Regional cerebral cortical activation in monoamine oxidase A-deficient mice: differential effects of chronic versus acute elevations in serotonin and norepinephrine

Abstract

Mice deficient in monoamine oxidase A have previously been shown to demonstrate a chronic elevation of serotonin and norepinephrine in the brain. Using the autoradiographic [14C]iodo-antipyrine method, we examined cerebral cortical blood flow in conscious, restrained four- to five-month-old knock-out and wild-type animals following the intraperitoneal administration of either saline or D-fenfluramine. Knock-out animals administered saline, compared to their wild-type counterparts, demonstrated a significantly higher regional 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. Regional cortical blood flow was significantly lower in knock-out than in wild-type mice in the entorhinal and midline motor cortex, with non-significant decreases noted in the olfactory, piriform and retrosplenial cortices and the amygdala. We compared the above findings to those obtained in response to D-fenfluramine which, in conjunction with its metabolite D-norfenfluramine, results in acute elevations of brain levels of serotonin and norepinephrine. Administration of D-fenfluramine (21. 2mg/kg) resulted in changes in regional cortical perfusion in most brain regions of both knock-out and wild-type 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 amygdala, and significantly decreased regional cortical blood flow in the somatosensory, barrel field, midline motor and retrosplenial cortices. Changes in regional perfusion in response to fenfluramine were topographically equivalent in knock-out and wild-type mice, although in knock-out mice such changes were of greater magnitude. Our study suggests that the effects on regional cortical blood flow of a lifelong absence of monoamine oxidase A, and the consequent chronic increase in serotonin and norepinephrine, differ from those attributable to acute increases in these neurotransmitters following fenfluramine administration. Such a differential response may reflect neurodevelopmental abnormalities and/or effects of a chronic physiological adaptation on the regulation of cortical activation.

Biochemical, behavioral, physiologic, and neurodevelopmental changes in mice deficient in monoamine oxidase A or B

“…MAO A mutant mice compared to wild-type mice demonstrate lower body weights (~10% lower), though it remains to be clarified whether this is related to alterations in serotonergic tone or if this simply reflects a slower weight gain due to behavioral difficulties and poor feeding in infancy. Consistent with the role of 5-HT in thermoregulation [45,50,86], fenfluramine elicits an exaggerated increase in core temperature in knock-out mice compared to wild-type mice [29]. Central serotonergic, as well as noradrenergic mechanisms have been implicated in the control of blood pressure and heart rate with most studies suggesting pressor and chronotropic effects of these biogenic amines.…”

“…That aspects of hindlimb dysfunction may extend into adult life is suggested by the observation that adult MAO A KO mice display abnormal walking on a balance-beam, with adults grasping the lateral aspects of the beam with the hindlimbs during movement [12,69]. However, the possibility needs to be considered that such abnormalities may also be the result of altered somatosensory processing [13,29].…”

“…Administration of fenfluramine which increases brain levels of 5-HT and NE through reuptake inhibition and presynaptic release [9,40,73,75] results in a more severe syndrome (tremor, rigidity, Straub tail, hindlimb abduction, lateral head weaving, and reciprocal forepaw treading). Here the serotonin syndrome is elicited at estimated doses in MAO A KO mice that are half those required to elicit this syndrome in wild-type animals [29].…”

“…[12] Increased sensitivity to developing the serotonin syndrome with fenfluramine challenge [29] Behavioral syndrome characterized by restlessness, attentional deficits, disrupted social interaction, feeding and self-grooming after administration of the MAO B inhibitors L-deprenyl or lazabemide [12] Enhancement of classical fear conditioning and step-down inhibitory avoidance learning (emotional memory) but not of eyeblink conditioning (motor learning) [36] Increased mobility in the Porsolt Forced Swim Test [12] Increased time spent in the center in the Open Field test with much hesitation as to which direction to take [12] Abnormal walking on a balance-beam with adults grasping the lateral aspects of the beam with hindlimbs during movement [12,69] Altered courtship with increased grasping events in males and concurrent increased frequency and intensity of vocalization in females. [12] Physiologic Decreased blood pressure and heart rate in the resting, restrained state [29] Exaggerated hyperthermic and tachycardic response to fenfluramine [29] Regional cerebral cortical blood flow: Higher in somatosensory and barrel field neocortex; lower in entorhinal and midline motor cortex [29] Decreased body weight (≈ −10%) [29] * Includes data from unpublished observations.…”

Transcranial Light Alters Melanopsin and Monoamine Production in Mouse (Mus musculus) Brain

“…The function of 5-HT is regulated by monoamine oxidase A (MAO-A), which is an important factor in metabolizing monoamines [57]. In general, if the amount of MAO-A increases, the amount of serotonin decreases [58]. There was a similar pattern in cortical noradrenaline and dopamine in the ML group also, although the changes were not statistically significant.…”