Tianeptine:: 5-HT uptake sites and 5-HT1-7 receptors modulate memory formation in an autoshaping Pavlovian/instrumental task

Recent studies using invertebrate and mammal species have revealed that, endogenous serotonin (5-hydroxytryptamine, 5-HT) modulates cognitive processes, particularly learning and memory, though, at present, it is unclear the manner, where, and how long 5-HT systems are involved. Hence in this work, an attempt was made to study the effects of 5-HT endogenous on memory formation, using a 5-HT uptake facilitator (tianeptine) and, selective 5-HT1-7 receptor antagonists to determine whether 5-HT uptake sites and which 5-HT receptors are involved, respectively. Results showed that post-training tianeptine injection enhanced memory consolidation in an autoshaping Pavlovian/ instrumental learning task, which has been useful to detect changes on memory formation elicited by drugs or aging. On interaction experiments, ketanserin (5-HT1D/2A/2C antagonist) slightly enhanced tianeptine effects, while WAY 100635 (5-HT1A antagonist), SB224289 (5-HT1B inverse agonist), SB-200646 (5-HT2B/2C antagonist), ondansetron (5-HT3 antagonist), GR 127487 (5-HT4 antagonist), Ro 04-6790 (5-HT6 antagonist), DR 4004 (5-HT7 antagonist), or fluoxetine (an inhibitor of 5-HT reuptake) blocked the facilitatory tianeptine effect. Notably, together tianeptine and Ro 04-6790 impaired learning consolidation. Moreover, 5-HT depletion completely reversed the tianeptine effect. Tianeptine also normalized an impaired memory elicited by scopolamine (an antimuscarinic) or dizocilpine (non-competitive glutamatergic antagonist), while partially reversed that induced by TFMPP (5-HT1B/1D/2A-2C/7 agonist/antagonist). Finally, tianeptine-fluoxetine coadministration had no effect on learning consolidation; nevertheless, administration of an acetylcholinesterase inhibitor, phenserine, potentiated subeffective tianeptine or fluoxetine doses. Collectively, these data confirmed that endogenously 5-HT modulates, via uptake sites and 5-HT1-7 receptors, memory consolidation, and are consistent with the emerging notion that 5-HT plays a key role on memory formation. (C) 2002 kElsevier Science Ltd. All rights reserved.