Stress-induced reinstatement of cocaine seeking is mediated by the kappa opioid system

Redila, Van A.; Chavkin, Charles

doi:10.1007/s00213-008-1122-y

Cited by 193 publications

(210 citation statements)

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“…Recent evidence supports a critical role of KOR in stress-induced reinstatement to drug seeking (6,7), but the sites of action in brain responsible and the relationship between KOR-dependent aversion and reinstatement are not clear. Animals injected with norBNI or saline in DRN showed equivalent cocaine place preference (CPP) after three training sessions and showed no differences in cocaineinduced locomotor activity during the training sessions (Fig.…”

Section: Kappa-opioid Receptors In the Drn Mediate Aversion And Drugmentioning

confidence: 99%

“…Corticotropin releasing factor (CRF) orchestrates the complex endocrine and neuronal responses to behavioral stress exposure (4), and recent studies have suggested that the dysphoric properties of stress are encoded by CRF-induced activation of the endogenous dynorphin opioid system (5). Systemic administration of kappa opioid receptor (KOR) antagonists block the aversive (5) and pro-addictive effects of stress (6)(7)(8)(9), and dynorphin activation of KOR is thought to mediate opponent processes evoked by addictive drugs (10), yet the key sites of dynorphin/KOR action mediating these behavioral responses are not resolved.…”

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confidence: 99%

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Activation of the kappa opioid receptor in the dorsal raphe nucleus mediates the aversive effects of stress and reinstates drug seeking

Land

Bruchas²,

Schattauer³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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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 KORdependent 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.depression ͉ drug addiction ͉ dynorphin ͉ serotonin S tress has profound effects on human health and can lead to mood disorders including clinical depression, anxiety, and can increase comorbid drug addiction risk (1-3). Corticotropin releasing factor (CRF) orchestrates the complex endocrine and neuronal responses to behavioral stress exposure (4), and recent studies have suggested that the dysphoric properties of stress are encoded by CRF-induced activation of the endogenous dynorphin opioid system (5). Systemic administration of kappa opioid receptor (KOR) antagonists block the aversive (5) and pro-addictive effects of stress (6-9), and dynorphin activation of KOR is thought to mediate opponent processes evoked by addictive drugs (10), yet the key sites of dynorphin/KOR action mediating these behavioral responses are not resolved.Mice subjected to behavioral stress show dynorphin release and robust KOR activation in both dopaminergic and serotonergic nuclei (5), implying that these neurotransmitters could be important for KOR-dependent stress-induced behavioral responses. Ventral tegmental area (VTA) dopaminergic projections to the nucleus accumbens (NAc) have been linked to addiction (11), making this an obvious target for the regulation of appetitive and aversive behaviors. However, prior studies have shown that mice lacking dopamine can still develop place preference for drugs of...

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Section: Kappa-opioid Receptors In the Drn Mediate Aversion And Drugmentioning

confidence: 99%

mentioning

confidence: 99%

Activation of the kappa opioid receptor in the dorsal raphe nucleus mediates the aversive effects of stress and reinstates drug seeking

Land

Bruchas²,

Schattauer³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

268

292

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“…Studies correlating the dysphoric effects of κOR agonists to the G-protein-independent activation of the p38 MAPK pathway (8,13,15) suggest that identification of κOR agonists biased to G-protein-mediated signaling could lead to the development of therapeutics with reduced side effects. This suggestion has spurred the search for novel κOR ligands or scaffolds that could provide novel treatment strategies for a variety of disorders where κOR involvement has been implicated (16,17).…”

mentioning

confidence: 99%

Collybolide is a novel biased agonist of κ-opioid receptors with potent antipruritic activity

Gupta

Gomes

Bobeck

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Among the opioid receptors, the κ-opioid receptor (κOR) has been gaining considerable attention as a potential therapeutic target for the treatment of complex CNS disorders including depression, visceral pain, and cocaine addiction. With an interest in discovering novel ligands targeting κOR, we searched natural products for unusual scaffolds and identified collybolide (Colly), a nonnitrogenous sesquiterpene from the mushroom Collybia maculata. This compound has a furyl-δ-lactone core similar to that of Salvinorin A (Sal A), another natural product from the plant Salvia divinorum. Characterization of the molecular pharmacological properties reveals that Colly, like Sal A, is a highly potent and selective κOR agonist. However, the two compounds differ in certain signaling and behavioral properties. Colly exhibits 10-to 50-fold higher potency in activating the mitogen-activated protein kinase pathway compared with Sal A. Taken with the fact that the two compounds are equipotent for inhibiting adenylyl cyclase activity, these results suggest that Colly behaves as a biased agonist of κOR. Behavioral studies also support the biased agonistic activity of Colly in that it exhibits ∼10-fold higher potency in blocking non-histamine-mediated itch compared with Sal A, and this difference is not seen in pain attenuation by these two compounds. These results represent a rare example of functional selectivity by two natural products that act on the same receptor. The biased agonistic activity, along with an easily modifiable structure compared with Sal A, makes Colly an ideal candidate for the development of novel therapeutics targeting κOR with reduced side effects.G-protein-coupled receptors | natural compounds | salvinorin A | dynorphin | antinociception

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“…[69][70][71] Similarly, several studies have shown that stress exposure induces the reinstatement of opioid-, amphetamine-, cocaine-, and nicotine-induced CPP. 64,[71][72][73][74] There is reasonable evidence to support the face validity of the reinstatement model, but neither its predictive validity nor its functional equivalence have been fully established. 60 …”

Section: Animal Studies Of Addictive Behaviormentioning

confidence: 99%

Animal models of alcohol and drug dependence

Planeta

2013

Rev. Bras. Psiquiatr.

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Drug addiction has serious health and social consequences. In the last 50 years, a wide range of techniques have been developed to model specific aspects of drug-taking behaviors and have greatly contributed to the understanding of the neurobiological basis of drug abuse and addiction. In the last two decades, new models have been proposed in an attempt to capture the more genuine aspects of addiction-like behaviors in laboratory animals. The goal of the present review is to provide an overview of the preclinical procedures used to study drug abuse and dependence and describe recent progress that has been made in studying more specific aspects of addictive behavior in animals.

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Stress-induced reinstatement of cocaine seeking is mediated by the kappa opioid system

Cited by 193 publications

References 55 publications

Activation of the kappa opioid receptor in the dorsal raphe nucleus mediates the aversive effects of stress and reinstates drug seeking

Activation of the kappa opioid receptor in the dorsal raphe nucleus mediates the aversive effects of stress and reinstates drug seeking

Collybolide is a novel biased agonist of κ-opioid receptors with potent antipruritic activity

Animal models of alcohol and drug dependence

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