Tag: dopamine

Categories : Neurodegenerative DiseasesTags :

Treatment with Dopamine Alleviates Symptoms in Alzheimer’s Disease

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Neurons in the brain of an Alzheimer’s patient, with plaques caused by tau proteins. Credit: NIH

A new way to combat Alzheimer’s disease has been discovered by Takaomi Saido and his team at the RIKEN Center for Brain Science (CBS) in Japan. Using mouse models, the researchers found that treatment with dopamine could alleviate physical symptoms in the brain as well as improve memory. Published in Science Signaling, the study examines dopamine’s role in promoting the production of neprilysin, an enzyme that can break down the harmful plaques in the brain that are the hallmark of Alzheimer’s disease. If demonstrated in human clinical trials, it could lead to a fundamentally new way to treat the disease.

The formation of hardened plaques around neurons is one of the earliest signs of Alzheimer’s disease, often beginning decades before behavioural symptoms such as memory loss are detected. These plaques are formed from pieces of the peptide beta-amyloid that accumulate over time. In the new study, Saido’s team at RIKEN CBS focuses on the enzyme neprilysin because previous experiments showed that genetic manipulation that produces excess neprilysin in the brain (a process called upregulation) resulted in fewer beta-amyloid plaques and improved memory in mice.

Neprilysin by itself cannot be a medication as it cannot enter the brain from the blood stream, so the researchers screened molecules to determine which ones can naturally upregulate neprilysin in the correct parts of the brain. The team’s previous research led them to narrow down the search to hormones produced by the hypothalamus, and they discovered that applying dopamine to brain cells cultured in a dish yielded increased levels of neprilysin and reduced levels of free-floating beta-amyloid.

Now the serious experiments began. Using a DREADD system, they inserted tiny designer receptors into the dopamine producing neurons of the mouse ventral tegmental area. By adding a matching designer drug to the mice’s food, the researchers were able to continuously activate those neurons, and only those neurons, in the mouse brains. As in the dish, activation led to increased neprilysin and decreased levels of free-floating beta-amyloid, but only in the front part of the mouse brain. But could the treatment remove plaques? Yes. The researchers repeated the experiment using a special mouse model of Alzheimer’s disease in which the mice develop beta-amyloid plaques. Eight weeks of chronic treatment resulted in significantly fewer plaques in the prefrontal cortex of these mice.

The DREADD system is an incredible system for precise manipulation of specific neurons. But it is not very useful for human clinical settings. The final experiments tested the effects of L-DOPA treatment. L-DOPA is a dopamine precursor molecule often used to treat Parkinson’s disease because it can enter the brain from the blood, where it is then converted into dopamine. Treating the model mice with L-DOPA led to increased neprilysin and decreased beta-amyloid plaques in both frontal and posterior parts of the brain. Model mice treated with L-DOPA for three months also performed better on memory tests than untreated model mice.

Tests showed that neprilysin levels naturally decreased with age in normal mice, particularly in the frontal part of the brain, perhaps making it a good biomarker for preclinical or at-risk Alzheimer’s disease diagnoses. How dopamine causes neprilysin levels to increase remains unknown, and is the next research topic for Saido’s group.

“We have shown that L-DOPA treatment can help reduce harmful beta-amyloid plaques and improve memory function in a mouse model of Alzheimer’s disease,” explains Watamura Naoto, first author of the study. “But L-DOPA treatment is known to have serious side effects in patients with Parkinson’s disease. Therefore, our next step is to investigate how dopamine regulates neprilysin in the brain, which should yield a new preventive approach that can be initiated at the preclinical stage of Alzheimer’s disease.”

Source: RIKEN

Categories : Exercise NeurologyTags :

Dopamine’s Role in Exercise Feeling ‘Hard’ or ‘Easy’

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Photo by Jonathan Borba on Unsplash

Dopamine, long associated with pleasure, motivation and reward-seeking, also appears to play an important role in why exercise and other physical efforts feel ‘easy’ to some people and exhausting to others. These are the findings of of a study of people with Parkinson’s disease, which is published in NPG Parkinson’s Disease. Parkinson’s disease is marked by a loss of dopamine-producing cells in the brain over time.

According to the researchers, the findings might eventually lead to more effective ways to help people establish and stick with exercise regimens, new treatments for fatigue associated with depression and many other conditions, and a better understanding of Parkinson’s disease.

“Researchers have long been trying to understand why some people find physical effort easier than others,” says study leader Vikram Chib, Ph.D., associate professor in the Department of Biomedical Engineering at the Johns Hopkins University School of Medicine and research scientist at the Kennedy Krieger Institute. “This study’s results suggest that the amount of dopamine availability in the brain is a key factor.”

Chib explains that after a bout of physical activity, people’s perception and self-reports of the effort they expended varies, and also guides their decisions about undertaking future exertions. Previous studies have shown that people with increased dopamine are more willing to exert physical effort for rewards, but the current study focuses on dopamine’s role in people’s self-assessment of effort needed for a physical task, without the promise of a reward.

For the study, Chib and his colleagues from Johns Hopkins Medicine and the Kennedy Krieger Institute recruited 19 adults diagnosed with Parkinson’s disease, a condition in which neurons in the brain that produce dopamine gradually die off, causing unintended and uncontrollable movements such as tremors, fatigue, stiffness and trouble with balance or coordination.

In Chib’s lab, 10 male volunteers and nine female volunteers with an average age of 67 were asked to perform the same physical task, that of squeezing a hand grip equipped with a sensor, on two different days within four weeks of each other. On one of the days, the patients were asked to take their standard, daily synthetic dopamine medication as they normally would. On the other, they were asked not to take their medication for at least 12 hours prior to performing the squeeze test.

On both days, the patients were initially taught to squeeze a grip sensor at various levels of defined effort, and then were asked to squeeze and report how many units of effort they put forth.

When the participants had taken their regular synthetic dopamine medication, their self-assessments of units of effort expended were more accurate than when they hadn’t taken the drug. They also had less variability in their efforts, showing accurate squeezes when the researchers cued them to squeeze at different levels of effort.

In contrast, when the patients hadn’t taken the medication, they consistently over-reported their efforts, meaning they perceived the task to be physically harder, and had significantly more variability among grips after being cued.

In another experiment, the patients were given a choice between a sure option of squeezing with a relatively low amount of effort on the grip sensor or flipping a coin and taking a chance on having to perform either no effort or a very high level of effort. When these volunteers had taken their medication, they were more willing to take a chance on having to perform a higher amount of effort than when they didn’t take their medication.

A third experiment offered participants the choice between getting a small amount of guaranteed money or, getting either nothing or a higher amount of money on a coin flip. Results showed no difference in the subjects on days when they took their medication and when they did not. This result, researchers say, suggests that dopamine’s influence on risk-taking preferences is specific to physical effort-based decision-making.

Together, Chib says, these findings suggest that dopamine level is a critical factor in helping people accurately assess how much effort a physical task requires, which can significantly affect how much effort they’re willing to put forth for future tasks. For example, if someone perceives that a physical task will take an extraordinary amount of effort, they may be less motivated to do it.

Understanding more about the chemistry and biology of motivation could advance ways to motivate exercise and physical therapy regimens, Chib says. In addition, inefficient dopamine signalling could help explain the pervasive fatigue present in conditions such as depression and long COVID, and during cancer treatments. Currently, he and his colleagues are studying dopamine’s role in clinical fatigue.

Source: John Hopkins Medicine

Categories : AddictionTags :

Single Pathway Controls Drug Withdrawal-induced Anxiety

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Depression, young man
Source: Andrew Neel on Unsplash

New research published today in Cell Reports finds that drug withdrawal-induced anxiety and return to drug seeking behaviours are controlled by a single pathway in the brain and are centred on dopamine cells, which are normally associated with reward behaviours.

Addiction occurs in phases: the initial drug exposures are rewarding, and then repeated administration leads to tolerance or sensitisation to the drug’s effects, with withdrawal leading to anxiety and a negative affective state, which, in turn, contributes to a return to drug taking or seeking.

“In order to prevent relapse among drug users, specifically cocaine users, we need to understand the factors in the brain that contribute to drug seeking behaviours and the vulnerability to relapse,” said Kevin Beier, PhD, assistant professor of physiology and biophysics from the University of California, Irvine. “In this study, we identified a brain circuit that is responsible for drug withdrawal-induced anxiety as well as relapse-related behaviour, along with the identification of a potential target for therapeutic interventions.”

The negative affective state induced by drug withdrawal is a critical factor in the relapse of drug users.

“Both the drug withdrawal-induced anxiety and reinstatement of drug seeking are controlled by a single pathway centred around dopamine cells in the ventral midbrain,” explained Dr Beier. “That a single pathway controls both sets of behavioural changes may help to explain many addiction-related behavioural phenomena. Importantly, it links them both directly to dopamine, which is more typically linked to reward-related behaviours.”

While midbrain dopamine circuits are central to motivated behaviours, just how experience modifies these circuits to facilitate subsequent behavioural adaptations is not well understood. This study demonstrates the selective role of a ventral tegmental area dopamine projection to the amygdala for cocaine induced anxiety, but not for cocaine reward or sensitisation. Silencing this projection prevents development of anxiety during protracted withdrawal after cocaine use.

According to the National Center for Drug Abuse Statistics, there are roughly 70 000 drug overdoses each year in the United States. In 2017, nearly one in five drug overdose deaths was cocaine-related, with the highest rate of cocaine-related overdoses and deaths occurring among non-Hispanic black populations. Between 2012 and 2018, the rate of cocaine-related overdose deaths increased from 1.4 to 4.5%. The American Addiction Centers state recent drug relapse statistics show that more than 85% of individuals relapse and return to drug use within a year following treatment.

Source: University of California – Irvine

Categories : AddictionTags :

Glutamate and Dopamine Interact in Addiction

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Image source: Pixabay

Drug addiction is a psychiatric disorder for which no pharmacological treatment with long-term efficacy currently exists: all addictive substances have in common the fact that they raise concentrations of the neurotransmitter dopamine within brain regions forming the neural reward circuit.

This increase in dopamine levels results in long-lasting alteration of signal transmission that is dependent on another neurotransmitter, glutamate, which causes addictive behaviours. Through a new study in mice and humans, an international team including scientists from the CNRS, INRAE, the CEA, Sorbonne University, Paris-Saclay University, the University of Bordeaux, and Université Côte d’Azur has uncovered, the molecular bases of this deleterious interplay between dopamine and glutamate.

The researchers’ findings demonstrate that the inhibition of interactions between dopamine and glutamate receptors prevents pathological behaviours provoked by cocaine in mice, without altering natural reward processing. Their findings, published in Science Advances, will help pave the way for the development of new therapeutic strategies to treat addiction, and a wider spectrum of psychiatric disorders.

Source: CNRS (Délégation Paris Michel-Ange)

Categories : Mental Health Metabolic DisordersTags :

Why Antipsychotic Drugs Cause Weight Gain

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A University of Pittsburgh study has discovered that the reason antipsychotic medications have weight gain as side effects is because the pancreas also produces and responds to dopamine.

Dopamine is a neurotransmitter involved in mood regulation, pleasure and reward signalling. Many psychological disorders are thought to involve dopamine imbalances and are treated by medications designed to this end.
“There are dopamine theories of schizophrenia, drug addiction, depression and neurodegenerative disorders, and we are presenting a dopamine theory of metabolism,” said lead author Despoina Aslanoglou, PhD, at the University of Pittsburgh. “We’re seeing now that it is not only interesting to study dopamine in the brain, but it is equally interesting and important to study it in the periphery.”

Senior author Zachary Freyberg, MD, PhD, assistant professor of psychiatry and cell biology at Pitt, observed that the dopamine theory is not as simple or as well understood as we would like to think.

“We still don’t really understand how dopamine signals biologically,” said Dr Freyberg. “Even decades after dopamine receptors have been discovered and cloned, we still deploy this ‘magical thinking’ approach: something happens that’s good enough. We use drugs that work on dopamine receptors, but how they intersect with this ‘magical system’ is even less understood.”

The researchers found that dopamine is not only produced in the brain but also in the alpha and beta cells of the pancreas, which secrete glucagon and insulin, respectively.

Alpha cells can produce their own dopamine with no precursors in response to glucose levels, while beta cells require an L-DOPA precursor. It may be possible that alpha cells secrete dopamine for their own receptors, while also supplying it to beta cells to suppress the release of insulin.

Surprisingly, the researchers also discovered that pancreatic dopamine can affect other receptors, such as noradrenaline and adrenaline.
At low concentrations, dopamine binds to D2-like dopamine receptors, blocking the release of glucagon or insulin. At high concentrations, dopamine binds to beta-adrenergic receptors, becoming stimulatory and pushing up glucagon levels while inhibiting insulin levels by blocking alpha-adrenergic receptors.

The study revealed how blocking inhibitory dopamine receptors causes an unchecked release of insulin and glucagon, leading to metabolic disorders and eventually, obesity and diabetes. This finding will help to formulate better drugs that target the dopamine system, reducing the effect on the pancreas.

Source: News-Medical.Net