Cocaine self-administration augments kappa opioid receptor system-mediated inhibition of dopamine activity in the mesolimbic dopamine system

Estave, Paige M.; Sun, Haiguo; Peck, Emily G.; Holleran, Katherine M.; Chen, Rong

doi:10.1016/j.ibneur.2023.01.004

Cited by 2 publications

(2 citation statements)

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“…Similar to stress, chronic cocaine exposure leads to an upregulation of the KOR system (Refs. 81 , 83 , 128 , 129 , and increases drug-seeking behaviors 77 , 130 . Additionally, stress-mediated elevations in dynorphin have been shown to reinstate cocaine self-administration in various animal models 75 , 77 , 131 , 132 —an effect which is blocked by KOR inhibition (nBNI, Ref.…”

Section: Discussionmentioning

confidence: 99%

“…Conversely, KOR antagonists reduce anxiety-like behaviors and prevent stress-induced reinstatement of cocaine-seeking 75 – 80 . Repeated cocaine exposure in animal models 81 – 83 and in humans 84 – 86 leads to an upregulation of KORs in the NAc, which is thought to reduce DA transmission. A recent study using PET imaging revealed a positive correlation between cocaine choice and KOR binding (availability) in many brain regions, including the ventral striatum, following an acute stressor 87 .…”

Section: Introductionmentioning

confidence: 99%

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Co-targeting the kappa opioid receptor and dopamine transporter reduces motivation to self-administer cocaine and partially reverses dopamine system dysregulation

Estave,

Albertson,

Karkhanis

et al. 2024

Sci Rep

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Cocaine disrupts dopamine (DA) and kappa opioid receptor (KOR) system activity, with long-term exposure reducing inhibiton of DA uptake by cocaine and increasing KOR system function. Single treatment therapies have not been successful for cocaine use disorder; therefore, this study focuses on a combination therapy targeting the dopamine transporter (DAT) and KOR. Sprague Dawley rats self-administered 5 days of cocaine (1.5 mg/kg/inf, max 40 inf/day, FR1), followed by 14 days on a progressive ratio (PR) schedule (0.19 mg/kg/infusion). Behavioral effects of individual and combined administration of phenmetrazine and nBNI were then examined using PR. Additionally, ex vivo fast scan cyclic voltammetry was then used to assess alterations in DA and KOR system activity in the nucleus accumbens before and after treatments. Chronic administration of phenmetrazine as well as the combination of phenmetrazine and nBNI—but not nBNI alone—significantly reduced PR breakpoints. In addition, the combination of phenmetrazine and nBNI partially reversed cocaine-induced neurodysregulations of the KOR and DA systems, indicating therapeutic benefits of targeting the DA and KOR systems in tandem. These data highlight the potential benefits of the DAT and KOR as dual-cellular targets to reduce motivation to administer cocaine and reverse cocaine-induced alterations of the DA system.

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