “Our findings add compelling evidence to support the model that sleep reduces the forgetting signal in the brain, thereby keeping memories intact,” Davis said. “As sleep progresses to deeper levels, dopamine neurons become less reactive to stimuli and this leads to more stable memories.

Dopamine toggling governs decision making

The voltammetry results showed that fluctuations in brain dopamine level were tightly associated with the animal's decision. The scientists were actually able to accurately predict the animal's upcoming choice of lever based on dopamine concentration alone. Interestingly, other mice that got a treat by pressing either lever (so removing the element of choice) experienced a dopamine increase as trials got under way, but in contrast their levels remained above baseline (didn't fluctuate below baseline) the entire time, indicating dopamine's evolving role when a choice is involved. "We are very excited by these findings because they indicate that dopamine could also be involved in ongoing decision, beyond its well-known role in learning," adds the paper's co-first author, Christopher Howard, a Salk research collaborator. To verify that dopamine level caused the choice change, rather than just being associated with it, the team used genetic engineering and molecular tools -- including activating or inhibiting neurons with light in a technique called optogenetics -- to manipulate the animals' brain dopamine levels in real time. They found they were able to bidirectionally switch mice from one choice of lever to the other by increasing or decreasing dopamine levels. Jin says these results suggest that dynamically changing dopamine levels are associated with the ongoing selection of actions. "We think that if we could restore the appropriate dopamine dynamics -- in Parkinson's disease, OCD and drug addiction -- people might have better control of their behavior. This is an important step in understanding how to accomplish that."

Addicted to Your iPhone? You’re Not Alone - The Atlantic

For example, rewarding someone with an instantaneous “like” after they post a photo can reinforce the action, and potentially shift it from an occasional to a daily activity.

Generation Adderall - The New York Times

During the first weeks of finally giving up Adderall, the fatigue was as real as it had been before, the effort required to run even a tiny errand momentous, the gym unthinkable. The cravings were a force of their own: If someone so much as said “Adderall” in my presence, I would instantly begin to scheme about how to get just one more pill. Or maybe two. I was anxious, terrified I had done something irreversible to my brain, terrified that I was going to discover that I couldn’t write at all without my special pills. I didn’t yet know that it would only be in the amphetamine-free years to follow that my book would finally come together.

Dopamine signaling as a neural correlate of consciousness

The neural correlates of consciousness are largely unknown but many neural circuits are likely to be involved. Our experiments with mice that cannot synthesize dopamine suggest that dopamine signaling is a critical component necessary for the expression of consciousness. Although dopamine-deficient mice are awake and respond to many stimuli, they are unmotivated and have profound deficits in all but the simplest learning tasks. Dopamine-deficient mice are unable to attend to salient sensory information, integrate it with prior experience, store it in long-term memory, or choose appropriate actions. While clearly conscious from a general anesthetic point of view, dopamine-deficient mice have marginal arousal and appear to be virtually unconscious from a behavioral point of view. Restoration of dopamine signaling within the striatum by viral gene therapy strategies restores most behaviors.

Research shows certain genes, in healthy environments, can lengthen lifespan -- ScienceDaily

The researchers found that the dopamine D2 receptor gene (D2R) significantly influences lifespan, body weight and locomotor activity, but only when combined with an enriched environment that included social interaction, sensory and cognitive stimulation and, most critically, exercise.

Dopamine's influence on preferences

The next day (once the L-DOPA had cleared from the body), all the participants were brought back and presented with 40 pairs of vacation spots, each pair containing locations to which they had given equal ratings in the first part of the experiment. Participants were asked to pick which of each pair of places they would prefer to visit. It turned out that those who had imagined themselves vacationing the previous day under the influence of dopamine were significantly more likely to predict they'd be happier in those same spots. That same preference didn't occur in the placebo group.

Smoking's double hit of dopamine

Recent research has shown how nicotine acts on the brain. Nicotine activates the circuitry that regulates feelings of pleasure, the so-called reward pathways. Research has shown that nicotine increases the levels of dopamine (a key brain chemical involved in mediating the desire to consume drugs) in the reward circuits. Nicotine's pharmacokinetic properties have been found to enhance its abuse potential. Cigarette smoking produces a rapid distribution of nicotine to the brain, with drug levels peaking within 10 seconds of inhalation. The acute effects of nicotine dissipate within a few minutes, causing the need to continue repeated intake throughout the day. A cigarette is a very efficient and highly engineered drug-delivery system. A smoker can get nicotine to the brain very rapidly with every inhalation. A typical smoker will take 10 puffs on a lit cigarette over a period of 5 minutes. Thus, a person who smokes about one-and-a-half packs (30 cigarettes) each day gets 300 nicotine hits to the brain daily. These factors contribute considerably to nicotine's highly addictive nature. Using advanced neuroimaging technology, research is beginning to show that nicotine may not be the only psychoactive ingredient in tobacco. Scientists can see the dramatic effect of cigarette smoking on the brain and are finding a marked decrease in the levels of monoamineoxidase (MAO), an enzyme responsible for breaking down dopamine. The change in MAO must be caused by some tobacco smoke ingredient other than nicotine, since nicotine itself does not dramatically alter MAO levels. The decrease in two forms of MAO, A and B, results in higher dopamine levels. The need to sustain the high dopamine levels results in the desire for repeated drug use.

Dopamine and memory

In 2015, a systematic review and a meta-analysis of high quality clinical trials found that, when used at low (therapeutic) doses, stimulants produce unambiguous improvements in working memory, episodic memory, and inhibitory control in adults.[83][84]

Hit of dopamine twelve hours after event is crucial for memory formation

The FMI scientists found that dopamine, through the D1/5 dopamine receptor on basket cells, helps maintain the changes induced in basket cells during learning. Interestingly, this is particularly important 12-14 hours after the learning experience, when enhanced network activity is thought to consolidate circuitry changes that encode long-term memories. Without the dopamine signal after 12 hours, basket cell plasticity is rapidly lost and no long-term memory is formed. "This time window at 12-14 hours is independent of the day-night cycle, and specifically associated to each memory. It is as if each new learning process starts a clock that will ultimately result in consolidation of memories 12-14 hours later. So, why 12-14 hours? We do not know," commented Caroni. "It might be that the processes occurring between acquisition and this critical 12-14 hours time window ensure that what is learned is validated through subsequent experience, and that what is consolidated into long-term memory is also compared and integrated with previous learning."

Drugs for Parkinson's -- Side Effects

After examining 2.7 million reports of drug reactions submitted to an FDA database between 2003 and 2012, researchers published a study in JAMA Internal Medicine that independently corroborated that a disproportionate number of people living with PD have reported impulse control disorders. The study results reflect that although dopamine medications (such as Mirapex, Requip and Neupro) are essential to treating Parkinson’s Disease (PD), the challenge is to find a balance between high and low levels of dopamine. Long-term exposure to dopamine medications, especially dopamine agonists (DAs), can cause a hypersensitivity to dopamine. The body overreacts, and this in turn can lead to an impulse control disorder (ICD) — a group of behaviors that includes gambling, uncontrollable shopping, compulsive eating, a sudden obsession with sex, punding (stereotypic, complex, and repetitive behavior involving meaningless activities) — as well as a related disorder, excessive daytime sleepiness.