Major depressive disorder (MDD) is a recurrent and complex psychiatric disorder. The available pharmacological therapies for MDD are associated with important limitations, including delayed onset of antidepressant effects and considerable side effects (Cipriani et al., 2018). Moreover, about half of patients with MDD do not respond to conventional antidepressants, and many of those who are responsive present recurrences (Kennedy, 2013; Shelton, 2015; Frodl, 2017; Pandarakalam, 2018). This data highlights the need for new antidepressants with more favorable therapeutic profile.

S-adenosyl-l-methionine (SAMe), an endogenous methyl donor compound with a wide range of physiological functions, including metabolism and synthesis of neurotransmitters (Mato et al., 1997; Miller, 2008), has shown therapeutic potential in MDD and other psychiatric disorders (Sarris et al., 2016, 2020; De Berardis et al., 2017; Sarris, 2017; Schefft et al., 2017; Sharma et al., 2017; Gao et al., 2018; Wilson, 2019). Clinical studies have shown that SAMe has similar or superior effects to other antidepressants (Alpert et al., 2004; Papakostas et al., 2010; Sharma et al., 2017). However, the mechanism underlying SAMe's antidepressant effects remains unclear.

SAMe has been implicated in the transfer of a methyl group to catechol substrate by the catechol-O-methyltransferase enzyme (COMT), thus increasing the synthetic activity of endogenous catecholamines, including neurotransmitters such as noradrenaline (NA, Muller, 2010). Similar to other antidepressant drugs, SAMe changes catecholamines and serotonin (5-hydroxytryptamine, 5-HT) levels in many regions of the brain related to stress and depression (Curcio et al., 1978; Bottiglieri et al., 1984; Losada and Rubio, 1989; Otero-Losada and Rubio, 1989), suggesting that their biosynthesis and metabolism could be involved in the antidepressant action of SAMe.

The prominent role of serotonin and its receptors, especially 5-HT1A, in the treatment and pathophysiology of depression is well known (Comley et al., 2015; Han et al., 2015; Gu et al., 2018; Salaciak and Pytka, 2021). Reduced levels of 5-HT are found in the brain of depressed patients while the activation of postsynaptic 5-HT1A heteroreceptors, inhibition of 5-HT1A autoreceptors, and serotonin reuptake inhibition cause antidepressant effects (Asberg et al., 1986; Ferres-Coy et al., 2013; Newman-Tancredi et al., 2018). However, the precise involvement of 5-HT signaling in the antidepressant-like effects induced by SAMe has not been directly tested to date. Therefore, we aimed to investigate the possible participation of 5-HT levels and 5-HT1A receptors in SAMe-induced behavioral effects in mice exposed to the predictive models of antidepressant effects (Yan et al., 2010).