INCREASE IN EXTRACELLULAR SEROTONIN BY THE SEROTONIN PRECURSOR 5-HTP AND THE SEROTONIN RELEASER FENFLURAMINE IMPAIR ACQUISITION AND EXPRESSION OF CONTEXT-CONDITIONED FEAR
Authors: Hagsäter *S Melker , Pettersson Robert , Anatasovski Daniela , Eriksson Elias 
Published: February 2025

Abstract

Background
Serotonin has been attributed both an anxiety-reducing and an anxiety-enhancing influence. For example, acute administration of selective serotonin reuptake inhibitors (SSRIs) as well as of a serotonin releaser, fenfluramine, may provoke anxiety in susceptible individuals (Targum and Marshall, 1989). In contrast, there are reports on acute administration of 5-HTP alleviating anxiety (Maron et al., 2004; Schruers et al., 2002). We have previously shown that acute administration of an SSRI to rat exacerbates unconditioned freezing behaviour without influencing context-conditioned freezing (Hagsater et al., 2019).

Aims & Objectives
To explore the possible impact of compounds (5-HTP and fenfluramine) exerting a more robust (and more non-physiological) increase in extracellular serotonin concentrations than that obtained with an SSRI (escitalopram) on acquisition and expression of context-conditioned fear.

Method
Male Sprague Dawley rats were tested in a paradigm of conditioned fear. Electric foot shocks (amperage: 0.6 mA, duration: 1 s, inter-shock intervals: 30 s) were used as unconditioned stimuli while the context constituted the conditioned stimulus. The effects of 5-HTP, fenfluramine and escitalopram administered i) before acquisition of contextual-conditioned fear, ii) immediately after acquisition of contextual- conditioned fear and iii) before expression of context-conditioned fear, were explored.

Results
Both 5-HTP (&gt; 25 mg/kg) and fenfluramine (&gt; 0.5 mg/kg) decreased expression of conditioned fear in a dose-dependent manner. At higher dosage, both 5-HTP (&gt; 250 mg/kg) and fenfluramine (5 mg/kg) administered prior to acquisition of context-conditioned fear eliminated freezing in subsequent testing. Neither 5-HTP (500 mg/kg) nor fenfluramine (5 mg/kg) administered immediately after fear conditioning impaired freezing in subsequent testing. No effect on acquisition or expression of context-conditioned fear was observed for escitalopram (30 mg/kg).

Discussion & Conclusion
The results suggest 5-HTP and fenfluramine at an intermediate dose to disrupt fear conditioning when administered prior to acquisition or prior to expression of conditioned fear. Since there, in contrast, was no effect of 5-HTP or fenfluramine when administered immediately after acquisition, the effects on conditioned freezing are not likely due to drug-induced memory impairment. The effects of the drugs on acquisition and expression of conditioned freezing suggest that the augmentation of the serotonergic output and/or the disruption of normal serotonergic transmission induced by 5-HTP and fenfluramine interfere with the processes underlying fear conditioning.

References
Hagsater SM, Thoren J, Pettersson R, Eriksson E. Selective serotonin reuptake inhibition increases noise burst-induced unconditioned and context-conditioned freezing. Acta neuropsychiatrica. 2019 Feb;31(1):46-51.
Maron E, Toru I, Vasar V, Shlik J (2004) The effect of 5-hydroxytryptophan on cholecystokinin-4-induced panic attacks in healthy volunteers. Journal of psychopharmacology 18:194-199.
Schruers K, van Diest R, Overbeek T, Griez E (2002) Acute L-5-hydroxytryptophan administration inhibits carbon dioxide-induced panic in panic disorder patients. Psychiatry research 113:237-243. Targum SD, Marshall LE (1989) Fenfluramine provocation of anxiety in patients with panic disorder. Psychiatry research 28:295-306.