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

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.