title: Regulator of G protein signaling 4 [corrected] is a crucial modulator of antidepressant drug action in depression and neuropathic pain models.
abstract: Regulator of G protein signaling 4 (Rgs4) is a signal transduction protein that controls the function of monoamine, opiate, muscarinic, and other G protein-coupled receptors via interactions with Gα subunits. Rgs4 is expressed in several brain regions involved in mood, movement, cognition, and addiction and is regulated by psychotropic drugs, stress, and corticosteroids. In this study, we use genetic mouse models and viral-mediated gene transfer to examine the role of Rgs4 in the actions of antidepressant medications. We first analyzed human postmortem brain tissue and found robust up-regulation of RGS4 expression in the nucleus accumbens (NAc) of subjects receiving standard antidepressant medications that target monoamine systems. Behavioral studies of mice lacking Rgs4, including specific knockdowns in NAc, demonstrate that Rgs4 in this brain region acts as a positive modulator of the antidepressant-like and antiallodynic-like actions of several monoamine-directed antidepressant drugs, including tricyclic antidepressants, selective serotonin reuptake inhibitors, and norepinephrine reuptake inhibitors. Studies using viral-mediated increases in Rgs4 activity in NAc further support this hypothesis. Interestingly, in prefrontal cortex, Rgs4 acts as a negative modulator of the actions of nonmonoamine-directed drugs that are purported to act as antidepressants: the N-methyl-D-aspartate glutamate receptor antagonist ketamine and the delta opioid agonist (+)-4-[(αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide. Together, these data reveal a unique modulatory role of Rgs4 in the brain region-specific actions of a wide range of antidepressant drugs and indicate that pharmacological interventions at the level of RGS4 activity may enhance the actions of such drugs used for the treatment of depression and neuropathic pain.
authors: Department of Basic Sciences, Faculty of Medicine, University of Crete, Heraklion, 71003 Crete, Greece.
authors: Maria
authors: M
authors: Stratinaki
authors: Artemis
authors: A
authors: Varidaki
authors: Vasiliki
authors: V
authors: Mitsi
authors: Subroto
authors: S
authors: Ghose
authors: Jane
authors: J
authors: Magida
authors: Caroline
authors: C
authors: Dias
authors: Scott J
authors: SJ
authors: Russo
authors: Vincent
authors: V
authors: Vialou
authors: Barbara J
authors: BJ
authors: Caldarone
authors: Carol A
authors: CA
authors: Tamminga
authors: Eric J
authors: EJ
authors: Nestler
authors: Venetia
authors: V
authors: Zachariou
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001522:Behavior, Animal; D001921:Brain / Q000473:pathology; D003863:Depression / Q000188:drug therapy*; D003891:Desipramine / Q000494:pharmacology; D005260:Female; D019204:GTP-Binding Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D019964:Mood Disorders / Q000188:drug therapy; D009437:Neuralgia / Q000188:drug therapy*; D020710:RGS Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D055815:Young Adult
chemical_list: D000928:Antidepressive Agents; D020710:RGS Proteins; C098799:RGS4 protein; D019204:GTP-Binding Proteins; D003891:Desipramine
keywords: adeno-associated viruses; conditional knockout mice; desipramine; mood disorders
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