Regulator of G protein signaling 4 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.

RGS9-2–controlled adaptations in the striatum determine the onset of action and efficacy of antidepressants in neuropathic pain states

“…The DMI dose-response may vary between genetic backgrounds, neuropathic pain models, and type of Von Frey hair, but overall, chronic DMI administration promotes antiallodynic responses in rodents. DMI treatment affects the activation of the transcription factor CREB and is associated with changes in phosphoprotein levels in the brain reward center (9,18,38,39). By controlling the availability of Gα and βγ subunits to effector molecules, RGS9-2 negatively regulates protein interactions and levels of phosphoproteins involved in antidepressant responsiveness.…”

“…The SNI operation was performed under Avertine (2,2,2-tribromoethanol; Sigma-Aldrich) general anesthesia (18). With the help of a stereomicroscope, skin incision of the left hind-limb at mid-thigh level, followed by muscle layers separation, revealed the sciatic nerve and its three branches.…”

“…The same procedure was followed in sham-operated mice, but the nerves were left intact (18). For the assessment of mechanical allodynia, we used Von Frey (18,19) with ascending forces expressed in grams (0.1-3.6 g; Electronic Von Frey Anesthesiometer; IITC). Each filament was applied five times in a row against the lateral area of the paw.…”

“…We use the murine spared-nerve injury (SNI) model of neuropathic pain, which produces several symptoms of neuropathic pain, including mechanical allodynia, thermal hyperalgesia, anxiety, and depression (17)(18)(19). The results indicate that RGS9-2 plays a prominent role in the onset and efficacy of TCAs with regard to the antiallodynic and antidepressant effects.…”

“…Here, we use genetically modified mice, viral-mediated gene transfer, and several biochemical and molecular biology assays to probe the mechanism via which RGS9-2 in the NAc modulates TCA responses under neuropathic pain states (17,18). We use the murine spared-nerve injury (SNI) model of neuropathic pain, which produces several symptoms of neuropathic pain, including mechanical allodynia, thermal hyperalgesia, anxiety, and depression (17)(18)(19).…”