The role of serotonin in lithium’s inhibitory effect on autonomic function and behaviour in mice

Background: Lithium has been the gold-standard mood stabiliser for bipolar disorder, yet its mechanisms remain poorly understood. We have proposed that lithium’s action starts peripherally in the gut and is mediated via the gut-brain axis. In experimental animals, lithium salt (LiCl) induces a lethargic response and a decrease in body temperature. Our unpublished data show that lithium-induced hypolocomotion and hypothermia depend on enterochromaffin cells in the gastrointestinal tract. These cells secrete serotonin (5-hydroxytryptamine, 5-HT) and substance P. This study investigated whether these substances are involved in the lithiuminduced physiological responses and examined whether blocking their receptors (5-HT2, 5- HT3, 5-HT7, and Neurokinin-1 (NK1)) inhibits these responses.

Method: Male C57BL/6J mice were implanted with a telemetry probe (ETA-F10, Data Sciences International) to measure body temperature, heart rate and locomotor activity. Mice were pre-treated with ondansetron (5-HT3 antagonist, i.p., 1,2 mg/kg), SB-269970 (5-HT7 antagonist, i.p., 20 mg/kg), RP67580 (NK1 antagonist, i.p., 1.5 mg/kg), xylamidine (peripheral 5-HT2 antagonist, i.p., 6 mg/kg) or a combination of xylamidine and SB-269970 (i.p., 6 and 20 mg/kg, respectively), 30 minutes before LiCl (2 mEq/kg, i.p.) administration.

Results: In control mice (n= 5), LiCl induced a dose-dependent reduction in body temperature (by 3.5 ˚C for 2mEq/kg) and locomotion. Blockade of 5-HT7 receptors with SB-269970 significantly attenuated lithium-induced hypothermia and locomotion suppression. Similarly, peripheral 5-HT2 blockade with xylamidine significantly attenuated both effects. Combined antagonism of 5-HT2/5-HT7 receptors further reduced hypothermic and behavioural responses. 5-HT3 (ondansetron) and NK1 (RP67580) antagonisms had no significant effects (p > 0.05).

Conclusion: These findings identify a dual serotonergic mechanism - via 5-HT7 and peripheral 5-HT2 receptors - as key mediators of lithium-induced autonomic and behavioural suppression. This suggests that peripheral serotonin release triggered by lithium plays a role in the therapeutic mechanisms of lithium in bipolar disorder