Effect of misonidazole on neurotransmitter systems

This study examines the effect of chronic administration of misonidazole on four neurotransmitter pathways (norepinephrine, dopamine, acetylcholine, and GABA) of the central nervous system (CNS). Biochemical assays examined the neurotransmitter synthesizing enzymes tyrosine hydroxylase (TOH) for catecholamines and choline acetyltransferase (CAT) for acetylcholine. An immunocytochemical stain for glutamic acid decarboxylase (GAD) was used as an enzymatic marker for GABAergic neurons. In drug-treated mice, enzymatic activity for TOH as well as the total concentration of enzyme was significantly increased in the locus coeruleus (LC), a principal norepinephrine-ontaining nucleus of the brainstem, but not in other brain regions. Correlative histofluorence examination of the LC also showed an increase in the fluorescence intensity of noradrenergic neurons of the nucleus. In contrast, CAT activity was not different from controls in any of the areas examined. In the brainstem, immunocytochemical staining for GAD showed a significant reduction in the number of immunoreactive varicosities juxtaposed to neurons of the lateral vestibular nucleus suggestive of a loss of afferent GABAergic input from the cerebellum. These data suggest that both norepinephrine and GABAergic systems may be altered in selective nuclei of the CNS by chronic administration of misonidazole, and that drug related changes in NE and GABA may underlie some of the neurotoxic side effects of MISO and/or exacerbate a patient's pre-existing cardiovascular or neurological problems.