Activation of the kappa opioid receptor in the dorsal raphe nucleus mediates the aversive effects of stress and reinstates drug seeking
- 10 November 2009
- journal article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 106 (45), 19168-19173
- https://doi.org/10.1073/pnas.0910705106
Abstract
Although stress has profound effects on motivated behavior, the underlying mechanisms responsible are incompletely understood. In this study we elucidate a functional pathway in mouse brain that encodes the aversive effects of stress and mediates stress-induced reinstatement of cocaine place preference (CPP). Activation of the dynorphin/kappa opioid receptor (KOR) system by either repeated stress or agonist produces conditioned place aversion (CPA). Because KOR inhibition of dopamine release in the mesolimbic pathway has been proposed to mediate the dysphoria underlying this response, we tested dopamine-deficient mice in this study and found that KOR agonist in these mice still produced CPA. However, inactivation of serotonergic KORs by injection of the KOR antagonist norBNI into the dorsal raphe nucleus (DRN), blocked aversive responses to the KOR agonist U50,488 and blocked stress-induced reinstatement of CPP. KOR knockout (KO) mice did not develop CPA to U50,488; however, lentiviral re-expression of KOR in the DRN of KOR KO mice restored place aversion. In contrast, lentiviral expression in DRN of a mutated form of KOR that fails to activate p38 MAPK required for KOR-dependent aversion, did not restore place aversion. DRN serotonergic neurons project broadly throughout the brain, but the inactivation of KOR in the nucleus accumbens (NAc) coupled with viral re-expression in the DRN of KOR KO mice demonstrated that aversion was encoded by a DRN to NAc projection. These results suggest that the adverse effects of stress may converge on the serotonergic system and offers an approach to controlling stress-induced dysphoria and relapse.This publication has 46 references indexed in Scilit:
- The molecular neurobiology of depressionNature, 2008
- Prodynorphin-Derived Peptides Are Critical Modulators of Anxiety and Regulate Neurochemistry and CorticosteroneNeuropsychopharmacology, 2008
- A Role for Brain Stress Systems in AddictionNeuron, 2008
- Stress-induced reinstatement of cocaine seeking is mediated by the kappa opioid systemPsychopharmacology, 2008
- Long-Acting κ Opioid Antagonists Disrupt Receptor Signaling And Produce Noncompetitive Effects By Activating C-Jun N-Terminal KinaseOnline Journal of Public Health Informatics, 2007
- Central serotonergic neurons are differentially required for opioid analgesia but not for morphine tolerance or morphine rewardProceedings of the National Academy of Sciences of the United States of America, 2007
- Reinstatement of cocaine place-conditioning prevented by the peptide kappa-opioid receptor antagonist arodynEuropean Journal of Pharmacology, 2007
- Pharmacological Evidence for a Motivational Role of κ-Opioid Systems in Ethanol DependenceNeuropsychopharmacology, 2007
- Cre recombinase-mediated restoration of nigrostriatal dopamine in dopamine-deficient mice reverses hypophagia and bradykinesiaProceedings of the National Academy of Sciences of the United States of America, 2006
- Kappa Opioid Receptor Activation of p38 MAPK Is GRK3- and Arrestin-dependent in Neurons and AstrocytesOnline Journal of Public Health Informatics, 2006