Feel-good hormone helps to jog the memory

The feel-good hormone dopamine improves long-term memory. This is the finding of a team lead by Emrah Düzel, neuroscientist at the German Center for Neurodegenerative Diseases (DZNE) and the University of Magdeburg. The researchers investigated test subjects ranging in age from 65 to 75 years, who were given a precursor of dopamine. Treated subjects performed better in a memory test than a comparison group, who had taken a placebo. The study provides new insights into the formation of long lasting memories and also has implications for understanding why memories fade more rapidly following the onset of Alzheimer’s disease. The results appear in the Journal of Neuroscience.

The Mysterious Motivational Functions of Mesolimbic Dopamine

Nucleus accumbens dopamine is known to play a role in motivational processes, and dysfunctions of mesolimbic dopamine may contribute to motivational symptoms of depression and other disorders, as well as features of substance abuse. Although it has become traditional to label dopamine neurons as “reward” neurons, this is an overgeneralization, and it is important to distinguish between aspects of motivation that are differentially affected by dopaminergic manipulations. For example, accumbens dopamine does not mediate primary food motivation or appetite, but is involved in appetitive and aversive motivational processes including behavioral activation, exertion of effort, approach behavior, sustained task engagement, Pavlovian processes, and instrumental learning. In this review, we discuss the complex roles of dopamine in behavioral functions related to motivation.

Challenging Parkinson’s Dogma: Dopamine may not be the only key player in this tragic neurodegenerative disease

Scientists may have discovered why the standard treatment for Parkinson’s disease is often effective for only a limited period of time. Their research could lead to a better understanding of many brain disorders, from drug addiction to depression, that share certain signaling molecules involved in modulating brain activity.

A team led by Bernardo Sabatini, Takeda Professor of Neurobiology at Harvard Medical School, used mouse models to study dopamine neurons in the striatum, a region of the brain involved in both movement and learning. In people, these neurons release dopamine, a neurotransmitter that allows us to walk, speak and even type on a keyboard. When those cells die, as they do in Parkinson’s patients, so does the ability to easily initiate movement. Current Parkinson’s drugs are precursors of dopamine that are then converted into dopamine by cells in the brain.

The flip side of dopamine dearth is dopamine hyperactivity. Heroin, cocaine and amphetamines rev up or mimic dopamine neurons, ultimately reinforcing the learned reward of drug-taking. Other conditions such as obsessive-compulsive disorder, Tourette syndrome and even schizophrenia may also be related to the misregulation of dopamine.

In the October 11 issue of Nature, Sabatini and co-authors Nicolas Tritsch and Jun Ding reported that midbrain dopamine neurons release not only dopamine but also another neurotransmitter called GABA, which lowers neuronal activity. The previously unsuspected presence of GABA could explain why restoring only dopamine could cause initial improvements in Parkinson’s patients to eventually wane. And if GABA is made by the same cells that produce other neurotransmitters, such as depression-linked serotonin, similar single-focus treatments could be less successful for the same reason.

“If what we found in the mouse applies to the human, then dopamine’s only half the story,” said Sabatini.

Placebo’s Effect May Depend on Your Genes

Your response to placebos, or dummy medicine, may depend on your genes, according to a new study.

People with a gene variant that codes for higher levels of the brain chemical dopamine respond better to placebos than those with the low-dopamine version.

The findings, reported online Oct. 23 in the journal PLoS One, could help researchers design medical studies that distinguish the placebo response from the underlying effect of a medicine — the real aim of drug trials.

Does motherhood dampen cocaine’s effects?

Mother rats respond much differently to cocaine than female rats that have never given birth, according to new University of Michigan research that looks at both behavior and brain chemistry.

The findings may help lay the groundwork for more tailored human addiction treatment, based on scientific understanding of how gender, hormones and life experience impact drug use.

In an oral presentation at the Society for Neuroscience meeting, U-M researcher Jennifer Cummings, Ph.D., summarized findings from experiments with rats at the Molecular and Behavioral Neuroscience Institute, part of the U-M Medical School. She worked with Jill Becker, Ph.D., of the U-M Department of Psychology.

They identified clear differences in how intensely the “pleasure centers” in the mother rats’ brains reacted to the drug, compared with non-mothers. Mother rats’ brains released less of a chemical called dopamine, which helps cause the “high” from cocaine.

They also found an interaction with stress: mother rats that were exposed to periods of increased stress weren’t willing to work as hard to get a dose of cocaine, compared with rats that had never given birth or mother rats that weren’t exposed to the stress – even though the stressed mother rats showed an increased tendency to use cocaine when it was easy to get.

Taken together, the findings suggest that the experience of becoming a mother alters a female’s overall response to cocaine – adding complexity to the issue of how best to treat addiction.

“While we have not yet identified a mechanism to explain these differences, they do suggest that the reward system and brain circuitry affected by cocaine is changed with maternal experience,” says Cummings, a research investigator at MBNI and former postdoctoral fellow in Becker’s laboratory. “The next step is to determine how factors such as hormone changes in pregnancy and early motherhood, and the experience of caring for offspring, might be differentially contributing to this response.”

Morphine and cocaine affect reward sensation differently

A new study by scientists in the US has found that the opiate morphine and the stimulant cocaine act on the reward centers in the brain in different ways, contradicting previous theories that these types of drugs acted in the same way.

Morphine and cocaine both affect the flow of the neurotransmitter dopamine, which has been shown to be important in the feeling of reward. When a dopamine neuron is stimulated it releases dopamine, which is then taken up by neighboring cells. Any excess is reabsorbed into the original dopamine neuron by a process known as “reuptake.”

Cocaine is known to block reuptake, and the excess dopamine leads to an enhanced reward effect. Cocaine is also known to make the cells in the nucleus accumbens, which receives signals from the VTA, more sensitive to cocaine. It was already known a protein called brain-derived neurotrophic factor (BDNF) in the VTA region of the brain enhances the reward response to cocaine.

The new study shows that BDNF has the opposite effect when morphine is present, decreasing the reward response and the development of addiction rather than enhancing it. The researchers identified numerous genes regulated by BDNF and associated with its effects. They used genetic techniques to suppress BDNF, and then directly excited the neurons in the nucleus accumbens that normally receives transmitted impulses from the VTA.

They found that suppressing BDNF in the VTA allowed morphine to increase the excitability of dopamine neurons and hence enhance the reward. When they optically excited the dopamine terminals in the nucleus accumbens that normally receive the transmissions from the VTA, they also found a reversal in the normal effect of BDNF.

Occupancy of Brain Dopamine D3 Receptors and Drug Craving: A Translational Approach

Selective dopamine D3 receptor (D3R) antagonists prevent reinstatement of drug-seeking behavior and decrease the rewarding effects of contextual cues associated with drug intake preclinically, suggesting that they may reduce drug craving in humans. GSK598809 is a selective D3R antagonist recently progressed in Phase I trials. The aim of this study was to establish a model, based on the determination of the occupancy of brain D3Rs (OD3R) across species, to predict the ability of GSK598809 to reduce nicotine-seeking behavior in humans, here assessed as cigarette craving in smokers. Using ex vivo [125I](R)-trans-7-hydroxy-2-[N-propyl-N-(3′-iodo-2′-propenyl)amino] tetralin ([125I]7OH-PIPAT) autoradiography and [11C]PHNO positron emission tomography, we demonstrated a dose-dependent occupancy of the D3Rs by GSK598809 in rat, baboon, and human brains. We also showed a direct relationship between OD3R and pharmacokinetic exposure, and potencies in line with the in vitro binding affinity. Likewise, GSK598809 dose dependently reduced the expression of nicotine-induced conditioned place preference (CPP) in rats, with an effect proportional to the exposure and OD3R at every time point, and 100% effect at OD3R values greater than or equal to 72%. In humans, a single dose of GSK598809, giving submaximal levels (72–89%) of OD3R, transiently alleviated craving in smokers after overnight abstinence. These data suggest that either higher OD3R is required for a full effect in humans or that nicotine-seeking behavior in CPP rats only partially translates into craving for cigarettes in short-term abstinent smokers. In addition, they provide the first clinical evidence of potential efficacy of a selective D3R antagonist for the treatment of substance-use disorders.

The mechanism of action of cocaine

Cocaine modifies the action of dopamine in the brain. The dopamine rich areas of the brain are the ventral tegmental area, the nucleus accumbens and the caudate nucleus – these areas are collectively known as the brain’s ‘reward pathway’. Cocaine binds to dopamine re-uptake transporters on the pre-synaptic membranes of dopaminergic neurones. This binding inhibits the removal of dopamine from the synaptic cleft and its subsequent degradation by monoamine oxidase in the nerve terminal. Dopamine remains in the synaptic cleft and is free to bind to its receptors on the post synaptic membrane, producing further nerve impulses. This increased activation of the dopaminergic reward pathway leads to the feelings of euphoria and the ‘high’ associated with cocaine use.

Schizophrenia

Credit: JOHN BAVOSI/SCIENCE PHOTO LIBRARY

Caption: Schizophrenia. Artwork of a man hearing non- existent women’s voices. Auditory hallucinations are one of the most common symptoms of schizophrenia. One explanation for this disease is known as the dopamine hypothesis. Dopamine (the molecules at lower left & right) is a type of neurotransmitter. This chemical (tiny red spheres) is released from the ends (synapses) of nerve cells (neurons, upper left & right) when they pass on nerve impulses to other neurons. In schizophr- enia, however, the dopamine-producing neurons of the brain are overactive. This causes the sufferer to lose contact with reality, suffering from confused thoughts and emotional responses.