Technology Aids Development of Drugs That Work Only in the Brain, Avoiding Side Effects in other Body Systems

Allan T. Gulledge, Ph.D. of Dartmouth Medical School
Allan T. Gulledge, Ph.D.

From The Quarterly, Fall 2011

The chemicals that act in the brain act in other parts of the body as well─in the heart, in the respiratory system, in muscles. Drugs that affect brain chemicals can therefore cause unwanted side effects in other body systems. Dr. Gulledge and his colleagues are working to isolate targets for the development of drugs that will work only in the brain, to help improve the cognitive malfunctions that occur with psychiatric diseases, which have yet to be adequately treated, and without the unwanted side effects of currently available psychoactive medications.

For the past few years, the laboratory has been working with the cholinergic system, the system governing the neurotransmitter acetylcholine. Neurotransmitters are the chemicals that carry messages from one nerve cell to another, binding to receptor molecules on receiving cells. Changes to acetylcholine activity change behaviors. Numerous studies have shown, for example, that smoking increases attention through nicotine activating receptors for acetylcholine.

A great diversity of receptors bind to acetylcholine. Recently, Dr. Gulledge and his team identified a subtype of so-called muscarinic receptors that are important in the cortex, the brain center critical to cognition. The human genome contains five types of muscarinic receptors, labeled M1, M2, M3, M4 and M5. The task the lab undertook was to learn which one or combination of these receptors was active in the cortex so as to be able to design a drug that interacted with those receptors only and not with muscarinic receptors in, for example, the digestive tract, where the drug might cause stomach problems.

A powerful genetic technology for posing such questions is the use of knockout mice, animals in which genes are inactivated─knocked out─and the resulting changes in their biology and behavior can pinpoint the gene’s function by its absence. The researchers engineered mice with inactivated genes for the muscarinic receptors─different mice for different receptors─to observe the effect on acetylcholine activity. Through this process, they were able to identify M1 as the key receptor for generating normal cholinergic responses in the cortex.

Current drugs interact with M1 but also with other muscarinic receptors in other parts of the body. The lab is now working to design a drug that hones in exclusively on M1 expressed by cells in the brain to help increase cognitive ability in people with schizophrenia and with other brain and behavior disorders in which the cholinergic system is affected.