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

Abstract

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_1AR) in antidepressant action, we sought to evaluate 5-HT_1AR 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_1AR agonist 8-OH-DPAT were determined. Brain 5-HT_1AR expression was assessed by [³H]-MPPF and [³H]-8-OH-DPAT autoradiography and 5-HT_1AR G-protein coupling by [³⁵S]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, [³H]-MPPF and [³H]-8-OH-DPAT binding was largely unaffected by genotype. [³⁵S]GTP-γ-S autoradiography suggested that altered 5-HT_1AR G-protein coupling only partially contributes to the functional presynaptic 5-HT_1AR desensitization, and not at all to the blunted postsynaptic 5-HT_1AR-mediated responses, seen in GABA_B1a^-/- mice.

Conclusion: These data demonstrate distinct functional links between 5-HT_1ARs 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.

Keywords: 5-HT1A receptor; 8-OH-DPAT; GABAB1 receptor subunit isoforms.