Impaired spatial and sequential learning in rats treated neonatally with <scp>d</scp>‐fenfluramine

TLDR

Substituted amphetamines can cause long‑term learning deficits, but the underlying mechanisms remain unclear. Neonatal d‑fenfluramine exposure (postnatal days 11–20) was followed by stress‑controlled spatial learning tests, showing drug‑specific deficits. Adult rats exposed to neonatal d‑fenfluramine exhibit dose‑dependent impairments in sequential and spatial learning, mirroring MDMA effects and distinct from d‑methamphetamine, with deficits not linked to persistent hippocampal 5‑HT changes.

Abstract

Abstract d ‐Fenfluramine, a serotonin releaser, was administered to neonatal rats on postnatal days 11–20 (a stage of hippocampal development analogous to third trimester human ontogeny). As adults, the d ‐fenfluramine‐treated offspring exhibited dose‐related impairments of sequential and spatial learning and reference memory in the absence of sensorimotor impairments. Procedures to minimize stress and to control for other performance effects prior to testing for spatial learning demonstrated that nonspecific factors did not account for the selective effects of d ‐fenfluramine on learning and memory. Developmental d ‐fenfluramine‐induced spatial and sequential learning deficits are similar to previous findings with developmental MDMA treatment. By contrast, recent findings with developmental d ‐methamphetamine treatment showed spatial learning deficits while sparing sequential learning. The spatial learning effects common to all three drugs suggest that they may share a common mechanism of action, however, the effects are not related to long‐lasting changes in hippocampal 5‐HT levels as no differences were found in adulthood. Whether the cognitive deficits are related to the effects of substituted amphetamines on corticosteroids, other aspects of the 5‐HT system, or some unidentified neuronal substrates is not known, but the data demonstrate that these drugs are all capable of inducing long‐term adverse effects on learning.