Thursday, April 22, 2004

More Neuroscience News
Cocaine Addiction and G-Protein-Coupled Receptors

Cocaine Addiction and G-Protein-Coupled Receptors

The journal Nature has a news article about basic science research that could have implications for treatment of cocaine addiction.  Cocaine addiction is, obviously, a very serious problem.  The http://www.drugabuse.gov/ResearchReports/Cocaine/Cocaine.html has the following information about cocaine:

Cocaine abuse and addiction continues to be a problem that plagues our nation. In 1997, for example, an estimated 1.5 million Americans age 12 and older were chronic cocaine users. Although this is an improvement over the 1985 estimate of 5.7 million users, we still have a substantial distance to go in reducing the use of this addictive stimulant. Science is helping. For example, we now know more about where and how cocaine acts in the brain, including how the drug produces its pleasurable effects and why it is so addictive.

Crack cocaine is particularly bad, because inhaling the smoke causes such a rapid, dramatic euphoria.  In a clinical setting, crack addiction is one of the hardest to treat.  Therefore, any help at all would be very much appreciated.  The question is, how feasible is it to come up with a medication to reduce craving?

Cravings reduced in rehab rats:
Discovery might help cocaine addicts kick the habit.

22 April 2004
from Nature


Researchers have been able to lessen cocaine cravings in rats by blocking certain signals in their brains.

The discovery could eventually help recovering human addicts to stave off withdrawal symptoms, says Peter Kalivas of the Medical University of South Carolina in Charleston, who led the work. Current therapies rely on behavioural techniques such as avoiding tempting situations.

The researchers studied the brains of cocaine-addicted rats that had been denied the drug for three weeks. The animals produced increased levels of a brain chemical called AGS3, the team reports in the latest issue of Neuron1.


The researchers suspect that the compound works by interfering with signalling molecules called G-proteins, which communicate with other brain areas involved in motivation. This fits with the idea that recovering addicts have skewed interests, for example becoming more excited by their drug than by the prospect of sex, says Kalivas.

The researchers tested this theory by injecting the part of the AGS3 molecule that binds to G-proteins into the brains of rats; the animals had previously been trained to press a lever to get cocaine, and were then weaned off the drug.

After being given a further small dose of cocaine, the treated rats pressed the lever more frequently than untreated ones, despite the fact that the drug was no longer available, suggesting that they experienced stronger cravings.

Kalivas's team then set out to see if AGS3 levels could be reduced, instead of raised, in order to alleviate these cravings. They injected into the rats' brains a type of molecule called an antisense oligonucleotide that was designed to block the production of AGS3, and found the animals pressed the lever less often than normal.  [...]

The authors go on to speculate that it might be possible to use a compound that reduces craving, when people are trying to quit.  No one thinks this would solve the problem, but like I said before, any help at all would be welcome.  Is this approach feasible?

Most central nervous system medication acts in one of three locations in the nerve cell.  Most either bind to a receptor, modify reuptake transporters, or act on the cell membrane.  A few medications are enzyme inhibitors.  Those that act on receptors, reuptake pumps, and enzymes are fairly specific, in that they leave most of the brain unaffected.  Drugs that have widespread effects tend to have more adverse effects.  The G-proteins are widespread.  They are important because many of the receptors that modify nerve cell activity are bound to G-proteins inside the cell.  A fair summary of the importance of these proteins can be found in the introduction to a recent symposium  on the subject:

G-protein-coupled receptors (GPCRs), which comprise one of the largest gene families identified in the human genome, also represent the largest number of currently used targets of therapeutic drugs. Recent work has indicated a number of intriguing observations in terms of GPCR structure, function and regulation, including existence of receptor homodimers and heterodimers, genetic identification of orphan GPCRs, novel receptor interacting proteins, clinically important polymorphisms and receptor mutations, mechanisms involved in receptor deactivation/desensitization, and receptor targeting/action in signaling microdomains. Definitive information about each of these topics is still being developed.

A good rule of thumb in biology is that complexity always has a purpose.  Since there are so many genes involved, in is a good bet that G proteins serve many important functions.  It also means that there are many potential targets for drug activity.  The challenge will be to find drugs that only act in the precise location that an effect is desired.  The G-protein-coupled receptors occur in many cell types, not just neurons.  Whether this can be accomplished remains to be seen.  For a more complete review of GPCRs, see the MIT site here.