RGS inhibition at Gα _i2 selectively potentiates 5-HT1A–mediated antidepressant effects

Abstract

Elevating serotonin (5-HT) levels with selective serotonin reuptake inhibitors (SSRIs) is the most widely used treatment for depression. However, current therapies are ineffective, have delayed benefit, or cause side effects in many patients. Here, we define a mechanism downstream of 5-HT1A receptors that mediates antidepressant-like behavior and is profoundly and selectively enhanced by genetic disruption of regulators of G protein signaling (RGS) activity at Gαi2. Animals rendered insensitive to RGS protein regulation through a mutation in Gαi2 (G184S) exhibited spontaneous antidepressant-and anxiolytic-like behaviors. Mice expressing RGS-insensitive Gαi2 also exhibited increased cortical and hippocampal phosphorylation of glycogen synthase kinase-3β, a constitutively active proapoptotic kinase that is inhibited through phosphorylation in response to serotonin, SSRIs, and 5-HT1 receptor agonists. Both behavioral and biochemical phenotypes were blocked by treatment with WAY 100635, a 5-HT1A-selective antagonist. RGS-insensitive mice were also 5-10 times more responsive to the antidepressant-like effects of the SSRI fluvoxamine and 5-HT1A-selective agonist 8-hydroxy-2-dipropylaminotetralin. In contrast, the antidepressant potency of agents acting through nonserotonergic mechanisms was unchanged as was 5-HT1A action on body temperature. The findings point to a critical role for endogenous RGS proteins to suppress the antidepressant-like effects of 5-HT1A receptor activation. By selectively enhancing the beneficial effects of serotonin, inhibition of RGS proteins represents a therapeutic approach for the treatment of mood disorders.5-HT1A receptors | depression | G protein | regulator of G protein signaling proteins | transgenic mouse S elective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed antidepressants (1). Their use is based on a strategy of augmenting the effects of endogenous serotonin by increasing synaptic concentrations. However, the therapeutic benefit of SSRI administration is delayed by weeks or even months. In addition, these drugs are ineffective in many patients and often cause unpleasant and harmful side effects (2). SSRI therapy causes general increases in synaptic serotonin that activate many types of serotonin (5-HT) receptors with a diverse distribution that couple to a wide array of signaling pathways. Manipulation of 5-HT1 receptor activity is generally thought to underlie the beneficial as well as the unfavorable effects of SSRIs. The 5-HT1 receptors are members of the superfamily of G protein-coupled receptors that activate the adenylyl cyclasecoupled inhibitory class of heterotrimeric G proteins. Although multiple lines of evidence suggest that 5-HT1 receptors preferentially couple to Gαi2 in vitro (3), the relative contribution of different Gαi/o-family proteins to these beneficial and unfavorable effects of 5-HT1A receptor activation is not known.Regulator of G protein signaling (RGS) proteins are a family of more than 30 members defined by a characteristic 120-...

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