New way to reduce the effects of cocaine

Source: http://www.abc.net.au/science/articles/2011/07/25/3275847.htm#artBookmarks

A new target for the treatment of drug addiction has been identified by US and Chinese scientists.

Research led by Dr Zheng-Xiong Xi of the National Institute on Drug Abuse in the USA has found that activation of receptors in the brains of mice can counteract the behavioural and rewarding effects of cocaine.

There are two major cannabinoid receptor types: CB1 and CB2.

CB1 receptors, which are found in large numbers in the brain activated by drugs such as marijuana. They are known to stimulate the brain's reward system, which is why they have been the focus of addiction research.

CB2 receptors are primarily located on the body's immune cells. They are also known to be involved in pain perception.

Until recently, it was thought that CB2 receptors were not present in the brain or that, if they were, it was in such low density that they were not involved in drug addiction.

"Due to the limitations of the technology we weren't able to detect low levels of CB2 receptors," says Xi.

But, six years ago, CB2 receptors were found to be present and active in the brainstem. They were subsequently detected in neurons in the brain.

"This prompted us to re-examine the role of CB2 receptors in drug reward and addiction," says Xi.

"Our research suggests that, even though the levels of CB2 receptors [in the brain] are very low, they are critically involved in cocaine's actions."

The results are published online today in Nature Neuroscience.

Rewarding behaviour

In their study, Xi and colleagues trained mice to self-administer cocaine intravenously. The researchers found that activating CB2 receptors with two different 'agonists' reduced drug-induced behaviour such as hyperactivity.

In addition, the CB2 receptor agonists reduced the bouts and amount of drug intake in normal (wild type) mice and mice who lacked the CB1 receptors, but not those that lacked CB2 receptors.

Further experiments showed the observed effects were mediated by the brain's CB2 receptors and that the rewarding effects of cocaine were blocked.

"Taken all together, the present findings, for the first time suggest that brain CB2 receptors functionally modulate the acute rewarding and locomotor-stimulating effects of cocaine in mice," says Xi.

Battling addiction

Xi adds that several pharmaceutical companies already have CB2 agonists in preclinical trials, but that they have been developed to treat pain.

"Our findings open a new field; CB2 agonists have a very high potential for treating addiction," he says.

Dr Nadia Solowij of the University of Wollongong agrees and speculates that the study will also have relevance for other drug addictions including opiates.

"They found minimal side-effects by specifically targeting these cannabinoid receptors and they showed specific effects on the dopamine [reward] system," she says.

However, Solowij adds that the addiction and reward systems involve interactions between many different receptor and neurochemical systems in the brain and that more research is needed to fully understand the changes that result from CB2 activation.

Xi acknowledges that "these are very early initial studies," and adds that they will now test their compounds in other animal species, starting with the rat.

He and his colleagues are also focussing on finding the mechanism by which activation of CB2 receptors inhibits dopamine release.

Visualizing Cell Transplants

This is an open-ended methods question for anyone out there. We're at the point in our lab where we're about to implant various cell populations into inbred hosts, with the hope of verifying that these cells are surviving and incorporating into normal tissue. Survival times range from 4 weeks to 26 weeks.

What methods does your lab use to do this? We've considered lentiviral transduction and transfection with GFP/luciferase expressing plasmids.

Scientists Use ‘Optogenetics’ to Control Reward-Seeking Behavior

From Neuroscience News

The findings suggest that therapeutics targeting the path between two critical brain regions, the amygdala and the nucleus accumbens, represent potential treatments for addiction and other neuropsychiatric diseases.

Using a combination of genetic engineering and laser technology, researchers at the University of North Carolina at Chapel Hill have manipulated brain wiring responsible for reward-seeking behaviors, such as drug addiction. The work, conducted in rodent models, is the first to directly demonstrate the role of these specific connections in controlling behavior.

The UNC study, published online on June 29, 2011, by the journal Nature, uses a cutting-edge technique called “optogenetics” to tweak the microcircuitry of the brain and then assess how those changes impact behavior. The findings suggest that therapeutics targeting the path between two critical brain regions, namely the amygdala and the nucleus accumbens, represent potential treatments for addiction and other neuropsychiatric diseases.

“For most clinical disorders we knew that one region or another in the brain was important, however until now we didn’t have the tools to directly study the connections between those regions,” said senior study author Garret D. Stuber, PhD, assistant professor in the departments of cell and molecular physiology, psychiatry and the Neuroscience Center in UNC School of Medicine. “Our ability to perform this level of sophistication in neural circuit manipulation will likely to lead to the discovery of molecular players perturbed during neuropsychiatric illnesses.”

Because the brain is comprised of diverse regions, cell types and connections in a compact space, pinpointing which entity is responsible for what function can be quite tricky. In the past, researchers have tried to get a glimpse into the inner workings of the brain using electrical stimulation or drugs, but those techniques couldn’t quickly and specifically change only one type of cell or one type of connection. But optogenetics, a technique that emerged six years ago, can.

In the technique, scientists transfer light-sensitive proteins called “opsins” – derived from algae or bacteria that need light to grow – into the mammalian brain cells they wish to study. Then they shine laser beams onto the genetically manipulated brain cells, either exciting or blocking their activity with millisecond precision.

In Stuber’s initial experiments, the target was the nerve cells connecting two separate brain regions associated with reward, the amygdala and the nucleus accumbens. The researchers used light to activate the connections between these regions, essentially “rewarding” the mice with laser stimulations for performing the mundane task of poking their nose into a hole in their cage. They found that the opsin treated mice quickly learned to “nosepoke” in order to receive stimulation of the neural pathway. In comparison, the genetically untouched control mice never caught on to the task.

Then Stuber and his colleagues wanted to see whether this brain wiring had a role in more natural behavioral processes. So they trained mice to associate a cue – a light bulb in the cage turning on – to a reward of sugar water. This time the opsin that the researchers transferred into the brains of their rodent subjects was one that would shut down the activity of neural connections in response to light. As they delivered the simple cue to the control mice, they also blocked the neuronal activity in the genetically altered mice. The control mice quickly began responding to the cue by licking the sugar-producing vessel in anticipation, whereas the treated mice did not give the same response.

The researchers are now exploring how changes to this segment of brain wiring can either make an animal sensitized to or oblivious to rewards. Stuber says their approach presents an incredibly useful tool for studying basic brain function, and could one day provide a powerful alternative to electrical stimulation or pharmacotherapy for neuropsychiatric illnesses like Parkinson’s disease.

“For late-stage Parkinson’s disease it has become more routine to use deep brain stimulation, where electrodes are chronically implanted into brain tissue, constantly stimulating the tissue to alleviate some of the disease symptoms,” said Stuber. “From the technical perspective, implanting our optical fibers is not going to be more difficult than that. But there is quite a bit of work to be done before we get to that point.”