While simple genetics is sufficient to explain heritability for some human characteristics, concepts of complex genetics are necessary to explain the heritable component of most behavioral characteristics and CNS diseases. One possible example of such complex heritability is "novelty-seeking" behavior (characterized by excitability and impulsiveness) and its recent association with one variant of the D₄ dopamine receptor, the D_4.7. The D₄ receptor is a G-protein-coupled receptor in the D₂ dopamine receptor family; it has certain structural features in common with the D₂ and D₃ receptors but has critical distinguishing structural and pharmacologic characteristics. Moreover, its distribution in human brain is distinctive, with the highest density in the neocortex, hippocampus, and entorhinal cortex (+see figure); its density is lower in caudate and putamen, regions where D₂ receptors are very dense. In addition, there exist approximately eight variants of the D₄ receptor, which differ from each other in the number of amino acid repeats in the third intracytoplasmic loop. The D_4.4 variant is found with the highest frequency (66%). The interesting distribution and variability have encouraged speculation about the function of the D₄ receptor in human brain. Every person has two D₄ receptor variants, one coded from each chromosome. They are detectable by using polymerase chain reaction (PCR) on a human blood sample. Two independent well-characterized human populations without psychiatric illness were analyzed for their D₄ receptor isoforms. They were also typed with respect to normal personality characteristics. Their personality test scores were then associated with the presence of the D₄ isoforms by using analysis of variance. The group of subjects with the longest variant, D_4.7, scored higher on novelty seeking than did subjects with the shorter, D_4.4, variant. A third study did not replicate this finding, although a tendency in that direction was seen. Additionally, it has been reported that in attention deficit/hyperactivity disorder (ADHD) the D_4.7 variant occurs more frequently than the D_4.4 variant. The distinctive functional characteristic that the D_4.7 variant brings (excitability/impulsiveness) to the human brain is potentially a contributing substrate for novelty-seeking behaviors and ADHD. The biologic mechanism that mediates this association remains to be identified.

Address reprint requests to Dr. Tamminga, Maryland Psychiatric Research Center, P.O. Box 21247, Baltimore, MD 21228. Photograph courtesy of Dr. Robert Lahti.