U50,488, a κ opioid receptor agonist, attenuates cocaine-induced increases in extracellular dopamine in the nucleus accumbens of rats

Brain kappa-opioid receptors (KORs) are implicated in states of motivation and emotion. Activation of KORs negatively regulates mesolimbic dopamine (DA) neurons, and KOR agonists produce depressive-like behavioral effects. To further evaluate how KOR function affects behavior, we developed mutant mice in which exon 3 of the KOR gene (Oprk1) was flanked with Cre-lox recombination (loxP) sites. By breeding these mice with lines that express Cre-recombinase (Cre) in early embryogenesis (EIIa-Cre) or only in DA neurons (dopamine transporter (DAT)-Cre), we developed constitutive KOR knockouts (KOR À / À ) and conditional knockouts that lack KORs in DA-containing neurons (DAT-KOR lox/lox ). Autoradiography demonstrated complete ablation of KOR binding in the KOR À / À mutants, and reduced binding in the DAT-KOR lox/lox mutants. Quantitative reverse transcription PCR (qPCR) studies confirmed that KOR mRNA is undetectable in the constitutive mutants and reduced in the midbrain DA systems of the conditional mutants. Behavioral characterization demonstrated that these mutant lines do not differ from controls in metrics, including hearing, vision, weight, and locomotor activity. Whereas KOR À / À mice appeared normal in the open field and light/dark box tests, DAT-KOR lox/lox mice showed reduced anxiety-like behavior, an effect that is broadly consistent with previously reported effects of KOR antagonists. Sensitization to the locomotor-stimulating effects of cocaine appeared normal in KOR À / À mutants, but was exaggerated in DAT-KOR lox/lox mutants. Increased sensitivity to cocaine in the DAT-KOR lox/lox mutants is consistent with a role for KORs in negative regulation of DA function, whereas the lack of differences in the KOR À / À mutants suggests compensatory adaptations after constitutive receptor ablation. These mouse lines may be useful in future studies of KOR function.

Section: Introductionmentioning

confidence: 67%

Section: Introductionmentioning

confidence: 67%

Ablation of Kappa-Opioid Receptors from Brain Dopamine Neurons has Anxiolytic-Like Effects and Enhances Cocaine-Induced Plasticity

Veer

Bechtholt

Onvani

et al. 2013

“…Natural and synthetic kappaopioid receptor agonists directly infused into the striatum or administered systemically to rodents will both attenuate cocaine-induced dopamine surges in the nucleus accumbens and block cocaine-induced conditioned place preference (Maisonneuve et al, 1994;Zhang et al, 2004a, b). Centrally penetrating kappa-opioid receptor agonists can be aversive in rodents, so studies showing a reduction in alcohol intake but an increased alcohol deprivation effect and a decrease in morphine and cocaine self-administration may be difficult to interpret (Glick et al, 1995;Hölter et al, 2000;Lindholm et al, 2001).…”

Section: Mu-and Kappa-opioid System and Addictionmentioning

confidence: 99%

Nalmefene Induced Elevation in Serum Prolactin in Normal Human Volunteers: Partial Kappa Opioid Agonist Activity?

Bart

Schluger

Borg

et al. 2005

123

In humans, mu-and kappa-opioid receptor agonists lower tuberoinfundibular dopamine, which tonically inhibits prolactin release. Serum prolactin is, therefore, a useful biomarker for tuberoinfundibular dopamine. The current study evaluated the unexpected finding that the relative mu-and kappa-opioid receptor selective antagonist nalmefene increases serum prolactin, indicating possible kappa-opioid receptor agonist activity. In all, 33 healthy human volunteers (14 female) with no history of psychiatric or substance use disorders received placebo, nalmefene 3 mg, and nalmefene 10 mg in a double-blind manner. Drugs were administered between 0900 and 1000 on separate days via 2-min intravenous infusion. Serial blood specimens were analyzed for serum levels of prolactin. Additional in vitro studies of nalmefene binding to cloned human kappa-opioid receptors transfected into Chinese hamster ovary cells were performed. Compared to placebo, both doses of nalmefene caused significant elevations in serum prolactin (po0.002 for nalmefene 3 mg and po0.0005 for nalmefene 10 mg). There was no difference in prolactin response between the 3 and 10 mg doses. Binding assays confirmed nalmefene's affinity at kappa-opioid receptors and antagonism of mu-opioid receptors. [ 35 S]GTPgS binding studies demonstrated that nalmefene is a full antagonist at mu-opioid receptors and has partial agonist properties at kappa-opioid receptors. Elevations in serum prolactin following nalmefene are consistent with this partial agonist effect at kappa-opioid receptors. As kappaopioid receptor activation can lower dopamine in brain regions important to the persistence of alcohol and cocaine dependence, the partial kappa agonist effect of nalmefene may enhance its therapeutic efficacy in selected addictive diseases.

“…Elevated levels of dynorphin and overexpression of kappa opioid receptors have also been found after chronic cocaine treatment (Spangler et al, 1996;Shippenberg et al, 2001;Yuferov et al, 2001). Administration of kappa agonists has been shown to decrease basal and cocaine-stimulated dopamine levels in microdialysis studies (Di Chiara and Imperato, 1988;Devine et al, 1993;Maisonneuve et al, 1994).…”

Section: Introductionmentioning

confidence: 99%

Effects of the Mixed Mu/Kappa Opioid Nalbuphine on Cocaine-Induced Changes in Subjective and Cardiovascular Responses in Men

Mello

Mendelson

Sholar

et al. 2004

Kappa opioid agonists functionally antagonize some abuse-related and locomotor effects of cocaine, and reduce cocaine selfadministration by rhesus monkeys. We compared the cardiovascular and subjective effects of acute doses of the mu/kappa opioid nalbuphine alone (5 mg/70 kg, intravenous (i.v.)), with cocaine alone (0.2 mg/kg, i.v.), and with nalbuphine þ cocaine in combination, under placebo-controlled, double-blind conditions. Subjects met American Psychiatric Association Diagnostic and Statistical Manual (DSM-IV) criteria for current cocaine abuse. Nalbuphine serum levels exceeded 50 ng/ml within 10 min after injection, and cocaine plasma levels exceeded 130 ng/ml within 4 min. Cocaine's pharmacokinetic profile did not change after concurrent nalbuphine administration. The nalbuphine þ cocaine combination was safe and without synergistic effects on heart rate and systolic or diastolic blood pressure. Moreover, the addition of cocaine did not increase the subjective effects of nalbuphine. Visual Analog Scale (VAS) ratings of High, Euphoria, Stimulated, and Good Effect were equivalent after nalbuphine þ cocaine and nalbuphine alone, and both were significantly higher than after cocaine alone (area under the curve analysis) (po0.05-0.01). Peak VAS ratings of High, Stimulated, Good Effect, and Drug Effect were also significantly higher after nalbuphine þ cocaine than after cocaine alone (po0.01). Addiction Research Center Inventory (ARCI) scores were equivalent for nalbuphine þ cocaine and nalbuphine alone, but the PCAG, MBG, and amphetamine scores were significantly higher after both nalbuphine þ cocaine and nalbuphine alone than after cocaine alone (po0.01-0.003). Thus, there were no additive interactions between nalbuphine and cocaine on cardiovascular, subjective, or drug level measures after acute administration.