Expression and localisation of CYP2D enzymes in rat basal ganglia.

P450 enzymes in the CYP2D subfamily have been suggested to contribute to the susceptibility of individuals in developing Parkinson's disease. We have used specific anti-peptide antisera and peroxidase immunohistochemistry to investigate the expression of CYP2D enzymes in the rat brain and some possible factors that may affect their regulation. In male Wistar rats, CYP2D1 was not detected in the basal ganglia or in any other brain region. CYP2D2 was weakly expressed within neurones of the subthalamic nucleus, substantia nigra and interpeduncular nucleus as well as in the hippocampus, dentate gyrus, red nucleus and pontine nucleus. CYP2D3 and CYP2D4 were absent from the basal ganglia, although moderate amounts of CYP2D3 were detected within fibres of the oculomotor root, and very low levels of CYP2D4 were present in white matter tracts. In contrast, CYP2D5 was extensively expressed in the basal ganglia, including neurones in the subthalamic nucleus, substantia nigra and interpeduncular nucleus, as well as other areas of the brain, including the ventral tegmental area, piriform cortex, hippocampus, dentate gyrus, medial habenular nucleus, thalamic nucleus and pontine nucleus. Lesioning of the nigro-striatal tract to cause almost a complete loss of tyrosine hydroxylase containing neurones in the substantia nigra, also reduced the number of neurones expressing CYP2D5 by 50%, indicating that CYP2D5 is expressed in dopaminergic neurones. Castration of pre-pubertal or adult Wistar rats had no effect on the number of CYP2D5-positive neurones in the substantia nigra. Although Dark Agouti rats lack hepatic CYP2D2, expression in the midbrain was similar to that of Wistar rats; furthermore, there was no difference in expression or distribution between male and female rats. In contrast to naive rats, extensive expression of CYP2D4 was found throughout the basal ganglia and in other brain nuclei in Wistar rats treated with not only clozapine, but also saline, suggesting that CYP2D4 may be induced as a result of mild stress. The function of CYP2D enzymes in the brain remains unknown, but their selective localisation suggests a physiological role in neuronal activity and in adaptation to abnormal situations.