The serotonin precursor 5-HTP and the serotonin releaser fenfluramine but not the serotonin reuptake inhibitor escitalopram impair acquisition and expression of context-conditioned fear

Abstract

Whereas preclinical and clinical studies suggest serotonin to play an important role in the regulation of anxiety, it remains unclear if its dominating impact is anxiety-dampening or anxiety-provoking. In male rats exposed to a well-established animal model of anxiety, i.e., context-conditioned freezing, we previously found serotonin depletion prior to acquisition and/or expression of conditioned fear to result in a reduction in freezing. We now explored the effect of increasing synaptic levels of serotonin in the same paradigm. Two compounds eliciting a robust increase in extracellular serotonin levels – the serotonin precursor 5-hydroxytryptophan (5-HTP) and the serotonin releaser d-fenfluramine – were administered i) prior to acquisition, ii) immediately after acquisition, or iii) prior to expression of conditioned fear; for comparison, a serotonin reuptake inhibitor (SSRI) escitalopram was also tested. Both 5-HTP (≥ 25 mg/kg) and fenfluramine (≥ 0.5 mg/kg), but not escitalopram (3, 10 and 30 mg/kg), decreased the expression of conditioned fear in a dose-dependent manner. At higher dosage, both 5-HTP (≥ 250 mg/kg) and fenfluramine (5 mg/kg), but not escitalopram (30 mg/kg), impaired acquisition of fear conditioning as well as freezing displayed during presentation of electric foot shocks. In contrast, neither 5-HTP nor fenfluramine impacted expression of conditioned fear when administered immediately after the exposure to shocks. The results underline the importance of an intact and physiologically regulated serotonergic transmission for fear conditioning in rats.