POSSIBLE NORADRENERGIC DYSFUNCTION IN SCHIZOPHRENIA

In spite of extensive studies over the last 2 decades to find direct e vidence in support of the dopamine hypothesis of schizophrenia, no und isputed experimental data has been obtained. In contrast, estimation o f noradrenalin (another major catecholamine) and its metabolites in po stmortem brain and in the cerebrospinal fluid appears to be producing consistent results. To understand the meaning of this change for the p athogenesis of the illness, we have carried out animal experiments in which reproducibility of schizophrenic signs and symptoms by noradrene rgic dysfunction, and treatability of the disorder by modulation of no radrenergic activity were studied. First, psychophysiological signs in skin conductance responsiveness (nonhabituating or nonresponding chan ge) and smooth pursuit eye movement (spiky or stepwise pursuit) could be reproduced by enhancing or suppressing central noradrenergic activi ty. Behavioral abnormalities resembling schizophrenic symptoms are kno wn to be reproducible by over- or underactivity of the system (overaro usal or underarousal syndrome). Secondly, the action of various drugs capable of modulating schizophrenic symptoms was analyzed in relation to noradrenergic activity. Haloperidol, in particular, had a potent su ppressing effect on skin conductance activity (spontaneous fluctuation rate and habituation rate) when administered chronically, suggesting its inhibitory action on noradrenergic activity.