title: Calcium-permeable AMPA receptors in the nucleus accumbens regulate depression-like behaviors in the chronic neuropathic pain state.
abstract: Depression is a salient emotional feature of chronic pain. Depression alters the pain threshold and impairs functional recovery. To date, however, there has been limited understanding of synaptic or circuit mechanisms that regulate depression in the pain state. Here, we demonstrate that depression-like behaviors are induced in a rat model of chronic neuropathic pain. Using this model, we show that chronic pain selectively increases the level of GluA1 subunits of AMPA-type glutamate receptors at the synapses of the nucleus accumbens (NAc), a key component of the brain reward system. We find, in addition, that this increase in GluA1 levels leads to the formation of calcium-permeable AMPA receptors (CPARs). Surprisingly, pharmacologic blockade of these CPARs in the NAc increases depression-like behaviors associated with pain. Consistent with these findings, an AMPA receptor potentiator delivered into the NAc decreases pain-induced depression. These results show that transmission through CPARs in the NAc represents a novel molecular mechanism modulating the depressive symptoms of pain, and thus CPARs may be a promising therapeutic target for the treatment of pain-induced depression. More generally, these findings highlight the role of central glutamate signaling in pain states and define the brain reward system as an important region for the regulation of depressive symptoms of pain.
authors.affiliation: Department of Anesthesiology, Molecular Neurobiology Program, The Helen and Martin Kimmel Center for Biology and Medicine at the Skirball Institute for Biomolecular Medicine, Departments of Otolaryngology and Physiology and Neuroscience, and Department of Biochemistry, New York University School of Medicine, New York, New York 10016.
authors.forename: Yossef
authors.initials: Y
authors.lastname: Goffer
authors.forename: Duo
authors.initials: D
authors.lastname: Xu
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Eberle
authors.forename: James
authors.initials: J
authors.lastname: D'amour
authors.forename: Michelle
authors.initials: M
authors.lastname: Lee
authors.forename: David
authors.initials: D
authors.lastname: Tukey
authors.forename: Robert C
authors.initials: RC
authors.lastname: Froemke
authors.forename: Edward B
authors.initials: EB
authors.lastname: Ziff
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000502:physiology*; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism*; D002908:Chronic Disease; D003080:Cold Temperature; D003863:Depression / Q000503:physiopathology* / Q000523:psychology*; D055724:Electrophysiological Phenomena / Q000502:physiology; D008297:Male; D008845:Microinjections; D009043:Motor Activity / Q000502:physiology; D009437:Neuralgia / Q000503:physiopathology* / Q000523:psychology*; D009714:Nucleus Accumbens / Q000502:physiology*; D010147:Pain Measurement / Q000187:drug effects; D010812:Physical Stimulation; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D013347:Subcellular Fractions / Q000502:physiology; D013395:Sucrose; D013550:Swimming / Q000523:psychology
chemical_list: D002118:Calcium; D018091:Receptors, AMPA; D013395:Sucrose