Gene Regulation: Drugs

To understand the regulation of genes, the following sequence of events must be appreciated: A gene, made of DNA, is "transcribed" to produce a messenger RNA, or mRNA, that is "translated" to produce a protein product. Gene regulation refers to the regulation of production of mRNA from the gene.

Although every organism contains a collection of genes necessary for its survival and reproduction, not every gene is turned on or is producing mRNA at any given moment. At any moment or stage of development such as in the adult, only a subpopulation of genes is expressed (i.e., producing mRNA). During the development and growth of an organism, certain gene products guide and program growth. Because only a subgroup of the genome is expressed at any stage of the life cycle, gene regulation must occur. Gene regulation also occurs during a life cycle as in the adult brain.

A gene contains an important part called the "promoter" that controls the rate at which mRNA is produced. A human gene, for example, can be expressed or turned on when the promoter is activated. For the purposes of our discussion here, the promoter of a gene is the site of gene regulation. Perhaps a reasonable analogy is that a promoter is like a light switch; the switch must be "activated" or turned to "on" before light can be produced, and not every light has to be turned on. There are many different kinds of promoters, each of which is turned on or off by its own "transcription factor", which is a protein that binds to the promoter region of a gene and alters the rate of transcription (production of mRNA).

The brain has evolved such that receptors for drugs and neurotransmitters, through complex biochemistry, can affect the state of the promoters for genes by activating transcription factors. The active transcription factor then regulates gene expression by binding to the promoter region of the gene.

A simplified summary of the events involved in gene regulation is as follows: A drug is taken and it goes to the brain where it interacts with its receptor; the activated receptor, through biochemical pathways, can activate transcription factors; the transcription factors then bind to the promoter of the gene; binding of the transcription factor to the promoter changes the rate (faster or slower) at which the gene produces mRNA, which ultimately changes the level of the protein product in the cell. The most important point for consideration here is that drugs of abuse can change the biochemical composition of the brain by this mechanism or pathway. Many scientists believe that change in brain composition by this mechanism are one of the bases for drug addiction. It is often said that the drug dependent brain is a changed brain, and this is what that statement means. Drugs change the balance of proteins in the brain and that influences how the brain functions.

Understanding how drugs change brain protein composition by altering gene regulation is an important area of research, because this is a key to understanding what makes a brain (and, of course, a person) addicted. Once that is understood, then we can begin to repair the addicted brain by intervening in various ways or by reversing such changes in brain protein composition. If gene regulation can be controlled or influenced, then the protein composition of the brain can be influenced, and the way the brain functions can be correspondingly influenced. Science does not have the knowledge or skill to do this now, but it is one of many hopes for the future.

MICHAEL J. KUHAR