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Interactions between VTA orexin and glutamate in cue-induced reinstatement of cocaine seeking in rats

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Abstract

Rationale

Glutamate and orexin/hypocretin systems are involved in Pavlovian cue-triggered drug seeking.

Objectives

Here, we asked whether orexin and glutamate interact within ventral tegmental area (VTA) to promote reinstatement of extinguished cocaine seeking in a rat self-administration paradigm.

Methods/results

We first found that bilateral VTA microinjections of the orexin 1 receptor (OX1R) antagonist SB-334867 (SB) or a cocktail of the AMPA and NMDA glutamate receptor antagonists CNQX/AP-5 reduced reinstatement of cocaine seeking elicited by cues. In contrast, neither of these microinjections nor systemic SB reduced cocaine-primed reinstatement. Additionally, unilateral VTA OX1R blockade combined with contralateral VTA glutamate blockade attenuated cue-induced reinstatement, indicating that VTA orexin and glutamate are simultaneously necessary for cue-induced reinstatement. We further probed the receptor specificity of glutamate actions in VTA, finding that CNQX, but not AP-5, dose-dependently attenuated cue-induced reinstatement, indicating that AMPA but not NMDA receptor transmission is required for this type of cocaine seeking. Given the necessary roles of both OX1 and AMPA receptors in VTA for cue-induced cocaine seeking, we hypothesized that these signaling pathways interact during this behavior. We found that PEPA, a positive allosteric modulator of AMPA receptors, completely reversed the SB-induced attenuation of reinstatement behavior. Intra-VTA PEPA alone did not alter cue-induced reinstatement, indicating that potentiating AMPA activity with this drug specifically compensates for OX1R blockade, rather than simply inducing or enhancing reinstatement itself.

Conclusions

These findings show that cue-induced, but not cocaine-primed, reinstatement of cocaine seeking is dependent upon orexin and AMPA receptor interactions in VTA.

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References

  • Ahmed AH, Ptak CP, Oswald RE (2010) Molecular mechanism of flop selectivity and subsite recognition for an AMPA receptor allosteric modulator: structures of GluA2 and GluA3 in complexes with PEPA. Biochemistry 49:2843–2850

    Article  PubMed  CAS  Google Scholar 

  • Aston-Jones G, Smith RJ, Moorman DE, Richardson KA (2009) Role of lateral hypothalamic orexin neurons in reward processing and addiction. Neuropharmacology 56(Suppl 1):112–121

    Article  PubMed  CAS  Google Scholar 

  • Aston-Jones G, Smith RJ, Sartor GC, Moorman DE, Massi L, Tahsili-Fahadan P, Richardson KA (2010) Lateral hypothalamic orexin/hypocretin neurons: a role in reward-seeking and addiction. Brain Res 1314:74–90

    Article  PubMed  CAS  Google Scholar 

  • Berridge KC, Robinson TE (1998) What is the role of dopamine in reward: hedonic impact, reward learning, or incentive salience? Brain Res Brain Res Rev 28:309–369

    Article  PubMed  CAS  Google Scholar 

  • Borgland SL, Malenka RC, Bonci A (2004) Acute and chronic cocaine-induced potentiation of synaptic strength in the ventral tegmental area: electrophysiological and behavioral correlates in individual rats. J Neurosci 24:7482–7490

    Article  CAS  Google Scholar 

  • Borgland SL, Taha SA, Sarti F, Fields HL, Bonci A (2006) Orexin A in the VTA is critical for the induction of synaptic plasticity and behavioral sensitization to cocaine. Neuron 49:589–601

    Article  PubMed  CAS  Google Scholar 

  • Borgland SL, Chang SJ, Bowers MS, Thompson JL, Vittoz N, Floresco SB, Chou J, Chen BT, Bonci A (2009) Orexin A/hypocretin-1 selectively promotes motivation for positive reinforcers. J Neurosci 29:11215–11225

    Article  PubMed  CAS  Google Scholar 

  • Bossert JM, Liu SY, Lu L, Shaham Y (2004) A role of ventral tegmental area glutamate in contextual cue-induced relapse to heroin seeking. J Neurosci 24:10726–10730

    Article  PubMed  CAS  Google Scholar 

  • Boutrel B, Kenny PJ, Specio SE, Martin-Fardon R, Markou A, Koob GF, de Lecea L (2005) Role for hypocretin in mediating stress-induced reinstatement of cocaine-seeking behavior. Proc Natl Acad Sci USA 102:19168–19173

    Article  PubMed  CAS  Google Scholar 

  • Cardinal RN, Everitt BJ (2004) Neural and psychological mechanisms underlying appetitive learning: links to drug addiction. Curr Opin Neurobiol 14:156–162

    Article  PubMed  CAS  Google Scholar 

  • Cason AM, Smith RJ, Tahsili-Fahadan P, Moorman DE, Sartor GC, Aston-Jones G (2010) Role of orexin/hypocretin in reward-seeking and addiction: implications for obesity. Physiol Behav 100:419–428

    Article  PubMed  CAS  Google Scholar 

  • Cheer JF, Aragona BJ, Heien ML, Seipel AT, Carelli RM, Wightman RM (2007) Coordinated accumbal dopamine release and neural activity drive goal-directed behavior. Neuron 54:237–244

    Article  PubMed  CAS  Google Scholar 

  • Chergui K, Charlety PJ, Akaoka H, Saunier CF, Brunet JL, Buda M, Svensson TH, Chouvet G (1993) Tonic activation of NMDA receptors causes spontaneous burst discharge of rat midbrain dopamine neurons in vivo. Eur J Neurosci 5:137–144

    Article  PubMed  CAS  Google Scholar 

  • Choi KH, Edwards S, Graham DL, Larson EB, Whisler KN, Simmons D, Friedman AK, Walsh JJ, Rahman Z, Monteggia LM, Eisch AJ, Neve RL, Nestler EJ, Han M, Self DW (2011) Reinforcement-related regulation of AMPA glutamate receptor subunits in the ventral tegmental area enhances motivation for cocaine. J Neurosci 31:7927–7937

    Article  PubMed  CAS  Google Scholar 

  • Christoffersen CL, Meltzer LT (1995) Evidence for N-methyl-d-aspartate and AMPA subtypes of the glutamate receptor on substantia nigra dopamine neurons: possible preferential role for N-methyl-d-aspartate receptors. Neuroscience 67:373–381

    Article  PubMed  CAS  Google Scholar 

  • Di Ciano P, Everitt BJ (2004) Contribution of the ventral tegmental area to cocaine-seeking maintained by a drug-paired conditioned stimulus in rats. Eur J Neurosci 19:1661–1667

    Article  PubMed  Google Scholar 

  • Enrico P, Bouma M, de Vries JB, Westerink BH (1998) The role of afferents to the ventral tegmental area in the handling stress-induced increase in the release of dopamine in the medial prefrontal cortex: a dual-probe microdialysis study in the rat brain. Brain Res 779:205–213

    Article  PubMed  CAS  Google Scholar 

  • Espana RA, Melchior JR, Roberts DC, Jones SR (2011) Hypocretin 1/orexin A in the ventral tegmental area enhances dopamine responses to cocaine and promotes cocaine self-administration. Psychopharmacology (Berl): 415–426

  • Espana RA, Oleson EB, Locke JL, Brookshire BR, Roberts DC, Jones SR (2010) The hypocretin–orexin system regulates cocaine self-administration via actions on the mesolimbic dopamine system. Eur J Neurosci 31:336–348

    Article  PubMed  Google Scholar 

  • Feltenstein MW, Do PH, See RE (2009) Repeated aripiprazole administration attenuates cocaine seeking in a rat model of relapse. Psychopharmacology 207:401–411

    Article  PubMed  CAS  Google Scholar 

  • Fiorillo CD, Tobler PN, Schultz W (2003) Discrete coding of reward probability and uncertainty by dopamine neurons. Science 299:1898–1902

    Article  PubMed  CAS  Google Scholar 

  • Fu Y, Matta SG, Gao W, Brower VG, Sharp BM (2000) Systemic nicotine stimulates dopamine release in nucleus accumbens: re-evaluation of the role of N-methyl-d-aspartate receptors in the ventral tegmental area. J Pharmacol Exp Ther 294:458–465

    PubMed  CAS  Google Scholar 

  • Fuchs RA, Branham RK, See RE (2006) Different neural substrates mediate cocaine seeking after abstinence versus extinction training: a critical role for the dorsolateral caudate-putamen. J Neurosci 26:3584–3588

    Article  CAS  Google Scholar 

  • Geisler S, Derst C, Veh RW, Zahm DS (2007) Glutamatergic afferents of the ventral tegmental area in the rat. J Neurosci 27:5730–5743

    Article  PubMed  CAS  Google Scholar 

  • Geisler S, Marinelli M, Degarmo B, Becker ML, Freiman AJ, Beales M, Meredith GE, Zahm DS (2008) Prominent activation of brainstem and pallidal afferents of the ventral tegmental area by cocaine. Neuropsychopharmacology 33:2688–2700

    Article  PubMed  CAS  Google Scholar 

  • Georges F, Aston-Jones G (2002) Activation of ventral tegmental area cells by the bed nucleus of the stria terminalis: a novel excitatory amino acid input to midbrain dopamine neurons. J Neurosci 22:5173–5187

    CAS  Google Scholar 

  • Harris GC, Aston-Jones G (2003) Critical role for ventral tegmental glutamate in preference for a cocaine-conditioned environment. Neuropsychopharmacology 28:73–76

    Article  PubMed  CAS  Google Scholar 

  • Harris GC, Aston-Jones G (2006) Arousal and reward: a dichotomy in orexin function. Trends Neurosci 29:571–577

    Article  PubMed  CAS  Google Scholar 

  • Harris GC, Wimmer M, Byrne R, Aston-Jones G (2004) Glutamate-associated plasticity in the ventral tegmental area is necessary for conditioning environmental stimuli with morphine. Neuroscience 129:841–847

    Article  PubMed  CAS  Google Scholar 

  • Harris GC, Wimmer M, Aston-Jones G (2005) A role for lateral hypothalamic orexin neurons in reward seeking. Nature 437:556–559

    Article  PubMed  CAS  Google Scholar 

  • Harris GC, Wimmer M, Randall-Thompson JF, Aston-Jones G (2007) Lateral hypothalamic orexin neurons are critically involved in learning to associate an environment with morphine reward. Behav Brain Res 183:43–51

    Article  PubMed  CAS  Google Scholar 

  • Ikemoto S, Panksepp J (1999) The role of nucleus accumbens dopamine in motivated behavior: a unifying interpretation with special reference to reward-seeking. Brain Res Brain Res Rev 31:6–41

    Article  PubMed  CAS  Google Scholar 

  • James MH, Charnley JL, Levi EM, Jones E, Yeoh JW, Smith DW, Dayas CV (2011) Orexin-1 receptor signalling within the ventral tegmental area, but not the paraventricular thalamus, is critical to regulating cue-induced reinstatement of cocaine-seeking. Int J Neuropsychopharmacol 14:684–690

    Article  PubMed  CAS  Google Scholar 

  • Kalivas PW (2008) Addiction as a pathology in prefrontal cortical regulation of corticostriatal habit circuitry. Neurotox Res 14:185–189

    Article  PubMed  Google Scholar 

  • Kessler M, Arai AC (2006) Use of [3H]fluorowillardiine to study properties of AMPA receptor allosteric modulators. Brain Res 1076:25–41

    Article  PubMed  CAS  Google Scholar 

  • Kippin TE, Fuchs RA, See RE (2006) Contributions of prolonged contingent and noncontingent cocaine exposure to enhanced reinstatement of cocaine seeking in rats. Psychopharmacology (Berl) 187:60–67

    Article  CAS  Google Scholar 

  • Korotkova TM, Sergeeva OA, Eriksson KS, Haas HL, Brown RE (2003) Excitation of ventral tegmental area dopaminergic and nondopaminergic neurons by orexins/hypocretins. J Neurosci 23:7–11

    PubMed  CAS  Google Scholar 

  • LaLumiere RT, Niehoff KE, Kalivas PW (2010) The infralimbic cortex regulates the consolidation of extinction after cocaine self-administration. Learn Mem 17:168–175

    Article  PubMed  CAS  Google Scholar 

  • Lalumiere RT, Smith KC, Kalivas PW (2012) Neural circuit competition in cocaine-seeking: roles of the infralimbic cortex and nucleus accumbens shell. Eur J Neurosci 35:614–622

    Article  PubMed  Google Scholar 

  • Lawrence AJ, Cowen MS, Yang HJ, Chen F, Oldfield B (2006) The orexin system regulates alcohol-seeking in rats. Br J Pharmacol 148:752–759

    Article  PubMed  CAS  Google Scholar 

  • LeSage MG, Perry JL, Kotz CM, Shelley D, Corrigall WA (2010) Nicotine self-administration in the rat: effects of hypocretin antagonists and changes in hypocretin mRNA. Psychopharmacology (Berl) 209:203–212

    Article  CAS  Google Scholar 

  • Lu L, Xue Y, Steketee JD, Rebec GV, Sun W (2011) Regulation of cocaine-induced reinstatement by group II metabotropic glutamate receptors in the ventral tegmental area. Psychopharmacology 220:75–85

    Google Scholar 

  • Marinelli S, Pascucci T, Bernardi G, Puglisi-Allegra S, Mercuri NB (2005) Activation of TRPV1 in the VTA excites dopaminergic neurons and increases chemical- and noxious-induced dopamine release in the nucleus accumbens. Neuropsychopharmacology 30:864–870

    Article  CAS  Google Scholar 

  • Moorman DE, Aston-Jones G (2010) Orexin/hypocretin modulates response of ventral tegmental dopamine neurons to prefrontal activation: diurnal influences. J Neurosci 30:15585–15599

    Article  PubMed  CAS  Google Scholar 

  • Murschall A, Hauber W (2006) Inactivation of the ventral tegmental area abolished the general excitatory influence of Pavlovian cues on instrumental performance. Learn Mem 13:123–126

    Article  PubMed  CAS  Google Scholar 

  • Muschamp JW, Dominguez JM, Sato SM, Shen RY, Hull EM (2007) A role for hypocretin (orexin) in male sexual behavior. J Neurosci 27:2837–2845

    Article  PubMed  CAS  Google Scholar 

  • Narita M, Nagumo Y, Hashimoto S, Khotib J, Miyatake M, Sakurai T, Yanagisawa M, Nakamachi T, Shioda S, Suzuki T (2006) Direct involvement of orexinergic systems in the activation of the mesolimbic dopamine pathway and related behaviors induced by morphine. J Neurosci 26:398–405

    Article  PubMed  CAS  Google Scholar 

  • Narita M, Nagumo Y, Miyatake M, Ikegami D, Kurahashi K, Suzuki T (2007) Implication of protein kinase C in the orexin-induced elevation of extracellular dopamine levels and its rewarding effect. Eur J Neurosci 25:1537–1545

    Article  PubMed  Google Scholar 

  • National Research Councils of the National Academies (2011) Guide for the care and use of laboratory animals, 8th edn. National Academies Press, Washington, DC

  • Nolan BC, Saliba M, Tanchez C, Ranaldi R (2010) Behavioral activating effects of selective AMPA receptor antagonism in the ventral tegmental area. Pharmacology 86:336–343

    Article  PubMed  CAS  Google Scholar 

  • Nomikos GG, Damsma G, Wenkstern D, Fibiger HC (1990) In vivo characterization of locally applied dopamine uptake inhibitors by striatal microdialysis. Synapse 6:106–112

    Article  PubMed  CAS  Google Scholar 

  • Paxinos G, Watson C (2007) The rat brain in stereotaxic coordinates, 6th edn. Academic Press/Elsevier, Amsterdam; Boston

    Google Scholar 

  • Peters J, LaLumiere RT, Kalivas PW (2008) Infralimbic prefrontal cortex is responsible for inhibiting cocaine seeking in extinguished rats. J Neurosci 28:6046–6053

    Article  PubMed  CAS  Google Scholar 

  • Ranaldi R, Kest K, Zellner MR, Lubelski D, Muller J, Cruz Y, Saliba M (2010) The effects of VTA NMDA receptor antagonism on reward-related learning and associated c-fos expression in forebrain. Behav Brain Res 216:424–432

    Google Scholar 

  • Richards JK, Simms JA, Steensland P, Taha SA, Borgland SL, Bonci A, Bartlett SE (2008) Inhibition of orexin-1/hypocretin-1 receptors inhibits yohimbine-induced reinstatement of ethanol and sucrose seeking in Long-Evans rats. Psychopharmacology (Berl) 199:109–117

    Article  CAS  Google Scholar 

  • Riegel AC, French ED (2002) Abused inhalants and central reward pathways: electrophysiological and behavioral studies in the rat. Ann N Y Acad Sci 965:281–291

    Article  PubMed  CAS  Google Scholar 

  • Robinson TE, Berridge KC (2001) Incentive-sensitization and addiction. Addiction 96:103–114

    Article  PubMed  CAS  Google Scholar 

  • Rogers JL, Ghee S, See RE (2008) The neural circuitry underlying reinstatement of heroin-seeking behavior in an animal model of relapse. Neuroscience 151:579–588

    Article  PubMed  CAS  Google Scholar 

  • Saal D, Dong Y, Bonci A, Malenka RC (2003) Drugs of abuse and stress trigger a common synaptic adaptation in dopamine neurons. Neuron 37:577–582

    Article  PubMed  CAS  Google Scholar 

  • Salamone JD, Correa M, Farrar A, Mingote SM (2007) Effort-related functions of nucleus accumbens dopamine and associated forebrain circuits. Psychopharmacology (Berl) 191:461–482

    Article  CAS  Google Scholar 

  • Satoh T, Nakai S, Sato T, Kimura M (2003) Correlated coding of motivation and outcome of decision by dopamine neurons. J Neurosci 23:9913–9923

    PubMed  CAS  Google Scholar 

  • Schmidt HD, Famous KR, Pierce RC (2009) The limbic circuitry underlying cocaine seeking encompasses the PPTg/LDT. Eur J Neurosci 30:1358–1369

    Article  PubMed  Google Scholar 

  • See RE (2009) Dopamine D1 receptor antagonism in the prelimbic cortex blocks the reinstatement of heroin-seeking in an animal model of relapse. Int J Neuropsychopharmacol 12:431–436

    Article  PubMed  CAS  Google Scholar 

  • Sekiguchi M, Fleck MW, Mayer ML, Takeo J, Chiba Y, Yamashita S, Wada K (1997) A novel allosteric potentiator of AMPA receptors: 4–2-(phenylsulfonylamino)ethylthio–2,6-difluoro-phenoxyaceta mide. J Neurosci 17:5760–5771

    PubMed  CAS  Google Scholar 

  • Shaham Y, Shalev U, Lu L, De Wit H, Stewart J (2003) The reinstatement model of drug relapse: history, methodology and major findings. Psychopharmacology (Berl) 168:3–20

    Article  CAS  Google Scholar 

  • Smith RJ, Aston-Jones G (in press) Orexin/hypocretin 1 receptor antagonist reduces heroin self-administration and cue-induced heroin seeking. Eur J Neurosci. doi:10.1111/j.1460-9568.2012.08013.x

  • Smith RJ, See RE, Aston-Jones G (2009) Orexin/hypocretin signaling at the orexin 1 receptor regulates cue-elicited cocaine-seeking. Eur J Neurosci 30:493–503

    Article  PubMed  Google Scholar 

  • Smith RJ, Tahsili-Fahadan P, Aston-Jones G (2010) Orexin/hypocretin is necessary for context-driven cocaine-seeking. Neuropharmacology 58:179–184

    Article  PubMed  CAS  Google Scholar 

  • Sombers LA, Beyene M, Carelli RM, Wightman RM (2009) Synaptic overflow of dopamine in the nucleus accumbens arises from neuronal activity in the ventral tegmental area. J Neurosci 29:1735–1742

    Article  PubMed  CAS  Google Scholar 

  • Sun W, Akins CK, Mattingly AE, Rebec GV (2005) Ionotropic glutamate receptors in the ventral tegmental area regulate cocaine-seeking behavior in rats. Neuropsychopharmacology 30:2073–2081

    Article  PubMed  CAS  Google Scholar 

  • Svensson TH, Mathe JM, Nomikos GG, Schilstrom B (1998) Role of excitatory amino acids in the ventral tegmental area for central actions of non-competitive NMDA-receptor antagonists and nicotine. Amino Acids 14:51–56

    Article  PubMed  CAS  Google Scholar 

  • Takahata R, Moghaddam B (2000) Target-specific glutamatergic regulation of dopamine neurons in the ventral tegmental area. J Neurochem 75:1775–1778

    Article  PubMed  CAS  Google Scholar 

  • Ungless MA, Whistler JL, Malenka RC, Bonci A (2001) Single cocaine exposure in vivo induces long-term potentiation in dopamine neurons. Nature 411:583–587

    Article  PubMed  CAS  Google Scholar 

  • Wang B, Shaham Y, Zitzman D, Azari S, Wise RA, You ZB (2005) Cocaine experience establishes control of midbrain glutamate and dopamine by corticotropin-releasing factor: a role in stress-induced relapse to drug seeking. J Neurosci 25:5389–5396

    Article  PubMed  CAS  Google Scholar 

  • Wang B, You ZB, Wise RA (2009) Reinstatement of cocaine seeking by hypocretin (orexin) in the ventral tegmental area: independence from the local corticotropin-releasing factor network. Biol Psychiatry 65:857–862

    Article  PubMed  CAS  Google Scholar 

  • Wang T, O’Connor WT, Ungerstedt U, French ED (1994) N-methyl-d-aspartic acid biphasically regulates the biochemical and electrophysiological response of A10 dopamine neurons in the ventral tegmental area: in vivo microdialysis and in vitro electrophysiological studies. Brain Res 666:255–262

    Article  PubMed  CAS  Google Scholar 

  • Westerink BH, Enrico P, Feimann J, De Vries JB (1998) The pharmacology of mesocortical dopamine neurons: a dual-probe microdialysis study in the ventral tegmental area and prefrontal cortex of the rat brain. J Pharmacol Exp Ther 285:143–154

    PubMed  CAS  Google Scholar 

  • White FJ, Hu XT, Zhang XF, Wolf ME (1995) Repeated administration of cocaine or amphetamine alters neuronal responses to glutamate in the mesoaccumbens dopamine system. J Pharmacol Exp Ther 273:445–454

    PubMed  CAS  Google Scholar 

  • Wise RA (2009) Ventral tegmental glutamate: a role in stress-, cue-, and cocaine-induced reinstatement of cocaine-seeking. Neuropharmacology 56(Suppl 1):174–176

    Article  PubMed  CAS  Google Scholar 

  • Wise RA, Wang B, You ZB (2008) Cocaine serves as a peripheral interoceptive conditioned stimulus for central glutamate and dopamine release. PLoS One 3:e2846

    Article  PubMed  Google Scholar 

  • Yamada D, Zushida K, Wada K, Sekiguchi M (2009) Pharmacological discrimination of extinction and reconsolidation of contextual fear memory by a potentiator of AMPA receptors. Neuropsychopharmacology 34:2574–2584

    Article  PubMed  CAS  Google Scholar 

  • You ZB, Wang B, Zitzman D, Azari S, Wise RA (2007) A role for conditioned ventral tegmental glutamate release in cocaine seeking. J Neurosci 27:10546–10555

    Article  PubMed  CAS  Google Scholar 

  • Zellner MR, Ranaldi R (2010) How conditioned stimuli acquire the ability to activate VTA dopamine cells: a proposed neurobiological component of reward-related learning. Neurosci Biobehav Rev 34:769–780

    Article  PubMed  CAS  Google Scholar 

  • Zellner MR, Kest K, Ranaldi R (2009) NMDA receptor antagonism in the ventral tegmental area impairs acquisition of reward-related learning. Behav Brain Res 197:442–449

    Article  PubMed  CAS  Google Scholar 

  • Zhang XF, Hu XT, White FJ, Wolf ME (1997) Increased responsiveness of ventral tegmental area dopamine neurons to glutamate after repeated administration of cocaine or amphetamine is transient and selectively involves AMPA receptors. J Pharmacol Exp Ther 281:699–706

    PubMed  CAS  Google Scholar 

  • Zushida K, Sakurai M, Wada K, Sekiguchi M (2007) Facilitation of extinction learning for contextual fear memory by PEPA: a potentiator of AMPA receptors. J Neurosci 27:158–166

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We would like to thank Phong Do and Lana Zhang for assistance with behavioral testing. These experiments were funded by NIDA P50 DA015369, R37 DA06214, F32 DA026692, and T32 DA007288.

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  1. Department of Neurosciences, Medical University of South Carolina, 403 BSB, 173 Ashley Ave., Charleston, SC, 29425, USA

    Stephen V. Mahler, Rachel J. Smith & Gary Aston-Jones

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  1. Stephen V. Mahler
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Correspondence to Gary Aston-Jones.

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Mahler, S.V., Smith, R.J. & Aston-Jones, G. Interactions between VTA orexin and glutamate in cue-induced reinstatement of cocaine seeking in rats. Psychopharmacology 226, 687–698 (2013). https://doi.org/10.1007/s00213-012-2681-5

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