title: Blunted 5-HT1Areceptor-mediated responses and antidepressant-like behavior in mice lacking the GABAB1abut not GABAB1bsubunit isoforms.
abstract: There is accumulating evidence for a role of GABABreceptors in depression. GABABreceptors are heterodimers of GABAB1and GABAB2receptor subunits. The predominant GABAB1subunit isoforms are GABAB1aand GABAB1b. GABAB1isoforms 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.
  
  
  
  Given the interactions between GABABreceptors and the serotonergic system and the involvement of 5-HT1Areceptors (5-HT1AR) in antidepressant action, we sought to evaluate 5-HT1AR function in GABAB1a-/-and GABAB1b-/-mice.
  
  
  
  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.
  
  
  
  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.
  
  
  
  These data demonstrate distinct functional links between 5-HT1ARs and the GABAB1asubunit isoform and suggest that the GABAB1aisoform may be implicated in the antidepressant-like effects of GABABreceptor antagonists and in neurobiological mechanisms underlying depression.
authors.affiliation: 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.
authors.forename: Laura H
authors.initials: LH
authors.lastname: Jacobson
authors.affiliation: 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.
authors.forename: Daniel
authors.initials: D
authors.lastname: Hoyer
authors.affiliation: Autoimmunity, Transplantation and Inflammation, Novartis Institutes for BioMedical Research, Novartis Pharma AG, CH-4002, Basel, Switzerland.
authors.forename: Dominique
authors.initials: D
authors.lastname: Fehlmann
authors.affiliation: Department of Biomedicine, Pharmazentrum, University of Basel, CH-4056, Basel, Switzerland.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Bettler
authors.affiliation: Autoimmunity, Transplantation and Inflammation, Novartis Institutes for BioMedical Research, Novartis Pharma AG, CH-4002, Basel, Switzerland.
authors.forename: Klemens
authors.initials: K
authors.lastname: Kaupmann
authors.affiliation: 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.
authors.forename: John F
authors.initials: JF
authors.lastname: Cryan
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000378:metabolism* / Q000494:pharmacology; D001831:Body Temperature / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003345:Corticosterone / Q000378:metabolism; D003863:Depression / Q000378:metabolism* / Q000523:psychology; D005260:Female; D018756:GABA Antagonists / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011485:Protein Binding / Q000502:physiology; D020033:Protein Isoforms / Q000378:metabolism; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D018080:Receptors, GABA-B / Q000172:deficiency*; D017366:Serotonin Receptor Agonists / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000928:Antidepressive Agents; D018756:GABA Antagonists; D020033:Protein Isoforms; D018080:Receptors, GABA-B; D017366:Serotonin Receptor Agonists; D044282:Receptor, Serotonin, 5-HT1A; D003345:Corticosterone
keywords: 5-HT1A receptor; 8-OH-DPAT; GABAB1 receptor subunit isoforms