The GABAβ receptor as a target for antidepressant drug action

Abstract

Preclinical and clinical data suggest that a modification in GABA(B) receptor expression and function may contribute to the symptoms of major depression and the response to antidepressants. This includes laboratory animal experiments demonstrating that antidepressants modify brain GABA(B) receptor expression and function and that GABA(B) receptor antagonists display antidepressant potential in animal models of this condition. Clinical and post-mortem studies reveal changes in GABAergic transmission associated with depression as well as depression-related changes in GABA(B) subunit expression that are localized to the cortical depression network. Detailed in this review are the preclinical and clinical data implicating a role for the GABA(B) receptor system in mediating symptoms of this disorder and its possible involvement in the response to antidepressants. Particular emphasis is placed on clinical and post-mortem studies, including previously unpublished work demonstrating regionally-selective modifications in GABA(B) receptor subunit expression in brain samples obtained from depressed subjects. Together with the earlier preclinical studies, these new data point to a role for the GABA(B) system in major depression and support the antidepressant potential of GABA(B) receptor antagonists.

Figure 1

Representation of the coordinates used to dissect the dentate gyrus (DG), CA1 and CA3 regions of the hippocampus.

Figure 2

GABA_B1a subunit gene expression in the CA3 region of the hippocampus of depressed (n= 6) and control (n= 7) male (blue) and depressed (n= 4) and control (n= 2) female (red) subjects. Horizontal lines indicate the means for each group. The level of significance for the difference between means for the male subjects is P= 0.03, as determined by an independent samples t-test.

Figure 3

GABA_B2 subunit gene expression in the orbital frontal cortex of depressed (n= 7) and control (n= 9) male (blue) and depressed (n= 5) and control (n= 2) female (red) subjects. Horizontal lines indicate the means for each group. The level of significance for the difference between means for the male subjects is P= 0.04, as determined by an independent samples t-test.