5-HT_1B receptor-AC-PKA signal pathway in the lateral habenula is involved in the regulation of depressive-like behaviors in 6-hydroxydopamine-induced Parkinson’s rats

ABSTRACT

Objective

The aim of the present study was to investigate whether serotonin_1B (5-HT_1B) receptor-adenylate cyclase (AC)-protein kinase A (PKA) signal pathway in the lateral habenula (LHb) is involved in Parkinson’s disease-related depression in sham-lesioned and substantia nigra pars compacta (SNc)-lesioned rats.

Methods

The sucrose preference and forced swim tests were used to measure depressive-like behaviors. In vivo electrophysiology and microdialysis were performed to observe the firing activity of LHb neurons and GABA and glutamate release in the LHb, respectively. Western blotting was used to analyze protein expression of 5-HT_1B receptors, AC and phosphorylated PKA at threonine 197 site (p-PKA-Thr197) in the LHb.

Results

Unilateral 6-hydroxydopamine lesions of the SNc in rats induced depressive-like behaviors. Intra-LHb injection of 5-HT_1B receptor agonist CP93129 produced antidepressant-like effects and the antagonist SB216641 induced depressive-like behaviors in sham-lesioned and SNc-lesioned rats. Further, pretreatment with AC inhibitor SQ22536 and PKA inhibitor KT5720 blocked the behavioral effects of CP93129 in the two groups of rats, respectively. CP93129 decreased the firing rate of LHb neurons and release of GABA and glutamate, but increased the GABA/glutamate ratio, while SB216641 induced the opposite effects. Compared with sham-lesioned rats, effects of CP93129 and SB216641 on the depressive-like behaviors, electrophysiology, and microdialysis were decreased in SNc-lesioned rats, which were associated with decreased expression of 5-HT_1B receptors, AC and p-PKA-Thr197 in the LHb.

Conclusion

5-HT_1B receptor-AC-PKA signal pathway in the LHb is involved in the regulation of depressive-like behaviors, and depletion of DA reduces activity of 5-HT_1B receptor-AC-PKA signal pathway.

KEYWORDS:

• 5-HT_1B receptors
• lateral habenula
• depression
• adenylate cyclase
• protein kinase A
• Parkinson’s disease

Acknowledgments

The authors wish to acknowledge Hui-Sheng Wang for technical support.

Author contributions

Performing experiments and writing-original draft: Guo Yi Tang

Supports for experiments and data analysis: Run Jia Wang, Yuan Guo

Resources, supervision, funding acquisition, writing-review and editing: Jian Liu

All authors have approved the final manuscript.

Disclosure statement

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

Additional information

Funding

This study was supported by the National Natural Science Foundation of China (No. 81771383).

Notes on contributors

Guo Yi Tang

Guo Yi Tang is a PhD student in Department of Physiology and Pathophysiology of Xi’an Jiaotong University mainly research the non-motor symptoms such as depression and anxiety in Parkinson’s disease.

Run Jia Wang

Run Jia Wang is an undergraduate in Xi’an Medical University major in clinical medicine and have participated in innovation competition for college students during school time.

Yuan Guo

Yuan Guo is an associate professor in Xi’an Jiaotong University. She has been working in the field of neuroscience and her main research interest is the central mechanism of Parkinson’s disease in recent years. She has presided several research projects such as National Natural Science Foundation of China and China Postdoctoral Science Foundation.

Jian Liu

Jian Liu is a professor in Xi’an Jiaotong University. His basic interest is in neuroscience research, currently focusing on neurobiology of Parkinson’s disease. Total international publications are more than 60. He has hosted and participated in the National Natural Science Foundation of China and other research projects.