Catechol-O-methyltransferase genotype and dopamine regulation in the human brain - PubMed (original) (raw)

Catechol-O-methyltransferase genotype and dopamine regulation in the human brain

Mayada Akil et al. J Neurosci. 2003.

Abstract

A functional polymorphism in the gene for catechol-O-methyltransferase (COMT) has been shown to affect executive cognition and the physiology of the prefrontal cortex in humans, probably by affecting prefrontal dopamine signaling. The COMT valine allele, associated with relatively poor prefrontal function, is also a gene that may increase risk for schizophrenia. Although poor performance on executive cognitive tasks and abnormal prefrontal function are characteristics of schizophrenia, so is psychosis, which has been related to excessive presynaptic dopamine activity in the striatum. Studies in animals have shown that diminished prefrontal dopamine neurotransmission leads to upregulation of striatal dopamine activity. We measured tyrosine hydroxylase (TH) mRNA in mesencephalic dopamine neurons in human brain and found that the COMT valine allele is also associated with increased TH gene expression, especially in neuronal populations that project to the striatum. This indicates that COMT genotype is a heritable aspect of dopamine regulation and it further explicates the mechanism by which the COMT valine allele increases susceptibility for psychosis.

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Figures

Fig. 1.

Fig. 1.

Illustration of the sampling procedure. Red circles indicate an area of 1.76 mm2 sampled in each of the five cell groups selecting the region of highest density.

Fig. 2.

Fig. 2.

Autoradiograms of midbrain tissue sections after_in situ_ hybridization with radiolabeled riboprobes for TH (A, B) or DAT (C,D) mRNA in two matched cases with val/met (case 1193,A, C) or val/val (case 1111, B,D) genotypes, respectively. Scale bar, 1 mm

Fig. 3.

Fig. 3.

Comparisons of mean optical density, reflecting TH mRNA levels, between subjects with val/met (circles) and val/val (triangles) genotypes in the SNV. Each_symbol_ indicates the mean value for one male or female subject (open and filled symbols, respectively), and horizontal lines indicate group means.

Fig. 4.

Fig. 4.

Diagram illustrating elements of the circuitry and their putative involvement in the effects of COMT genotype on DA levels in prefrontal cortex and TH gene expression in the brainstem. Relative to val/met, the val/val genotype of the COMT enzyme leads to reduced DA levels in the PFC. It is speculated that indirect PFC projections via GABA neurons in the striatum or mesencephalon lead to increased gene expression of TH mRNA in DA cell groups projecting subcortically. The_question mark_ is to indicate that some of the GABA projections remain to be confirmed. Sources of anatomical information include the following: Lewis (1992), Deutch (1993),Murase et al. (1993), Williams and Goldman-Rakic (1995), Haber and Fudge (1997), Carr and Sesack (2000),Chiba et al. (2001), and Seamans et al. (2001).

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