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.
Given the interactions between GABA(B) 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 GABA(B1a) (-/-) and GABA(B1b) (-/-) mice.
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-HT1AR agonist 8-OH-DPAT were determined. Brain 5-HT1AR expression was assessed by [H-3]-MPPF and [H-3]-8-OH-DPAT autoradiography and 5-HT1AR G-protein coupling by [S-35]GTP-gamma-S autoradiography.
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, [H-3]-MPPF and [H-3]-8-OH-DPAT binding was largely unaffected by genotype. [S-35]GTP-gamma-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 GABA(B1a) (-/-) mice.
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.