Rationale: In view of the difficulties in using antidepressant agents as training drugs in drug discrimination research, it was reasoned that tianeptine, because of its short duration of action and its lack of toxicity associated with long-term administration, would be well-suited to establish a discriminative stimulus cue in rats and, hence, a valuable tool in the investigation of the neural basis of depression.

Objectives: A drug discrimination procedure was used to determine whether tianeptine was associated with a specific discriminative stimulus effect, and substitution tests were conducted to determine whether this effect was mediated by serotonergic mechanisms.

Method: Rats were trained to discriminate 10 mg/kg tianeptine from saline and were tested with fluoxetine, a selective serotonin (5-HT) reuptake inhibitor; venlafaxine, a 5-HT/noradrenaline reuptake inhibitor; 8-hydroxy-(2-di-n-propylamino)tetralin (8-OH-DPAT), a selective 5-HT1A agonist; and caffeine, a nonselective antagonist of adenosine receptors.

Results: Tianeptine induced a specific, robust, and sustained discriminative stimulus in rats. Fluoxetine and 8-OH-DPAT partially substituted for tianeptine by producing >50% of tianeptine-appropriate lever responding. In contrast, venlafaxine and caffeine induced responding on a saline-associated lever.

Conclusion: The discriminative stimulus effect of tianeptine is mediated by serotonergic mechanisms, but what is surprising is that this mechanism seems to be, at least partially, enhanced by serotonergic transmission.