Dopamine Related Genes

The expression of the dopamine D4 receptor (DRD4) gene in the anterior cingulate cortex is of particular interest. As reviewed by Williams and Rakic from Yale University, the anterior cingulate cortex contains high levels of DA innervation in layers II-VI. Dopaminergic axonal fibers arising from the VTA form axon-axononal connections and allow large regions of this cortical area to be globally regulated. The cingulate cortex contains interneuron populations expressing dopamine D2 receptor (DRD2) and DRD4 receptors and pyramidal neurons expressing dopamine D1 receptor (DRD1) receptors. Whereas most DA receptors are expressed widely throughout the brain, DRD4 shows its highest levels of expression in the frontal and cingulate areas. Interestingly, a polymorphism in the cytoplasmic loop of the DRD4 gene has been associated with attention deficit hyperactivity disorder. Similarly, a specific polymorphism of the dopamine D3 receptor (DRD3) and DRD2 genes was associated with schizophrenia, as were the dopamine b-hydroxylase (DBH) and catechol-O-methyl transferase (COMT) genes. Figure 5 illustrates the various alleles (see Glossary) of the DRD4 gene in normal volunteers based on DNA samples from cheek cells. Basic genotyping studies of this format no doubt will increase given the publication of the human genome in Science and Nature.

Gene expression studies have also shown that the anterior cingulate cortex is highly sensitive to environmental stress. Anoxia, maternal separation, amyloid protein expression, and drug abuse all induce hypo-metabolism, gliosis, and programmed cell death in the anterior cingulate cortex. Exposure to stress induces the expression of glucocorticoid receptor (GR), a transcription factor that mediates the cellular response to stress as shown by Bruce McEwen of Rockefeller University. Stress-induced excitatoxic damage has

been noted in the anterior cingulate cortex in schizophrenia. Specifically, Francis Benes of Harvard Medical School has shown that dopaminergic innervation of interneurons in layers II and V is increased in post mortem analyses of schizophrenia. Under normal conditions, the synaptic contacts on local interneurons that utilize DRD2 receptors result in inhibition of cell activity. The hyperinnervation of interneuronal DRD2 contacts is suspected to disable local inhibition of pyramidal cells and lead to excess glutamatergic signaling and excitotoxicity in downstream brain areas. Because this type of excitotoxic damage is mediated by the GR gene, it is likely that genetic variation in this gene and/or its downstream targets explains the phenomenon of a gene x environment interaction seen in many psychiatric disorders.

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