Tianeptine was initially considered to be a selective serotonin reuptake enhancer (SSRE) as its acute and long-term administration decreased extracellular 5-HT levels in the brain stem, striatum, cerebral cortex and hippocampus in rats [
22,
23].
Later studies, however, contradicted these findings—albeit this discrepancy may be explained by technical differences in the micro-dialysis techniques employed.
Nevertheless, recent evidence in humans demonstrates a reduction in plasma serotonin and increase in platelet serotonin following acute administration of tianeptine, consistent with the effect of enhanced serotonin reuptake [
50].
In addition, tianeptine has also been shown to: (1) regulate stress-induced glutamate release, (2) modulate plasticity in the amygdala; (3) reverse stress-induced hippocampal dystrophy [
51]; and (4) be a
μ-opioid receptor agonist [
52].
Given that we only investigated the brain response after a single dose of tianeptine, it is unlikely that our results are due to modulating plasticity or the reversal of dystrophy.
However, we cannot rule out the possibility that our results may be partially explained by modulation of the glutamatergic and μ-opioid systems. For example, the glutamatergic system has been widely reported to be abnormal in ASD [
53].
Also, alterations in the μ-opioid system have been proposed to contribute to ASD [
54]. Hence, future studies are required to investigate which of the proposed mechanisms underlie the reported modulating effect.