Serotonin stimulates lateral habenula via activation of the post-synaptic serotonin 2/3 receptors and transient receptor potential channels

•5-HT induced an inward current (I(5-HTi)) and increased firing in ∼80% LHb cells.•A 5-HT uptake blocker induced I(5-HTi), indicating endogenous 5-HT activity.•I(5-HTi) was blocked/activated by 5-HT2/3 antagonists/agonists.•A transient receptor potential channel blocker inhibited I(5-HTi).

There is growing interest on the role of the lateral habenula (LHb) in depression, because it closely and bilaterally connects with the serotoninergic raphe nuclei. The LHb sends glutamate efferents to the raphe nuclei, while it receives serotoninergic afferents, and expresses a high density of serotonin (5-HT) receptors. Recent studies suggest that 5-HT receptors exist both in the presynaptic and postsynaptic sites of LHb neurons, and activation of these receptors may have different effects on the activity of LHb neurons. The current study focused on the effect of 5-HT on the postsynaptic membrane. We found that 5-HT initiated a depolarizing inward current (I(5-HTi)) and accelerated spontaneous firing in ∼80% of LHb neurons in rat brain slices. I(5-HTi) was also induced by the 5-HT uptake blocker citalopram, indicating activity of endogenous 5-HT. I(5-HTi) was diminished by 5-HT2/3 receptor antagonists (ritanserin, SB-200646 or ondansetron), and activated by the selective 5-HT2/3 agonists 1-(3-Chlorophenyl) piperazine hydrochloride or 1-(3-Chlorophenyl) biguanide hydrochloride. Furthermore, I(5-HTi) was attenuated by 2-Aminoethyl diphenylborinate, a blocker of transient receptor potential channels, and an IP3 receptor inhibitor, indicating the involvement of transient receptor potential channels. These results demonstrate that the reciprocal connection between the LHb and the 5-HT system highlights a key role for 5-HT stimulation of LHb neurons that may be important in the pathogenesis of depression.