RGS inhibition at G(alpha)i2 selectively potentiates 5-HT1A-mediated antidepressant effects.
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 G(alpha)i2. Animals rendered insensitive to RGS protein regulation through a mutation in G(alpha)i2 (G184S) exhibited spontaneous antidepressant- and anxiolytic-like behaviors. Mice expressing RGS-insensitive G(alpha)i2 also exhibited increased cortical and hippocampal phosphorylation of glycogen synthase kinase-3beta, 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.
Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109, USA.
Jeffery N
JN
Talbot
Emily M
EM
Jutkiewicz
Steven M
SM
Graves
Crystal F
CF
Clemans
Melanie R
MR
Nicol
Richard M
RM
Mortensen
Xinyan
X
Huang
Richard R
RR
Neubig
John R
JR
Traynor
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001007:Anxiety / Q000188:drug therapy / Q000503:physiopathology / Q000523:psychology; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D051960:GTP-Binding Protein alpha Subunit, Gi2 / Q000235:genetics / Q000378:metabolism*; D055879:Gene Knock-In Techniques; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D010641:Phenotype; D010879:Piperazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D020710:RGS Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D015398:Signal Transduction
D000928:Antidepressive Agents; D051960:GTP-Binding Protein alpha Subunit, Gi2; D010879:Piperazines; D011725:Pyridines; D020710:RGS Proteins; D044282:Receptor, Serotonin, 5-HT1A; D017367:Selective Serotonin Reuptake Inhibitors; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide