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. 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. 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 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.