Effects of N-ethyl,N-nitrosourea on monoamine concentrations and metabolizing enzymes in mouse brain regions

Abstract

N-ethyl,N-nitrosourea is a well known alkylating agent and produces central nervous system-specific tumors in several laboratory animal species. In the present study, young male CD-1 mice were treated by i.p. injections of 0, 2, 8, or 32 mg/kg body weight N-ethyl,N-nitrosourea, twice a week for 3 weeks. Endogenous levels of brain monoamine neurotransmitters and their selected metabolites; norepinephrine (NE), dopamine (DA), 5-hydroxytryptamine (5-HT), vanillylmandelic acid (VMA), dihydroxyphenyl acetic acid (dopac), homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), and dihydroxyphenylalanine (dopa) were measured using HPLC with electrochemical detection. N-ethyl,N-nitrosourea treatment caused an increase of NE and 5-HT in the hypothalamus and striatum. Increased levels of 5-HIAA were noticed in the same brain regions. Elevated levels of NE were also observed in the cerebral cortex, medulla oblongata and the cerebellum. The major metabolite of NE, VMA, was decreased in several brain regions to non-detectable levels. Histopathological examination of brain tissue did not reveal any pathologic lesions. The increases in brain amines were associated with increased activity of tryptophan hydroxylase in the hypothalamus and corpus striatum. Dopa-decarboxylase was elevated in the cerebral cortex at a low dose of N-ethyl,N-nitrosourea only, whereas the monoamine oxidase activity was unaltered. Results indicated that N-ethyl,N-nitrosourea exposure may cause an elevation of steady state levels of various biogenic amines in brain areas and these changes to some extent are consistent with the altered activity of metabolizing enzymes.