Why Just Saying No Is Not Enough
An Interview with Michael Kuhar, Ph.D.

by Brenda Patoine

April, 2007

Q: Why is the idea that drug addicts can “just say no” to drugs misguided?

A: A current view in the field of drug abuse research is that the action of addictive drugs on the brain is partly to impair judgment and cognitive function. We are all aware how strong ordinary habits can be and how difficult some are to break. Becoming dependent on drugs is not only like a habit but like a habit in which other brain functions are impaired. This makes it more difficult to stop taking drugs. The evidence that drugs change the brain is abundant and really cannot be argued against. These brain changes are the basis of drug dependence and cognitive impairments. Sometimes, the reaction to drugs or even to things associated with drugs (so-called drug cues such as a crack house or white powder) are so strongly conditioned that it becomes somewhat unconscious. In this case, the craving for drugs cannot be stopped simply by saying, “go away”; treatment is necessary to reduce these automatic responses.

In summary, drugs impair our ability to just say no.

Q: For years, you have studied the effects of CART (or cocaine- and amphetamine-regulated transcription factor), a genetic switch by which cocaine and other psychostimulants disrupt dopamine signaling. What are the clinical implications of your discovery about CART, and where do we stand as far as applying this finding to the development of therapeutics for drug addiction?

A: We started working on CART shortly after its discovery when there were only a few papers in the literature; now there are hundreds. CART is a peptide found in many places in the brain, including drug reward/reinforcement areas. We found that injecting CART into these areas has little or no effect by itself, but co-injecting CART and cocaine results in an attenuation of the effects of cocaine. This attenuation suggests that drugs that mimic CART (agonists) could be used to blunt the effects of psychostimulants and thus be useful medications to treat drug addiction. The fact that they don’t totally block the cocaine effect is likely to be an advantage, since complete blockers are not always accepted by addicts. Recently, we have identified a CART receptor, a molecule that binds to CART to initiate a signaling cascade. These new understandings about the underlying mechanisms by which CART acts to blunt cocaine’s effects make it possible to develop small-molecule medications that would be testable in classical clinical trials. While the receptor hasn’t yet been cloned—a key step to designing agonists—the binding and signaling assays we used to discover the receptor are adequate for screening potential pharmaceutical compounds. This is a very interesting and potentially clinically useful area of research.

Q: You have found that separating rat pups from their mothers early in life increases the pups’ vulnerability to addiction. What is your current thinking in terms of the neural mechanisms underlying this increased vulnerability, and how does it apply to humans?

A: This also is a very interesting field. The work in our lab and elsewhere shows that separating rat pups from dams (moms) daily, for varying periods of 15 or 180 minutes during the first two weeks of life, changes the vulnerability of the pups to addiction when they are adults. It appears that perinatal treatments can actually change an animal’s vulnerability to take drugs for the rest of its life. This is remarkable!

How does it happen? The answer is not fully known, but data suggest that the dams behave differently after the separations, which influences the pup brains. It also appears that stress is linked to this response because the stress-response axis is changed in some of the separated pups. A combination of stress to the offspring and the mother’s responses seems to be involved in producing lifelong changes in the offspring.

It is known that early life stresses in humans predispose them to many problems later in life, including various neuropsychiatric disorders. This maternal separation model with rats is likely to be helpful in testing various ideas about treating humans who have a history of perinatal stressors.

Q: What are the next steps in your research?

A: In the CART project, we want to work with the receptor and set up a drug-screening protocol to identify possible medications. This is a reasonable and achievable goal. We also want to unravel how CART produces the cocaine-blunting effects in brain areas such as the nucleus accumbens. If we understand the mechanisms, then maybe we can use that knowledge to manipulate the effects in novel and helpful ways.

In the maternal separation project, we hope to determine the changes in the dopamine system that cause the changes in vulnerability to drugs. We want to clarify the mechanisms for this, in general. We also want to see what can reverse the increased vulnerability: Will antidepressants do it? Will an enriched rearing environment do it? Findings in the field suggest that the answer to these questions is yes, and we want to extend that work. This is a very exciting area with important implications for humans.