Altered regulation of the 5‐HT system in the brain of MAO‐A knock‐out mice

Abstract

Genetic deficiency of monoamine oxidase‐A (MAO‐A) induces major alterations of mood and behaviour in human. Because serotonin (5‐HT) is involved in mood regulation, and MAO‐A is responsible for the catabolism of 5‐HT, we investigated 5‐HT mechanisms in knock‐out mice (2‐month‐old) lacking MAO‐A, using microdialysis, electrophysiological, autoradiographic and molecular biology approaches. Compared to paired wild‐type mice, basal extracellular 5‐HT levels were increased in ventral hippocampus (+202%), frontal cortex (+96%) and dorsal raphe nucleus (DRN, +147%) of MAO‐A mutant mice. Conversely, spontaneous firing rate of 5‐HT neurons in the DRN (recorded under chloral hydrate anaesthesia) was ∼40% lower in mutants. Acute 5‐HT reuptake blockade by citalopram (0.2 and 0.8 mg/kg i.v.) produced a much larger increase in extracellular 5‐HT levels (by ∼4 fold) and decrease in DRN neuronal firing (with a ∼4.5 fold decrease in the drug's ED₅₀) in MAO‐A knock‐out mice, which expressed lower levels of the 5‐HT transporter throughout the brain (−13 to −34% compared to wild‐type levels). The potency of the 5‐HT_1A agonist 8‐OH‐DPAT to produce hypothermia and to reduce the firing of DRN serotoninergic neurons was significantly less in the mutants, indicating a desensitization of 5‐HT_1A autoreceptors. This was associated with a decreased autoradiographic labelling of these receptors (−27%) in the DRN. Altogether, these data indicate that, in MAO‐A knock‐out mice, the enhancement of extracellular 5‐HT levels induces a down‐regulation of the 5‐HT transporter, and a desensitization of 5‐HT_1A autoreceptors which allows the maintenance of tonic activity of 5‐HT neurons in the DRN.