Expression and localisation of CYP2D enzymes in rat basal ganglia

P450 enzymes in the CYP2D subfamily have been suggested to contribute to th e 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 possi ble factors that may affect their regulation. In male Wistar rats, CYP2D1 w as not detected in the basal ganglia or in any other brain region. CYP2D2 w as weakly expressed within neurones of the subthalamic nucleus, substantia nigra and interpeduncular nucleus as well as in the hippocampus, dentate gy rus, red nucleus and pontine nucleus. CYP2D3 and CYP2D4 were absent from th e basal ganglia, although moderate amounts of CYP2D3 were detected within f ibres 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 ni gra and interpeduncular nucleus, as well as other areas of the brain, inclu ding the ventral tegmental area, piriform cortex, hippocampus, dentate gyru s, medial habenular nucleus, thalamic nucleus and pontine nucleus. Lesionin g of the nigro-striatal tract to cause almost a complete loss of tyrosine h ydroxylase containing neurones in the substantia nigra, also reduced the nu mber of neurones expressing CYP2D5 by 50%, indicating that CYP2D5 is expres sed in dopaminergic neurones. Castration of pre-pubertal or adult Wistar ra ts had no effect on the number of CYP2D5-positive neurones in the substanti a nigra. Although Dark Agouti rats lack hepatic CYP2D2, expression in the m idbrain was similar to that of Wistar rats; furthermore, there was no diffe rence in expression or distribution between male and female rats. In contra st to naive rats, extensive expression of CYP2D4 was found throughout the b asal 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 res ult of mild stress. The function of CYP2D enzymes in the brain remains unkn own, but their selective localisation suggests a physiological role in neur onal activity and in adaptation to abnormal situations. (C) 1999 Elsevier S cience B.V. All rights reserved.