Blunted 5-HT 1A receptor-mediated responses and antidepressant-like behavior in mice lacking the GABA B1a but not GABA B1b subunit isoforms.

Autor: Jacobson LH; Florey Institute of Neuroscience and Mental Health, Parkville, VIC, 3052, Australia. laura.jacobson@florey.edu.au.; Department of Pharmacology and Therapeutics, University of Melbourne, Parkville, VIC, 3052, Australia. laura.jacobson@florey.edu.au., Hoyer D; Florey Institute of Neuroscience and Mental Health, Parkville, VIC, 3052, Australia.; Department of Pharmacology and Therapeutics, University of Melbourne, Parkville, VIC, 3052, Australia.; Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA, 92037, USA., Fehlmann D; Autoimmunity, Transplantation and Inflammation, Novartis Institutes for BioMedical Research, Novartis Pharma AG, CH-4002, Basel, Switzerland., Bettler B; Department of Biomedicine, Pharmazentrum, University of Basel, CH-4056, Basel, Switzerland., Kaupmann K; Autoimmunity, Transplantation and Inflammation, Novartis Institutes for BioMedical Research, Novartis Pharma AG, CH-4002, Basel, Switzerland., Cryan JF; APC Microbiome Institute, University College Cork, Cork, Ireland. j.cryan@ucc.ie.; Department of Anatomy and Neuroscience, University College Cork, Western Gateway Building, Cork, Ireland. j.cryan@ucc.ie.
Jazyk: angličtina
Zdroj: Psychopharmacology [Psychopharmacology (Berl)] 2017 May; Vol. 234 (9-10), pp. 1511-1523. Date of Electronic Publication: 2017 Jan 09.
DOI: 10.1007/s00213-016-4521-5
Abstrakt: Rationale: There is accumulating evidence for a role of GABA B receptors in depression. GABA B receptors are heterodimers of GABA B1 and GABA B2 receptor subunits. The predominant GABA B1 subunit isoforms are GABA B1a and GABA B1b . GABA B1 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 GABA B receptors and the serotonergic system and the involvement of 5-HT 1A receptors (5-HT 1A R) in antidepressant action, we sought to evaluate 5-HT 1A R function in GABA B1a -/- and GABA B1b -/- mice.
Methods: GABA B1a -/- and GABA B1b -/- mice were assessed in the forced swim test (FST), and body temperature and hypothalamic-pituitary-adrenal (HPA) responses to the 5-HT 1A R agonist 8-OH-DPAT were determined. Brain 5-HT 1A R expression was assessed by [ 3 H]-MPPF and [ 3 H]-8-OH-DPAT autoradiography and 5-HT 1A R G-protein coupling by [ 35 S]GTP-γ-S autoradiography.
Results: As previously described, GABA B1a -/- mice showed an antidepressant-like profile in the FST. GABA B1a -/- 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 GABA B1a -/- mice. Interestingly, [ 3 H]-MPPF and [ 3 H]-8-OH-DPAT binding was largely unaffected by genotype. [ 35 S]GTP-γ-S autoradiography suggested that altered 5-HT 1A R G-protein coupling only partially contributes to the functional presynaptic 5-HT 1A R desensitization, and not at all to the blunted postsynaptic 5-HT 1A R-mediated responses, seen in GABA B1a -/- mice.
Conclusion: These data demonstrate distinct functional links between 5-HT 1A Rs and the GABA B1a subunit isoform and suggest that the GABA B1a isoform may be implicated in the antidepressant-like effects of GABA B receptor antagonists and in neurobiological mechanisms underlying depression.
Databáze: MEDLINE
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