title: Stress produces aversion and potentiates cocaine reward by releasing endogenous dynorphins in the ventral striatum to locally stimulate serotonin reuptake.
abstract: Activation of the dynorphin/κ-opioid receptor (KOR) system by repeated stress exposure or agonist treatment produces place aversion, social avoidance, and reinstatement of extinguished cocaine place preference behaviors by stimulation of p38α MAPK, which subsequently causes the translocation of the serotonin transporter (SERT, SLC6A4) to the synaptic terminals of serotonergic neurons. In the present study we extend those findings by showing that stress-induced potentiation of cocaine conditioned place preference occurred by a similar mechanism. In addition, SERT knock-out mice did not show KOR-mediated aversion, and selective reexpression of SERT by lentiviral injection into the dorsal raphe restored the prodepressive effects of KOR activation. Kinetic analysis of several neurotransporters demonstrated that repeated swim stress exposure selectively increased the V(max) but not K(m) of SERT without affecting dopamine transport or the high-capacity, low-affinity transporters. Although the serotonergic neurons in the dorsal raphe project throughout the forebrain, a significant stress-induced increase in cell-surface SERT expression was only evident in the ventral striatum, and not in the dorsal striatum, hippocampus, prefrontal cortex, amygdala, or dorsal raphe. Stereotaxic microinjections of the long-lasting KOR antagonist norbinaltorphimine demonstrated that local KOR activation in the nucleus accumbens, but not dorsal raphe, mediated this stress-induced increase in ventral striatal surface SERT expression. Together, these results support the hypothesis that stress-induced activation of the dynorphin/KOR system produces a transient increase in serotonin transport locally in the ventral striatum that may underlie some of the adverse consequences of stress exposure, including the potentiation of the rewarding effects of cocaine.
authors.affiliation: Department of Pharmacology, University of Washington, School of Medicine, Seattle, Washington 98195, USA.
authors.forename: Abigail G
authors.initials: AG
authors.lastname: Schindler
authors.forename: Daniel I
authors.initials: DI
authors.lastname: Messinger
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Smith
authors.forename: Haripriya
authors.initials: H
authors.lastname: Shankar
authors.forename: Richard M
authors.initials: RM
authors.lastname: Gustin
authors.forename: Selena S
authors.initials: SS
authors.lastname: Schattauer
authors.forename: Julia C
authors.initials: JC
authors.lastname: Lemos
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Chavkin
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Hagan
authors.forename: John F
authors.initials: JF
authors.lastname: Neumaier
authors.forename: Charles
authors.initials: C
authors.lastname: Chavkin
mesh_terms: D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects / Q000502:physiology*; D001921:Brain / Q000378:metabolism; D003042:Cocaine / Q000494:pharmacology*; D003342:Corpus Striatum / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism; D004399:Dynorphins / Q000378:metabolism / Q000502:physiology*; D054770:G-Protein-Coupled Receptor Kinase 3 / Q000235:genetics / Q000502:physiology; D008297:Male; D026901:Membrane Transport Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008845:Microinjections / Q000379:methods; D009271:Naltrexone / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000008:administration & dosage / Q000493:pharmacokinetics; D009538:Nicotine / Q000009:adverse effects; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D011903:Raphe Nuclei / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D017473:Receptors, Opioid, kappa / Q000037:antagonists & inhibitors / Q000502:physiology; D012201:Reward; D012701:Serotonin / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013315:Stress, Psychological / Q000378:metabolism* / Q000523:psychology*; D013375:Substance Withdrawal Syndrome / Q000378:metabolism; D013574:Synaptosomes / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000502:physiology
chemical_list: D026901:Membrane Transport Proteins; D009292:Narcotic Antagonists; D017473:Receptors, Opioid, kappa; D050486:Serotonin Plasma Membrane Transport Proteins; D012701:Serotonin; C051844:norbinaltorphimine; D009271:Naltrexone; D009538:Nicotine; D004399:Dynorphins; D054770:G-Protein-Coupled Receptor Kinase 3; C517850:GRK3 protein, mouse; D048051:p38 Mitogen-Activated Protein Kinases; D003042:Cocaine; D004298:Dopamine