Grabbing addiction by the tail

November 24, 2005

Canadian scientists have developed some clever molecular trickery that is helping to reduce the drug cravings of addicted rats. One of the problems in addiction is that neurons in some parts of the brain lose glutamate receptors from the cell surface, and those receptors are important for communication between neurons. The researchers have sidestepped this problem by crafting a peptide that mimics a portion of the tail of the glutamate receptor and, once inside a neuron, serves as a decoy to prevent the loss of glutamate receptors.

Yu Tian Wang, an HHMI international research scholar, and colleagues at the University of British Columbia in Vancouver report their findings in the November 25, 2005, issue of the journal Science.

In addicted rats, cell-to-cell communication is compromised as a result of certain long-term changes at the level of individual neurons. Their research has produced a targeted drug that tricks brain cells into preventing those changes. "We think this is a good candidate for a drug against addiction that has very few side effects," said Wang, a neuroscientist . Although the initial studies are promising, Wang cautioned that the drug is in the early stages of development and is years away from testing in humans.

During addiction to drugs, cells in the nucleus accumbens - a tiny ball of tissue deep in the brain involved in pleasure and motivation - mis-communicate. Normally, one neuron triggers activity in a neighbor by using neurotransmitters such as glutamate. "This is the 'go' signal," said Wang. "The receiving cell uses glutamate receptors on its surface to listen to the signal.

But after repeated abuse of a drug, cells in the nucleus accumbens internalize glutamate receptors, compromising their ability to listen to the signals. Earlier research showed that receptor internalization in addicted rats accompanies behavioral sensitization, a model of craving.

Until now, though, no one knew how these receptors were removed from the cell surface, whether the process could be halted, and, if it could, whether the addicted rats would exhibit fewer signs of behavioral sensitization. Wang's research has made significant progress toward answering these questions.

The researchers began by building a peptide - a long molecule made from a string of amino acids - with a structure similar to the tail of the glutamate receptor that is anchored inside the cell. In addiction, cellular machinery tugs on this tail, pulling the entire receptor into the cell. Without its business end sticking out into the synapse, or space between neurons, the receptor no longer works.

Wang's peptide tricks the cellular machinery into tugging on it instead of the receptor's tail. "Once it gets inside the neuron, the peptide competes with the receptor for binding to the machinery," Wang explained. With the cellular machinery otherwise occupied, the glutamate receptors stay on the cell surface, where they continue to receive signals.

After confirming these results in cell cultures, Wang and colleagues tested the peptide in rats that had been given amphetamine once every other day for 20 days. During this period, the animals displayed stereotypical behavior such as repeated sniffing, licking, and grooming, indicating a craving for the drug. Such behavior parallels the compulsive thought patterns that people addicted to drugs experience, said Anthony Phillips, Wang's colleague at the University of British Columbia and a co-author of the article.

After keeping the rats drug-free for 21 days, the researchers gave the animals a small amount of drug again. The rats immediately displayed intense stereotypical behavior - a sign of behavioral sensitization. The behavior meant that the glutamate receptors in the animals' neurons were rapidly internalized, said Wang. "It's the trigger that leads to sustained motivation to seek a drug."

In contrast, addicted animals who received an intravenous injection of the artificial peptide displayed no sensitized behavior. "The effect was immediate and very noticeable," said Wang.

There are several types of glutamate receptors involved in memory and learning, but because the artificial peptide specifically targets only the deleterious internalization process of addiction-affected neurons, and not normal receptor function, the animals who received it behaved normally and were able to learn as usual. "So far, we have not seen any obvious side effects at all," said Wang.

By inserting a tiny tube into the rats' brains, the researchers delivered the peptide directly to the nucleus accumbens and to another area of the brain involved in reward and motivation, the ventral tegmental area. The peptide reduced the rats' drug-seeking behavior only when injected into the nucleus accumbens, evidence that the structure is critical for the expression of some of the devastating behaviors of addiction.
-end-
Wang and colleagues recently received grants from the Brain Repair Program of NeuroScience Canada and the Canadian Institutes of Health Research to continue testing the peptide.

Howard Hughes Medical Institute

Related Neurons Articles from Brightsurf:

Paying attention to the neurons behind our alertness
The neurons of layer 6 - the deepest layer of the cortex - were examined by researchers from the Okinawa Institute of Science and Technology Graduate University to uncover how they react to sensory stimulation in different behavioral states.

Trying to listen to the signal from neurons
Toyohashi University of Technology has developed a coaxial cable-inspired needle-electrode.

A mechanical way to stimulate neurons
Magnetic nanodiscs can be activated by an external magnetic field, providing a research tool for studying neural responses.

Extraordinary regeneration of neurons in zebrafish
Biologists from the University of Bayreuth have discovered a uniquely rapid form of regeneration in injured neurons and their function in the central nervous system of zebrafish.

Dopamine neurons mull over your options
Researchers at the University of Tsukuba have found that dopamine neurons in the brain can represent the decision-making process when making economic choices.

Neurons thrive even when malnourished
When animal, insect or human embryos grow in a malnourished environment, their developing nervous systems get first pick of any available nutrients so that new neurons can be made.

The first 3D map of the heart's neurons
An interdisciplinary research team establishes a new technological pipeline to build a 3D map of the neurons in the heart, revealing foundational insight into their role in heart attacks and other cardiac conditions.

Mapping the neurons of the rat heart in 3D
A team of researchers has developed a virtual 3D heart, digitally showcasing the heart's unique network of neurons for the first time.

How to put neurons into cages
Football-shaped microscale cages have been created using special laser technologies.

A molecule that directs neurons
A research team coordinated by the University of Trento studied a mass of brain cells, the habenula, linked to disorders like autism, schizophrenia and depression.

Read More: Neurons News and Neurons Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.