Aberrant anxiety in schizophrenia: a potential target for early intervention

Schizophrenia, as a neurodevelopmental disorder, arises from interaction of genetic predisposition and early life risk factors that lead to the onset of psychosis in late adolescence or early adulthood. Several studies on adolescents at high risk for schizophrenia have found higher level of anxiety associated with emergence of psychosis later in life. Thus alleviating this heightened anxiety might be an effective way to prevent the transition to psychosis.\ud Rats exposed during gestational day (GD) 17 to the mitotoxin methyl azoxymethanol acetate (MAM) exhibit behavioral, pharmacological, and anatomical characteristics consistent with an animal model of schizophrenia. These rats exhibit increases in dopamine neuron population activity (i.e. the proportion of spontaneously active DA neurons) and the enhanced locomotor response to amphetamine, which correlate with the psychosis. This hyperresponsivity of dopamine system could be driven by abnormal activity of the hippocampus, resulted from loss of parvalbumin interneurons. \ud In this study, we observed in peripubertal MAM rats higher level of anxiety as tested in elevated plus maze and higher firing rate of basolateral amygdala neurons, which persisted into adulthood. In addition, peripubertal MAM rats demonstrated increased conditioned stimuli-induced freezing in a standard fear conditioning paradigm. Although adult MAM rats did not show significant difference on such freezing behaviors, they had significantly more increase in power of theta oscillations in response to these conditioned stimuli.\ud To alleviate anxiety, a widely used anti-anxiety drug diazepam was administered to rats during peripubertal period. Peripubertal administration of diazepam was found to prevent the increase in dopamine neuron activity and attenuate the behavioral hyper-responsivity to amphetamine in MAM rats. These effects of peripubertal administration of diazepam could be partially due to its attenuation of loss of parvalbumin positive neurons in the ventral subiculum of the hippocampus in these rats. In addition, peripubertal administration of diazepam has a persistent effect to reduce anxiety-like behaviors in the elevated plus maze, reduce conditioned stimuli induced freezing behaviors, and normalize hyperactivity of basolateral amygdala in MAM rats.\ud Altogether, these results suggest that pathophysiological factors leading to the onset of psychosis in early adulthood may be circumvented by controlling anxiety during adolescence.\u