Archival Report| Volume 64, ISSUE 11, P982-988, December 01, 2008

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The Kappa-Opioid Agonist U69,593 Blocks Cocaine-Induced Enhancement of Brain Stimulation Reward


      Increasing evidence indicates that brain kappa-opioid receptors (KORs) are involved in regulation of mood states. In animal models often used to study psychiatric illness, KOR agonists produce depressive-like effects (e.g., anhedonia), whereas KOR antagonists produce antidepressant- and anxiolytic-like effects. The ability of KOR agonists to produce anhedonia-like signs in laboratory animals raises the possibility that this class of drugs might be useful to ameliorate states characterized by excess reward or motivation, such as mania or stimulant intoxication.


      We examined how the selective KOR agonist U69,593 affects cocaine-induced facilitation of intracranial self-stimulation (ICSS), a model of the abnormally increased reward function that characterizes mania and stimulant intoxication. Rats with stimulating electrodes implanted in the medial forebrain bundle (MFB) were tested with intraperitoneal injections of U69,593 (.063–.5 mg/kg) alone, cocaine (1.25–10 mg/kg) alone, and combinations of the drugs.


      Cocaine dose-dependently decreased ICSS thresholds, indicating that it enhanced the rewarding impact of MFB stimulation. In contrast, U69,593 dose-dependently increased ICSS thresholds, indicating that it decreased the rewarding impact of the stimulation. Pretreatment with U69,593 blocked cocaine-induced decreases in ICSS thresholds at doses that had negligible effects on their own.


      Activation of KORs reduces the reward-related effects of cocaine. Inasmuch as cocaine-induced behavioral stimulation in rodents may model key aspects of enhanced mood in humans, these findings raise the possibility that KOR agonists might ameliorate symptoms of conditions characterized by increased motivation and hyperfunction of brain reward systems, such as mania and stimulant intoxication.

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        • DiChiara G.
        • Imperato A.
        Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats.
        Proc Natl Acad Sci U S A. 1988; 85: 5274-5278
        • Jordan S.
        • Kramer G.L.
        • Zukas P.K.
        • Moeller M.
        • Petty F.
        In vivo biogenic amine efflux in medial prefrontal cortex with imipramine, fluoxetine, and fluvoxamine.
        Synapse. 1994; 18: 294-297
        • Pliakas A.M.
        • Carlson R.R.
        • Neve R.L.
        • Konradi C.
        • Nestler E.J.
        • Carlezon Jr, W.A.
        Altered responsiveness to cocaine and increased immobility in the forced swim test associated with elevated cAMP response element-binding protein expression in nucleus accumbens.
        J Neurosci. 2001; 21: 7397-7403
        • Newton S.S.
        • Thome J.
        • Wallace T.L.
        • Shirayama Y.
        • Schlesinger L.
        • Sakai N.
        • et al.
        Inhibition of cAMP response element-binding protein or dynorphin in the nucleus accumbens produces an antidepressant-like effect.
        J Neurosci. 2002; 22: 10883-10890
        • Mague S.D.
        • Pliakas A.M.
        • Todtenkopf M.S.
        • Tomasiewicz H.C.
        • Zhang Y.
        • Stevens Jr, W.C.
        • et al.
        Antidepressant-like effects of kappa-opioid receptor antagonists in the forced swim test in rats.
        J Pharmacol Exp Ther. 2003; 305: 323-330
        • McLaughlin J.P.
        • Marton-Popovici M.
        • Chavkin C.
        Kappa opioid receptor antagonism and prodynorphin gene disruption block stress-induced behavioral responses.
        J Neurosci. 2003; 23: 5674-5683
        • Shirayama Y.
        • Ishida H.
        • Iwata M.
        • Hazama G.I.
        • Kawahara R.
        • Duman R.S.
        Stress increases dynorphin immunoreactivity in limbic brain regions and dynorphin antagonism produces antidepressant-like effects.
        J Neurochem. 2004; 90: 1258-1268
        • Beardsley P.M.
        • Howard J.L.
        • Shelton K.L.
        • Carroll F.I.
        Differential effects of the novel kappa opioid receptor antagonist, JDTic, on reinstatement of cocaine-seeking induced by footshock stressors vs cocaine primes and its antidepressant-like effects in rats.
        Psychopharmacology. 2005; 183: 118-126
        • Knoll A.T.
        • Meloni E.G.
        • Thomas J.B.
        • Carroll F.I.
        • Carlezon Jr, W.A.
        Anxiolytic-like effects of k-opioid receptor antagonists in behavioral models of unlearned and learned fear in rats.
        J Pharmacol Exper Ther. 2007; 323: 838-845
        • Todtenkopf M.S.
        • Marcus J.F.
        • Portoghese P.S.
        • Carlezon Jr, W.A.
        Effects of kappa-opioid receptor ligands on intracranial self-stimulation in rats.
        Psychopharmacology. 2004; 172: 463-470
        • Carlezon Jr, W.A.
        • Beguin C.
        • DiNieri J.A.
        • Baumann M.H.
        • Richards M.R.
        • Todtenkopf M.S.
        • et al.
        Depressive-like effects of the kappa-opioid receptor agonist salvinorin A on behavior and neurochemistry in rats.
        J Pharmacol Exp Ther. 2006; 316: 440-447
        • Nestler E.J.
        • Carlezon Jr, W.A.
        The mesolimbic dopamine reward circuit in depression.
        Biol Psychiatry. 2006; 59: 1151-1159
        • Mah L.
        • Zarate Jr, C.A.
        • Singh J.
        • Duan Y.F.
        • Luckenbaugh D.A.
        • Manji H.K.
        • Drevets W.C.
        Regional cerebral glucose metabolic abnormalities in bipolar II depression.
        Biol Psychiatry. 2007; 61: 765-775
        • American Psychiatric Association
        Diagnostic and Statistical Manual of Mental Disorders.
        4th ed. American Psychiatric Press, Washington, DC1994
        • Carlezon Jr, W.A.
        • Chartoff E.H.
        Intracranial self-stimulation (ICSS) in rodents to study the neurobiology of motivation.
        Nat Protoc. 2007; 2: 2987-2995
        • Routtenberg A.
        • Lindy J.
        Effects of availability of rewarding septal and hypothalamic stimulation on bar pressing for food under conditions of deprivation.
        J Compar Physiolog Psychol. 1965; 60: 158-161
        • Carlisle H.J.
        • Snyder E.
        The interaction of hypothalamic self-stimulation and temperature regulation.
        Experentia. 1970; 26: 1092-1093
        • Gallistel C.R.
        • Freyd G.
        Quantitative determination of the effects of catecholaminergic agonists and antagonists on the rewarding efficacy of brain stimulation.
        Pharmacol Biochem Behav. 1987; 26: 731-741
        • Tomasiewicz H.C.
        • Mague S.D.
        • Cohen B.M.
        • Carlezon Jr, W.A.
        Behavioral effects of acute and sub-acute administration of lithium and valproic acid in rats.
        Brain Res. 2006; 1093: 83-94
        • Wise R.A.
        Addictive drugs and brain stimulation reward.
        Annu Rev Neurosci. 1996; 19: 319-340
        • Roybal K.
        • Theobold D.
        • Birnbaum S.
        • DiNieri J.A.
        • Graham A.
        • Russo S.
        • et al.
        Mania-like behavior induced by disruption of CLOCK function.
        Proc Nat Acad Sci U S A. 2007; 104: 6406-6411
        • Crawford C.A.
        • McDougall S.A.
        • Bolanos C.A.
        • Hall S.
        • Berger S.P.
        The effects of the kappa agonist U-50,488 on cocaine-induced conditioned and unconditioned behaviors and Fos immunoreactivity.
        Psychopharmacology. 1995; 120: 392-399
        • Shippenberg T.S.
        • LeFevour A.
        • Heidbreder C.
        kappa-Opioid receptor agonists prevent sensitization to the conditioned rewarding effects of cocaine.
        J Pharmacol Exp Ther. 1996; 276: 545-554
        • McLaughlin J.P.
        • Land B.B.
        • Li S.
        • Pintar J.E.
        • Chavkin C.
        Prior activation of kappa opioid receptors by U50,488 mimics repeated forced swim stress to potentiate cocaine place preference conditioning.
        Neuropsychopharmacology. 2006; 31: 787-794
        • Chartoff E.H.
        • Potter D.
        • Damez-Werno D.
        • Cohen B.M.
        • Carlezon Jr, W.A.
        Exposure to the selective kappa agonist salvinorin A modulates the behavioral and molecular effects of cocaine in rats.
        Neuropsychopharmacology. 2008; ([published online ahead of print May 21])
        • Paxinos G.
        • Watson C.
        The Rat Brain in Stereotaxic Coordinates.
        2nd ed. Academic Press, San Diego, CA1986
        • Miliaressis E.
        • Rompre P.P.
        • Laviolette P.
        • Philippe L.
        • Coulombe D.
        The curve-shift paradigm in self-stimulation.
        Physiol Behav. 1986; 37: 85-91
        • Carlezon Jr, W.A.
        • Todtenkopf M.
        • McPhie D.L.
        • Pimentel P.
        • Pliakas A.M.
        • Stellar J.
        • Trzcinska M.
        Downregulation of GluR1 expression in the ventral tegmental area following repeated rewarding brain stimulation.
        Neuropsychopharmacology. 2001; 25: 234-241
        • Mague S.D.
        • Andersen S.L.
        • Carlezon Jr, W.A.
        Early developmental exposure to methylphenidate reduces cocaine-induced potentiation of brain stimulation reward in rats.
        Biol Psychiatry. 2005; 57: 120-125
        • Carlezon Jr, W.A.
        Place conditioning to study drug reward and aversion.
        Methods Molec Med. 2003; 84: 243-249
        • Thompson A.C.
        • Zapata A.
        • Justice Jr, J.B.
        • Vaughan R.A.
        • Sharpe L.G.
        • Shippenberg T.S.
        Kappa-opioid receptor activation modifies dopamine uptake in the nucleus accumbens and opposes the effects of cocaine.
        J Neurosci. 2000; 20: 9333-9340
        • Edmonds D.E.
        • Gallistel C.R.
        Parametric analysis of brain stimulation reward in the rat: III.
        J Comp Physiol Psychol. 1974; 87: 876-883
        • Wise R.A.
        • Rompre P.P.
        Brain dopamine and reward.
        Annu Rev Psychol. 1987; 40: 191-225
        • Wise R.A.
        Neuroleptics and operant behavior: The anhedonia hypothesis.
        Behav Brain Sci. 1982; 5: 39-87
        • Mizrahi R.
        • Rusjan P.
        • Agid O.
        • Graff A.
        • Mamo D.C.
        • Zipursky R.B.
        • Kapur S.
        Adverse subjective experience with antipsychotics and its relationship to striatal and extrastriatal D2 receptors: a PET study in schizophrenia.
        Am J Psychiatry. 2007; 164: 630-637
        • Pfeiffer A.
        • Brantl V.
        • Herz A.
        • Emrich H.M.
        Psychotomimesis mediated by kappa opiate receptors.
        Science. 1986; 233: 774-776
        • Kalivas P.W.
        • Stewart J.
        Dopamine transmission in the initiation and expression of drug- and stress-induced sensitization of motor activity.
        Brain Res Rev. 1991; 16: 223-244
        • Fitzgerald L.W.
        • Ortiz J.
        • Hamedani A.G.
        • Nestler E.J.
        Drugs of abuse and stress increase the expression of GluR1 and NMDAR1 glutamate receptor subunits in the rat ventral tegmental area: common adaptations among cross-sensitizing agents.
        J Neurosci. 1996; 16: 274-282
        • Ma J.
        • Ye N.
        • Lange N.
        • Cohen B.M.
        Dynorphinergic GABA neurons are a target of both typical and atypical antipsychotic drugs in the nucleus accumbens shell, central amygdaloid nucleus and thalamic central medial nucleus.
        Neuroscience. 2003; 121: 991-998
        • Cohen B.M.
        • Murphy B.
        The effects of pentazocine, a kappa agonist, in patients with mania.
        Int J Neuropsychopharmacol. 2008; 11: 243-247
        • Walsh S.L.
        • Geter-Douglas B.
        • Strain E.C.
        • Bigelow G.E.
        Enadoline and butorphanol: Evaluation of kappa-agonists on cocaine pharmacodynamics and cocaine self-administration in humans.
        J Pharmacol Exp Ther. 2001; 299: 147-158
        • Preston K.L.
        • Umbricht A.
        • Schroeder J.R.
        • Abreu M.E.
        • Epstein D.H.
        • Pickworth W.B.
        Cyclazocine: Comparison to hydromorphone and interaction with cocaine.
        Behav Pharmacol. 2004; 15: 91-102
        • Chappell P.B.
        • Leckman J.F.
        • Scahill L.D.
        • Hardin M.T.
        • Anderson G.
        • Cohen D.J.
        Neuroendocrine and behavioral effects of the selective kappa agonist spiradoline in Tourette's syndrome: A pilot study.
        Psychiatry Res. 1993; 47: 267-280
        • Walsh S.L.
        • Strain E.C.
        • Abreu M.E.
        • Bigelow G.E.
        Enadoline, a selective kappa opioid agonist: Comparison with butorphanol and hydromorphone in humans.
        Psychopharmacology. 2001; 157: 151-162
        • Vortherms T.A.
        • Roth B.L.
        Salvinorin A: From natural product to human therapeutics.
        Mol Interv. 2006; 6: 257-265