Abstract
Kappa-opioid receptors (KORs) are important for motivation and other medial prefrontal cortex (mPFC)-dependent behaviors. Although KORs are present in the mPFC, their role in regulating transmission in this brain region and their contribution to KOR-mediated aversion are not known. Using in vivo microdialysis in rats and mice, we demonstrate that intra-mPFC administration of the selective KOR agonist U69,593 decreased local dopamine (DA) overflow, while reverse dialysis of the KOR antagonist nor-Binaltorphimine (nor-BNI) enhanced mPFC DA overflow. Extracellular amino-acid levels were also affected by KORs, as U69,593 reduced glutamate and GABA levels driven by the glutamate reuptake blocker, l-trans-pyrrolidine-2,4-dicarboxylate. Whole-cell recordings from mPFC layer V pyramidal neurons revealed that U69,593 decreased the frequency, but not amplitude, of glutamatergic mini EPSPs. To determine whether KOR regulation of mPFC DA overflow was mediated by KOR on DA terminals, we utilized a Cre recombinase-driven mouse line lacking KOR in DA neurons. In these mice, basal DA release or uptake was unaltered relative to controls, but attenuation of mPFC DA overflow by local U69,593 was not observed, indicating KOR acts directly on mPFC DA terminals to locally inhibit DA levels. Conditioning procedures were then used to determine whether mPFC KOR signaling was necessary for KOR-mediated aversion. U69,593-mediated conditioned place aversion was blocked by intra-mPFC nor-BNI microinjection. These findings demonstrate that mPFC KORs negatively regulate DA and amino-acid neurotransmission, and are necessary for KOR-mediated aversion.
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References
Backman CM, Malik N, Zhang Y, Shan L, Grinberg A, Hoffer BJ et al (2006). Characterization of a mouse strain expressing Cre recombinase from the 3′ untranslated region of the dopamine transporter locus. Genesis 44: 383–390.
Bals-Kubik R, Ableitner A, Herz A, Shippenberg TS (1993). Neuroanatomical sites mediating the motivational effects of opioids as mapped by the conditioned place preference paradigm in rats. J Pharmacol Exp Ther 264: 489–495.
Bruchas MR, Land BB, Chavkin C (2010). The dynorphin/kappa opioid system as a modulator of stress-induced and pro-addictive behaviors. Brain Res 1314: 44–55.
Chefer VI, Denoroy L, Zapata A, Shippenberg TS (2009). Mu opioid receptor modulation of somatodendritic dopamine overflow: GABAergic and glutamatergic mechanisms. Eur J Neurosci 30: 272–278.
Chefer VI, Czyzyk T, Bolan EA, Moron J, Pintar JE, Shippenberg TS (2005). Endogenous kappa-opioid receptor systems regulate mesoaccumbal dopamine dynamics and vulnerability to cocaine. J Neurosci 25: 5029–5037.
Devine DP, Leone P, Pocock D, Wise RA (1993). Differential involvement of ventral tegmental mu, delta and kappa opioid receptors in modulation of basal mesolimbic dopamine release: in vivo microdialysis studies. J Pharmacol Exp Ther 266: 1236–1246.
Endoh T, Matsuura H, Tanaka C, Nagase H (1992). Nor-binaltorphimine: a potent and selective kappa-opioid receptor antagonist with long-lasting activity in vivo. Arch Int Pharmacodyn Ther 316: 30–42.
Grilli M, Neri E, Zappettini S, Massa F, Bisio A, Romussi G et al (2009). Salvinorin A exerts opposite presynaptic controls on neurotransmitter exocytosis from mouse brain nerve terminals. Neuropharmacology 57: 523–530.
Heijna MH, Padt M, Hogenboom F, Portoghese PS, Mulder AH, Schoffelmeer AN (1990). Opioid receptor-mediated inhibition of dopamine and acetylcholine release from slices of rat nucleus accumbens, olfactory tubercle and frontal cortex. Eur J Pharmacol 181: 267–278.
Herrera-Marschitz M, You ZB, Goiny M, Meana JJ, Silveira R, Godukhin OV et al (1996). On the origin of extracellular glutamate levels monitored in the basal ganglia of the rat by in vivo microdialysis. J Neurochem 66: 1726–1735.
Hjelmstad GO, Fields HL (2001). Kappa opioid receptor inhibition of glutamatergic transmission in the nucleus accumbens shell. J Neurophysiol 85: 1153–1158.
Hjelmstad GO, Fields HL (2003). Kappa opioid receptor activation in the nucleus accumbens inhibits glutamate and GABA release through different mechanisms. J Neurophysiol 89: 2389–2395.
Iremonger KJ, Bains JS (2009). Retrograde opioid signaling regulates glutamatergic transmission in the hypothalamus. J Neurosci 29: 7349–7358.
Knoll AT, Carlezon WA Jr. (2010). Dynorphin, stress, and depression. Brain Res 1314: 56–73.
Kreuter JD, Mattson BJ, Wang B, You ZB, Hope BT (2004). Cocaine-induced Fos expression in rat striatum is blocked by chloral hydrate or urethane. Neuroscience 127: 233–242.
Lemos JC, Roth CA, Messinger DI, Gill HK, Phillips PE, Chavkin C (2012). Repeated stress dysregulates κ-opioid receptor signaling in the dorsal raphe through a p38α MAPK-dependent mechanism. J Neurosci 32: 12325–12336.
Margolis EB, Hjelmstad GO, Bonci A, Fields HL (2003). Kappa-opioid agonists directly inhibit midbrain dopaminergic neurons. J Neurosci 23: 9981–9986.
Margolis EB, Lock H, Chefer VI, Shippenberg TS, Hjelmstad GO, Fields HL (2006). Kappa opioids selectively control dopaminergic neurons projecting to the prefrontal cortex. Proc Natl Acad Sci USA 103: 2938–2942.
Melendez RI, Vuthiganon J, Kalivas PW (2005). Regulation of extracellular glutamate in the prefrontal cortex: focus on the cystine glutamate exchanger and group I metabotropic glutamate receptors. J Pharmacol Exp Ther 314: 139–147.
Meng F, Xie GX, Thompson RC, Mansour A, Goldstein A, Watson SJ et al (1993). Cloning and pharmacological characterization of a rat kappa opioid receptor. Proc Natl Acad Sci USA 90: 9954–9958.
Mu P, Neumann PA, Panksepp J, Schluter OM, Dong Y (2011). Exposure to cocaine alters dynorphin-mediated regulation of excitatory synaptic transmission in nucleus accumbens neurons. Biol Psychiatry 69: 228–235.
Mucha RF, Herz A (1985). Motivational properties of kappa and mu opioid receptor agonists studied with place and taste preference conditioning. Psychopharmacology 86: 274–280.
Paxinos G, Franklin KBJ (2001) The Mouse Brain in Stereotaxic Coordinates. Academic Press: San Diego.
Paxinos G, Watson C (1998) The Rat Brain in Stereotaxic Coordinates. Academic Press: San Diego.
Peters J, Kalivas PW, Quirk GJ (2009). Extinction circuits for fear and addiction overlap in prefrontal cortex. Learn Mem 16: 279–288.
Pfeiffer A, Brantl V, Herz A, Emrich HM (1986). Psychotomimesis mediated by kappa opiate receptors. Science 233: 774–776.
Ranganathan M, Schnakenberg A, Skosnik PD, Cohen BM, Pittman B, Sewell RA et al (2012). Dose-related behavioral, subjective, endocrine, and psychophysiological effects of the kappa opioid agonist Salvinorin A in humans. Biol Psychiatry 72: 871–879.
Rawls SM, McGinty JF (1997). L-trans-pyrrolidine-2,4-dicarboxylic acid-evoked striatal glutamate levels are attenuated by calcium reduction, tetrodotoxin, and glutamate receptor blockade. J Neurochem 68: 1553–1563.
Rawls SM, McGinty JF (1998). Kappa receptor activation attenuates L-trans-pyrrolidine-2,4-dicarboxylic acid-evoked glutamate levels in the striatum. J Neurochem 70: 626–634.
Sbrenna S, Marti M, Morari M, Calo G, Guerrini R, Beani L et al (1999). L-glutamate and gamma-aminobutyric acid efflux from rat cerebrocortical synaptosomes: modulation by kappa- and mu- but not delta- and opioid receptor like-1 receptors. J Pharmacol Exp Ther 291: 1365–1371.
Seamans JK, Yang CR (2004). The principal features and mechanisms of dopamine modulation in the prefrontal cortex. Prog Neurobiol 74: 1–58.
Shippenberg TS, Bals-Kubik R, Herz A (1993). Examination of the neurochemical substrates mediating the motivational effects of opioids: role of the mesolimbic dopamine system and D-1 vs D-2 dopamine receptors. J Pharmacol Exp Ther 265: 53–59.
Shippenberg TS, Zapata A, Chefer VI (2007). Dynorphin and the pathophysiology of drug addiction. Pharmacol Ther 116: 306–321.
Spanagel R, Herz A, Shippenberg TS (1992). Opposing tonically active endogenous opioid systems modulate the mesolimbic dopaminergic pathway. Proc Natl Acad Sci USA 89: 2046–2050.
Sutor B, Zieglgansberger W (1984). Actions of D-Ala2-D-Leu5-enkephalin and dynorphin A (1-17) on neocortical neurons in vitro. Neuropeptides 5: 241–244.
Svingos AL, Colago EE (2002). Kappa-opioid and NMDA glutamate receptors are differentially targeted within rat medial prefrontal cortex. Brain Res 946: 262–271.
Tejeda HA, Shippenberg TS, Henriksson R (2012). The dynorphin/kappa-opioid receptor system and its role in psychiatric disorders. Cell Mol Life Sci 69: 857–896.
Thompson AC, Zapata A, Justice JB Jr., Vaughan RA, Sharpe LG, Shippenberg TS (2000). Kappa-opioid receptor activation modifies dopamine uptake in the nucleus accumbens and opposes the effects of cocaine. J Neurosci 20: 9333–9340.
Todtenkopf MS, Marcus JF, Portoghese PS, Carlezon WA Jr. (2004). Effects of kappa-opioid receptor ligands on intracranial self-stimulation in rats. Psychopharmacology 172: 463–470.
Wall PM, Messier C (2000). U-69,593 microinjection in the infralimbic cortex reduces anxiety and enhances spontaneous alternation memory in mice. Brain Res 856: 259–280.
Wall PM, Messier C (2002). Infralimbic kappa opioid and muscarinic M1 receptor interactions in the concurrent modulation of anxiety and memory. Psychopharmacology 160: 233–244.
Walsh SL, Strain EC, Abreu ME, Bigelow GE (2001). Enadoline, a selective kappa opioid agonist: comparison with butorphanol and hydromorphone in humans. Psychopharmacology 157: 151–162.
Yamaguchi T, Wang HL, Li X, Ng TH, Morales M (2011). Mesocorticolimbic glutamatergic pathway. J Neurosci 31: 8476–8490.
Young GA, Khazan N (1984). Differential neuropharmacological effects of mu, kappa and sigma opioid agonists on cortical EEG power spectra in the rat. Stereospecificity and naloxone antagonism. Neuropharmacology 23: 1161–1165.
Zapata A, Kivell B, Han Y, Javitch JA, Bolan EA, Kuraguntla D et al (2007). Regulation of dopamine transporter function and cell surface expression by D3 dopamine receptors. J Biol Chem 282: 35842–35854.
Acknowledgements
This work was supported by the National Institute on Drug Abuse Intramural Research Program, grants from the National Institutes of Health (PO, MH57683; TSS and SR, MH083928), a National Science Foundation Graduate Research Fellowship (HAT), a Meyerhoff Graduate Fellowship (HAT), and a Ford Foundation Predoctoral Fellowship (HAT). The authors would like to thank Dr Jennifer Whistler for her generous donation of the KORloxp mice. The authors would like to thank Drs Brad Alger, Antonello Bonci, Joe Cheer, and Greg Elmer for their helpful comments and discussion.
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Dr Patricio O’Donnell receives compensation as a consultant for Roche Pharmaceuticals. All remaining authors declare no have conflict of interest.
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HAT, KNS-K, and VC performed microdialysis experiments. HAT and EO executed conditioning experiments. CMB performed genotyping and FISH experiments using transgenic animals. DS performed electrophysiology experiments. SR performed dopamine uptake studies. HAT, VC and DS analyzed the results. HAT, VC, PO, and TS designed the study. HAT, VC, and PO wrote the manuscript.
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Tejeda, H., Counotte, D., Oh, E. et al. Prefrontal Cortical Kappa-Opioid Receptor Modulation of Local Neurotransmission and Conditioned Place Aversion. Neuropsychopharmacol 38, 1770–1779 (2013). https://doi.org/10.1038/npp.2013.76
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DOI: https://doi.org/10.1038/npp.2013.76
