Blunted 5-HT Receptor-mediated Responses and Antidepressant-like Behavior in Mice Lacking the GABA but Not GABA Subunit Isoforms

Rationale: There is accumulating evidence for a role of GABA receptors in depression. GABA receptors are heterodimers of GABA and GABA receptor subunits. The predominant GABA subunit isoforms are GABA and GABA. GABA 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 receptors and the serotonergic system and the involvement of 5-HT receptors (5-HTR) in antidepressant action, we sought to evaluate 5-HTR function in GABA and GABA mice.

Methods: GABA and GABA mice were assessed in the forced swim test (FST), and body temperature and hypothalamic-pituitary-adrenal (HPA) responses to the 5-HTR agonist 8-OH-DPAT were determined. Brain 5-HTR expression was assessed by [H]-MPPF and [H]-8-OH-DPAT autoradiography and 5-HTR G-protein coupling by [S]GTP-γ-S autoradiography.

Results: As previously described, GABA mice showed an antidepressant-like profile in the FST. GABA 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 mice. Interestingly, [H]-MPPF and [H]-8-OH-DPAT binding was largely unaffected by genotype. [S]GTP-γ-S autoradiography suggested that altered 5-HTR G-protein coupling only partially contributes to the functional presynaptic 5-HTR desensitization, and not at all to the blunted postsynaptic 5-HTR-mediated responses, seen in GABA mice.

Conclusion: These data demonstrate distinct functional links between 5-HTRs and the GABA subunit isoform and suggest that the GABA isoform may be implicated in the antidepressant-like effects of GABA receptor antagonists and in neurobiological mechanisms underlying depression.