Pindolol potentiates the antidepressant effect of venlafaxine by inhibiting 5-HT1A receptor in DRN neurons of mice

Abstract

Introduction

Antidepressants increase the level of 5-HT in the somatodendritic region of the serotonergic dorsal raphe nucleus (DRN) neurons in the first few days of their usage, which, in turn, inhibits the serotonergic neurons locally. Pindolol may eliminate this inhibition when used in combination with antidepressants.

Material and methods

We aimed to determine the effect of pindolol on 5-HT1A receptor response in the DRN neurons, using voltage clamp recordings and prove the potentiation of antidepressant effect of venlafaxine by pindolol through behavior experiments. Balb/c mice, 28–35 days-old were used.

Results

5-HT application (25 µM) induced an outward current by 23.36 ± 3.79 pA at the neurons in the dorsal subnucleus of DRN. This effect was inhibited by pre-administration of WAY-100135 (21 µM) and pindolol (10 µM) separately. The current induced by 5-HT and 8-OHDPAT have no statistically significance. 8-OHDPAT (30 µM) induced a 5-HT-like outward current, which was inhibited by pre-administration of pindolol (10 µM). Combination of venlafaxine (20 mg/kg/day) and pindolol (15 mg/kg/day) significantly reduced immobilization time when compared to the control group in tail suspension test and forced swim test without any significant change in locomotor activity. Administration of venlafaxine (20 mg/kg/day) alone or pindolol (15 mg/kg/day) alone did not significantly reduce immobilization time.

Conclusion

Pindolol has the potential to prevent the inhibition of serotonergic neurons after antidepressant use. Hence, we, for the first time, demonstrated that pindolol can potentiate antidepressant effect of venlafaxine. In the mood disorders, pindolol is likely to increase the effectiveness of antidepressant drugs when given in combination.

Keywords:

• 5-HT
• dorsal raphe nucleus
• major depression
• pindolol
• venlafaxine

Acknowledgements

The use of animals in the present study was approved by Gaziantep University Animal Use Committee (Project decision no: 2019/28). Gaziantep University Research Center for Experımental Animals and Gaziantep University BAPYB are gratefully acknowledged for their help and support with experimental studies on animals.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Authors' contributions

All authors conceived and designed the study. All authors performed the experiments and wrote the draft of the manuscript. All authors contributed to and approved the final manuscript.

Additional information

Funding

This work was supported by the Gaziantep University BAPYB under Grant number TF.DT.19.21, Turkey, which had no role in the study design; collection; analysis or interpretation of the data; writing of the report and in the decision to submit the paper for publication.