Regional cerebral cortical activation in monoamine oxidase A-deficient mice: Differential effects of chronic versus acute elevations in serotonin andnorepinephrine

Mice deficient in monoamine oxidase A have previously been shown to demonst rate a chronic elevation of serotonin and norepinephrine in the brain. Usin g the autoradiographic [C-14]iodo-antipyrine method, we examined cerebral c ortical blood flow in conscious, restrained four- to five-month-old knock-o ut and wild-type animals following the intraperitoneal administration of ei ther saline or D-fenfluramine. Knock-out animals administered saline, compa red to their wild-type counterparts, demonstrated a significantly higher re gional cortical blood flow in somatosensory and barrel field neocortex, an area which previous histological studies have shown to be characterized by abnormal serotonergic projection fibers and absent barrel formation. Region al cortical blood how was significantly lower in knock-out than in wild-typ e mice in the entorhinal and midline motor cortex, with nonsignificant decr eases noted in the olfactory, piriform and retrosplenial cortices and the a mygdala. We compared the above findings to those obtained in response to D- fenfluramine which, in conjunction with its metabolite D-norfenfluramine, r esults in acute elevations of brain levels of serotonin and norepinephrine. Administration of D-fenfluramine (21.2 mg/kg) resulted in changes in regio nal cortical perfusion in most brain regions of both knock-out and wild-typ e mice that were opposite to the genotypic differences seen in perfusion in response to saline. Fenfluramine significantly increased regional cortical blood flow in the allocortex (olfactory, piriform, entorhinal) and the amy gdala, and significantly decreased regional cortical blood flow in the soma tosensory, barrel field, midline motor and retrosplenial cortices. Changes in regional perfusion in response to fenfluramine were topographically equi valent in knock-out and wild-type mice, although in knock-out mice such cha nges were of greater magnitude. Our study suggests that the effects on regional cortical blood how of a lif elong absence of monoamine oxidase A, and the consequent chronic increase i n serotonin and norepinephrine, differ from those attributable to acute inc reases in these neurotransmitters following fenfluramine administration. Su ch a differential response may reflect neurodevelopmental abnormalities and /or effects of a chronic physiological adaptation on the regulation of cort ical activation. (C) 2000 IBRO. Published by Elsevier Science Ltd. All righ ts reserved.