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Blunted 5-HT1A receptor-mediated responses and antidepressant-like behavior in mice lacking the GABAB1a but not GABAB1b subunit isoforms

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Abstract

Rationale

There is accumulating evidence for a role of GABAB receptors in depression. GABAB receptors are heterodimers of GABAB1 and GABAB2 receptor subunits. The predominant GABAB1 subunit isoforms are GABAB1a and GABAB1b. GABAB1 isoforms in mice differentially influence cognition, conditioned fear, and susceptibility to stress, yet their influence in tests of antidepressant-like activity has not been fully investigated.

Objectives

Given the interactions between GABAB receptors and the serotonergic system and the involvement of 5-HT1A receptors (5-HT1AR) in antidepressant action, we sought to evaluate 5-HT1AR function in GABAB1a −/− and GABAB1b −/− mice.

Methods

GABAB1a −/− and GABAB1b −/− mice were assessed in the forced swim test (FST), and body temperature and hypothalamic-pituitary-adrenal (HPA) responses to the 5-HT1AR agonist 8-OH-DPAT were determined. Brain 5-HT1AR expression was assessed by [3H]-MPPF and [3H]-8-OH-DPAT autoradiography and 5-HT1AR G-protein coupling by [35S]GTP-γ-S autoradiography.

Results

As previously described, GABAB1a −/− mice showed an antidepressant-like profile in the FST. GABAB1a −/− mice also demonstrated profoundly blunted hypothermic and motoric responses to 8-OH-DPAT. Furthermore, 8-OH-DPAT-induced corticosterone and adrenocorticotropic hormone (ACTH) release were both attenuated in GABAB1a −/− mice. Interestingly, [3H]-MPPF and [3H]-8-OH-DPAT binding was largely unaffected by genotype. [35S]GTP-γ-S autoradiography suggested that altered 5-HT1AR G-protein coupling only partially contributes to the functional presynaptic 5-HT1AR desensitization, and not at all to the blunted postsynaptic 5-HT1AR-mediated responses, seen in GABAB1a −/− mice.

Conclusion

These data demonstrate distinct functional links between 5-HT1ARs and the GABAB1a subunit isoform and suggest that the GABAB1a isoform may be implicated in the antidepressant-like effects of GABAB receptor antagonists and in neurobiological mechanisms underlying depression.

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Acknowledgements

This work was supported by the National Institutes of Mental Health/National Institute on Drug Abuse grant U01 MH69062 (LHJ, KK, JFC, and Athina Markou) and the Swiss Science Foundation (31003A-152970, BB). LHJ, DH, BB and JFC were former employees and KK and DF are current employees of the Novartis Institutes for Biomedical Research. The authors thank Doncho Uzunov, Hugo Bürki, and Christian Kohler for expert technical assistance and Véronique Fabre for advice on [35S]GTP-γ-S autoradiography. The Florey Institute of Neuroscience and Mental Health acknowledges the support of the Victorian Government and in particular the funding from the Operational Infrastructure Support Grant.

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Authors and Affiliations

  1. Florey Institute of Neuroscience and Mental Health, Parkville, VIC, 3052, Australia

    Laura H. Jacobson & Daniel Hoyer

  2. Department of Pharmacology and Therapeutics, University of Melbourne, Parkville, VIC, 3052, Australia

    Laura H. Jacobson & Daniel Hoyer

  3. Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA, 92037, USA

    Daniel Hoyer

  4. Autoimmunity, Transplantation and Inflammation, Novartis Institutes for BioMedical Research, Novartis Pharma AG, CH-4002, Basel, Switzerland

    Dominique Fehlmann & Klemens Kaupmann

  5. Department of Biomedicine, Pharmazentrum, University of Basel, CH-4056, Basel, Switzerland

    Bernhard Bettler

  6. APC Microbiome Institute, University College Cork, Cork, Ireland

    John F. Cryan

  7. Department of Anatomy and Neuroscience, University College Cork, Western Gateway Building, Cork, Ireland

    John F. Cryan

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  1. Laura H. Jacobson
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  2. Daniel Hoyer
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Correspondence to Laura H. Jacobson or John F. Cryan.

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Jacobson, L.H., Hoyer, D., Fehlmann, D. et al. Blunted 5-HT1A receptor-mediated responses and antidepressant-like behavior in mice lacking the GABAB1a but not GABAB1b subunit isoforms. Psychopharmacology 234, 1511–1523 (2017). https://doi.org/10.1007/s00213-016-4521-5

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