Molecular Genetics and Psychopharmacology

In recent years the psychopharmacologist has paid increasing attention to the examination of brain proteins with which psychotropic drugs react, and also the molecular mechanisms that control the synthesis and cellular function of these proteins. For this reason, any understanding of psychopharmacology requires some knowledge of the basic techniques of molecular genetics.

Genes are composed of deoxyribonucleic acid (DNA) which is a long polymer composed of deoxyribonucleotides. Each deoxyribose nucleotide has one of the following purine or pyrimidine bases, namely adenosine, guanine, thymine or cystosine. A single gene may contain from a few thousand to several hundred thousand bases that are arranged in a specific sequence according to the information contained in the gene. It is this sequence of bases which determines the structure of the gene product which is a protein. In addition, the gene also contains information regarding the way in which the gene is expressed during development and in response to environmental stimuli.

The role of DNA in storing and transferring genetic material is dependent on the properties of the four bases. These bases are complementary in that guanine is always associated with cytosine, and adenosine with thymine. Watson and Crick, some 40 years ago, showed that the stability of DNA is due to the double helix structure of the molecule that protects it from major perturbations. Information is ultimately transferred by separating these strands which then act as templates for the synthesis of new nucleic acid molecules.

There are two ways in which DNA molecules may act as templates. Firstly, DNA is used as a template for replicating additional copies during cell division. This occurs by free deoxyribonucleotides binding to the complementary bases of the exposed DNA strand and then being linked by the enzyme DNA polymerase to form a new DNA double helix. Secondly, small sections of the DNA molecule are used as a template for the synthesis of messenger ribonucleotides (mRNAs) which are responsible

Fundamentals of Psychopharmacology. Third Edition. By Brian E. Leonard © 2003 John Wiley & Sons, Ltd. ISBN 0 471 52178 7

for carrying the message for the synthesis of specific proteins. mRNAs differ from DNA in that they are much shorter (generally 7000 base pairs in length) and are single stranded. mRNAs contain the information necessary for the synthesis of a specific protein and also contain the pentose sugar moiety ribose instead of deoxyribose found in DNA. In addition, thymine is replaced by the pyrimidine base uracil which, like thymine, is complementary to adenine.

The human genome contains approximately 100000 genes which are distributed with a total DNA sequence of 3 billion nucleotides. The DNA of the human genome is divided into 24 exceptionally large molecules each of which is a constituent of a particular chromosome, of which 22 are autosomes and two are sex chromosomes (X and Y chromosomes).

Translation of the information encoded in DNA, expressed as a particular nucleotide sequence, into a protein, expressed as an amino acid sequence, depends on the genetic code. In this code, sequences of three nucleotides (termed a codon) represent one of the 20 amino acids that compose the protein molecule. Because there are 64 codons which can be constructed for the four different bases, and only 20 different amino acids that are coded for, several amino acids may be coded for by more than one codon. There are also three codons, called stop codons, that terminate the transfer of information. Furthermore, although all cells contain the same complement of genes, certain cells (for example, the neurons) have specialized genes that encode specific proteins for the synthesis of specific transmitters. The expression of such genes is under the control of regulatory proteins called transcription factors which control the transcription of mRNAs from the genes they control.

The expression of enzymes that control neurotransmitter systems is controlled not only by factors operating during embryonic development, but also by the degree of neuronal activity. Thus the more active the nervous system, the greater the genetically controlled synthesis of the neurotransmitters which clearly play an important role in the behaviour of the organism. Regulation of the genes also determines the response of the brain to drugs, hence the importance of molecular genetics to psychopharmacology.

One of the most important areas of molecular genetics concerns the role of specific base sequences, called regulatory sequences, that surrounded the sections of the gene that encode the amino acid sequence of a protein. These regulatory sequences are activated or inactivated by specific transcription factors and it is the complex interaction of regulatory sequences and transcription factors that underlies the adaptation of brain function to the effects of some psychotropic drugs. For example, it is well known that the optimal response to an antidepressant or neuroleptic drug requires several weeks of treatment. Such adaptive changes are probably a reflection of the molecular genetics of neurotransmitter function and may help to explain the lack of success in developing antidepressants or neuroleptics that have a rapid therapeutic action.

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