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Differential effects of the metabotropic glutamate 2/3 receptor agonist LY379268 on nicotine versus cocaine self-administration and relapse in squirrel monkeys

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Abstract

Rationale

Group II metabotropic glutamate receptors (mGluR2 and mGluR3) have been suggested to play an important role in mediation of drug-reinforced behaviors, as well as in the mechanisms underlying relapse in abstinent subjects. The prototypical mGluR2/3 agonist, LY379268, has been shown to attenuate nicotine reinforcement and cue-induced reinstatement of drug seeking in rats, as well as reinstatement induced by drug-associated stimuli and contexts across different drugs of abuse (i.e., cocaine, heroin, and methamphetamine). However, in primates, LY379268 has been shown to produce conflicting results on abuse-related effects of cocaine, and there are no data available for nicotine.

Objectives

To explore the therapeutic potential of mGluR2/3 agonists, we compared the effects of LY379268 (0.03–1.0 mg/kg) on nicotine, cocaine, and food self-administration under a fixed-ratio (FR10) schedule in three separate groups of squirrel monkeys. Moreover, we studied the effects of LY379268 on nicotine/cocaine priming-induced and cue-induced reinstatement of drug-seeking behavior in nicotine- and cocaine-experienced groups of animals.

Results

LY379268 blocked nicotine, but not cocaine, self-administration in monkeys. There was a partial overlap between doses that affected nicotine and food self-administration. In abstinent monkeys, LY379268 dose-dependently blocked nicotine, but not cocaine, priming-induced reinstatement of drug seeking. In both cocaine-experienced and nicotine-experienced groups of animals, LY379268 potently reduced cue-induced reinstatement of drug-seeking behavior.

Conclusions

The present findings provide strong support for the potential utility of mGlu2/3 receptor agonists for the treatment of nicotine dependence and suggest their utility for prevention of relapse induced by environmental cues associated with drug taking.

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References

  • Adewale AS, Platt DM, Spealman RD (2006) Pharmacological stimulation of group ii metabotropic glutamate receptors reduces cocaine self-administration and cocaine-induced reinstatement of drug seeking in squirrel monkeys. J Pharmacol Exp Ther 318:922–931

    Article  CAS  PubMed  Google Scholar 

  • Arroyo M, Markou A, Robbins TW, Everitt BJ (1998) Acquisition, maintenance and reinstatement of intravenous cocaine self-administration under a second-order schedule of reinforcement in rats: effects of conditioned cues and continuous access to cocaine. Psychopharmacology (Berlin) 140:331–344

    Article  CAS  Google Scholar 

  • Backstrom P, Hyytia P (2005) Suppression of alcohol self-administration and cue-induced reinstatement of alcohol seeking by the mGlu2/3 receptor agonist LY379268 and the mGlu8 receptor agonist (S)-3,4-DCPG. Eur J Pharmacol 528:110–118

    Article  PubMed  Google Scholar 

  • Baker DA, Xi ZX, Shen H, Swanson CJ, Kalivas PW (2002) The origin and neuronal function of in vivo nonsynaptic glutamate. J Neurosci 22:9134–9141

    CAS  PubMed  Google Scholar 

  • Baptista MA, Martin-Fardon R, Weiss F (2004) Preferential effects of the metabotropic glutamate 2/3 receptor agonist LY379268 on conditioned reinstatement versus primary reinforcement: comparison between cocaine and a potent conventional reinforcer. J Neurosci 24:4723–4727

    Article  CAS  PubMed  Google Scholar 

  • Bauzo RM, Kimmel HL, Howell LL (2009) Interactions between the mGluR2/3 agonist, LY379268, and cocaine on in vivo neurochemistry and behavior in squirrel monkeys. Pharmacol Biochem Behav 94:204–210

    Article  CAS  PubMed  PubMed Central  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  CAS  PubMed  Google Scholar 

  • Bossert JM, Busch RF, Gray SM (2005) The novel mGluR2/3 agonist LY379268 attenuates cue-induced reinstatement of heroin seeking. Neuroreport 16:1013–1016

    Article  CAS  PubMed  Google Scholar 

  • Bossert JM, Gray SM, Lu L, Shaham Y (2006) Activation of group II metabotropic glutamate receptors in the nucleus accumbens shell attenuates context-induced relapse to heroin seeking. Neuropsychopharmacology 31:2197–2209

    CAS  PubMed  PubMed Central  Google Scholar 

  • Cannella N, Halbout B, Uhrig S, Evrard L, Corsi M, Corti C, Deroche-Gamonet V, Hansson AC, Spanagel R (2013) The mGluR2/3 agonist LY379268 induced anti-reinstatement effects in rats exhibiting addiction-like behavior. Neuropsychopharmacology 38:2048–2056

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cornish JL, Kalivas PW (2000) Glutamate transmission in the nucleus accumbens mediates relapse in cocaine addiction. J Neurosci 20:RC89

    CAS  PubMed  Google Scholar 

  • Corrigall WA (1999) Nicotine self-administration in animals as a dependence model. Nicotine Tob Res 1:11–20

    Article  CAS  PubMed  Google Scholar 

  • Dhanya RP, Sidique S, Sheffler DJ, Nickols HH, Herath A, Yang L, Dahl R, Ardecky R, Semenova S, Markou A, Conn PJ, Cosford ND (2011) Design and synthesis of an orally active metabotropic glutamate receptor subtype-2 (mGluR2) positive allosteric modulator (PAM) that decreases cocaine self-administration in rats. J Med Chem 54:342–353

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Donny EC, Chaudhri N, Caggiula AR, Evans-Martin FF, Booth S, Gharib MA, Clements LA, Sved AF (2003) Operant responding for a visual reinforcer in rats is enhanced by noncontingent nicotine: implications for nicotine self-administration and reinforcement. Psychopharmacology (Berlin) 169:68–76

    Article  CAS  Google Scholar 

  • D'Souza MS, Liechti ME, Ramirez-Nino AM, Kuczenski R, Markou A (2011) The metabotropic glutamate 2/3 receptor agonist LY379268 blocked nicotine-induced increases in nucleus accumbens shell dopamine only in the presence of a nicotine-associated context in rats. Neuropsychopharmacology 36:2111–2124

    Article  PubMed  PubMed Central  Google Scholar 

  • Everitt BJ, Robbins TW (2000) Second-order schedules of drug reinforcement in rats and monkeys: measurement of reinforcing efficacy and drug-seeking behaviour. Psychopharmacology (Berlin) 153:17–30

    Article  CAS  Google Scholar 

  • Goldberg SR (1973) Comparable behavior maintained under fixed-ratio and second-order schedules of food presentation, cocaine injection or d-amphetamine injection in the squirrel monkey. J Pharmacol Exp Ther 186:18–30

    CAS  PubMed  Google Scholar 

  • Goldberg SR, Spealman RD (1982) Maintenance and suppression of behavior by intravenous nicotine injections in squirrel monkeys. Fed Proc 41:216–220

    CAS  PubMed  Google Scholar 

  • Goldberg SR, Spealman RD, Goldberg DM (1981) Persistent behavior at high rates maintained by intravenous self-administration of nicotine. Science 214:573–575

    Article  CAS  PubMed  Google Scholar 

  • Greenslade RG, Mitchell SN (2004) Selective action of (-)-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate (LY379268), a group II metabotropic glutamate receptor agonist, on basal and phencyclidine-induced dopamine release in the nucleus accumbens shell. Neuropharmacology 47:1–8

    Article  CAS  PubMed  Google Scholar 

  • Hao Y, Martin-Fardon R, Weiss F (2010) Behavioral and functional evidence of metabotropic glutamate receptor 2/3 and metabotropic glutamate receptor 5 dysregulation in cocaine-escalated rats: factor in the transition to dependence. Biol Psychiatry 68:240–248

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hotsenpiller G, Giorgetti M, Wolf ME (2001) Alterations in behaviour and glutamate transmission following presentation of stimuli previously associated with cocaine exposure. Eur J Neurosci 14:1843–1855

    Article  CAS  PubMed  Google Scholar 

  • Jin X, Semenova S, Yang L, Ardecky R, Sheffler DJ, Dahl R, Conn PJ, Cosford ND, Markou A (2010) The mGluR2 positive allosteric modulator BINA decreases cocaine self-administration and cue-induced cocaine-seeking and counteracts cocaine-induced enhancement of brain reward function in rats. Neuropsychopharmacology 35:2021–2036

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Justinova Z, Tanda G, Redhi GH, Goldberg SR (2003) Self-administration of Delta(9)-tetrahydrocannabinol (THC) by drug naive squirrel monkeys. Psychopharmacology (Berlin) 169:135–140

    Article  CAS  Google Scholar 

  • Justinova Z, Mangieri RA, Bortolato M, Chefer SI, Mukhin AG, Clapper JR, King AR, Redhi GH, Yasar S, Piomelli D, Goldberg SR (2008) Fatty acid amide hydrolase inhibition heightens anandamide signaling without producing reinforcing effects in primates. Biol Psychiatry 64:930–937

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Karasawa J, Yoshimizu T, Chaki S (2006) A metabotropic glutamate 2/3 receptor antagonist, MGS0039, increases extracellular dopamine levels in the nucleus accumbens shell. Neurosci Lett 393:127–130

    Article  CAS  PubMed  Google Scholar 

  • Kufahl PR, Watterson LR, Nemirovsky NE, Hood LE, Villa A, Halstengard C, Zautra N, Olive MF (2013) Attenuation of methamphetamine seeking by the mGluR2/3 agonist LY379268 in rats with histories of restricted and escalated self-administration. Neuropharmacology 66:290–301

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Le Foll B, Wertheim C, Goldberg SR (2007) High reinforcing efficacy of nicotine in non-human primates. PLoS One 2, e230

    Article  PubMed  PubMed Central  Google Scholar 

  • Liechti ME, Lhuillier L, Kaupmann K, Markou A (2007) Metabotropic glutamate 2/3 receptors in the ventral tegmental area and the nucleus accumbens shell are involved in behaviors relating to nicotine dependence. J Neurosci 27:9077–9085

    Article  CAS  PubMed  Google Scholar 

  • Lu L, Xue Y, Steketee JD, Rebec GV, Sun W (2012) Regulation of cocaine-induced reinstatement by group II metabotropic glutamate receptors in the ventral tegmental area. Psychopharmacology (Berlin) 220:75–85

    Article  CAS  Google Scholar 

  • Mansvelder HD, Keath JR, McGehee DS (2002) Synaptic mechanisms underlie nicotine-induced excitability of brain reward areas. Neuron 33:905–919

    Article  CAS  PubMed  Google Scholar 

  • Markou A, Paterson NE, Semenova S (2004) Role of gamma-aminobutyric acid (GABA) and metabotropic glutamate receptors in nicotine reinforcement: potential pharmacotherapies for smoking cessation. Ann N Y Acad Sci 1025:491–503

    Article  CAS  PubMed  Google Scholar 

  • Mascia P, Pistis M, Justinova Z, Panlilio LV, Luchicchi A, Lecca S, Scherma M, Fratta W, Fadda P, Barnes C, Redhi GH, Yasar S, Le FB, Tanda G, Piomelli D, Goldberg SR (2011) Blockade of nicotine reward and reinstatement by activation of alpha-type peroxisome proliferator-activated receptors. Biol Psychiatry 69:633–641

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McFarland K, Lapish CC, Kalivas PW (2003) Prefrontal glutamate release into the core of the nucleus accumbens mediates cocaine-induced reinstatement of drug-seeking behavior. J Neurosci 23:3531–3537

    CAS  PubMed  Google Scholar 

  • Ohishi H, Shigemoto R, Nakanishi S, Mizuno N (1993a) Distribution of the messenger RNA for a metabotropic glutamate receptor, mGluR2, in the central nervous system of the rat. Neuroscience 53:1009–1018

    Article  CAS  PubMed  Google Scholar 

  • Ohishi H, Shigemoto R, Nakanishi S, Mizuno N (1993b) Distribution of the mRNA for a metabotropic glutamate receptor (mGluR3) in the rat brain: an in situ hybridization study. J Comp Neurol 335:252–266

    Article  CAS  PubMed  Google Scholar 

  • Panlilio LV, Justinova Z, Mascia P, Pistis M, Luchicchi A, Lecca S, Barnes C, Redhi GH, Adair J, Heishman SJ, Yasar S, Aliczki M, Haller J, Goldberg SR (2012) Novel use of a lipid-lowering fibrate medication to prevent nicotine reward and relapse: preclinical findings. Neuropsychopharmacology 37:1838–1847

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Peters J, Kalivas PW (2006) The group II metabotropic glutamate receptor agonist, LY379268, inhibits both cocaine- and food-seeking behavior in rats. Psychopharmacology (Berlin) 186:143–149

    Article  CAS  Google Scholar 

  • Picciotto MR, Corrigall WA (2002) Neuronal systems underlying behaviors related to nicotine addiction: neural circuits and molecular genetics. J Neurosci 22:3338–3341

    CAS  PubMed  Google Scholar 

  • Richards G, Messer J, Malherbe P, Pink R, Brockhaus M, Stadler H, Wichmann J, Schaffhauser H, Mutel V (2005) Distribution and abundance of metabotropic glutamate receptor subtype 2 in rat brain revealed by [3H]LY354740 binding in vitro and quantitative radioautography: correlation with the sites of synthesis, expression, and agonist stimulation of [35S]GTPgammas binding. J Comp Neurol 487:15–27

    Article  CAS  PubMed  Google Scholar 

  • Rodd ZA, McKinzie DL, Bell RL, McQueen VK, Murphy JM, Schoepp DD, McBride WJ (2006) The metabotropic glutamate 2/3 receptor agonist LY404039 reduces alcohol-seeking but not alcohol self-administration in alcohol-preferring (P) rats. Behav Brain Res 171:207–215

    Article  CAS  PubMed  Google Scholar 

  • Sannerud CA, Prada J, Goldberg DM, Goldberg SR (1994) The effects of sertraline on nicotine self-administration and food-maintained responding in squirrel monkeys. Eur J Pharmacol 271:461–469

    Article  CAS  PubMed  Google Scholar 

  • Schindler CW, Panlilio LV, Goldberg SR (2002) Second-order schedules of drug self-administration in animals. Psychopharmacology (Berlin) 163:327–344

    Article  CAS  Google Scholar 

  • Schoepp DD, Jane DE, Monn JA (1999) Pharmacological agents acting at subtypes of metabotropic glutamate receptors. Neuropharmacology 38:1431–1476

    Article  CAS  PubMed  Google Scholar 

  • Tamaru Y, Nomura S, Mizuno N, Shigemoto R (2001) Distribution of metabotropic glutamate receptor mGluR3 in the mouse CNS: differential location relative to pre- and postsynaptic sites. Neuroscience 106:481–503

    Article  CAS  PubMed  Google Scholar 

  • Xi ZX, Baker DA, Shen H, Carson DS, Kalivas PW (2002) Group II metabotropic glutamate receptors modulate extracellular glutamate in the nucleus accumbens. J Pharmacol Exp Ther 300:162–171

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

With great sadness, we dedicate this article to memory of Dr. Steven R. Goldberg (†November 25, 2014).

We thank Dr. Ira Baum and Philip White for their excellent veterinary assistance during the study. We thank Dr. Sevil Yasar for advice and administrative assistance with the study and Dr. Charles Schindler for his comments on the manuscript.

This work was supported in part by the Intramural Research Program, National Institute on Drug Abuse, NIH, DHHS, and in part by NIDA grant DA011946 to Dr. Markou.

Conflict of interest

Athina Markou holds a patent on the use of metabotropic glutamate receptors for the treatment of drug dependence. During the last 3 years, Athina Markou has received contract research support by Astra-Zeneca, Forest Laboratories, and Bristol-Myers Squibb and honoraria from AbbVie, Germany.

The other authors have no conflicts of interest to declare.

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    Authors and Affiliations

    1. Preclinical Pharmacology Section, Behavioral Neuroscience Research Branch, Intramural Research Program, Department of Health and Human Services, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, 21224, USA

      Zuzana Justinova, Godfrey H. Redhi & Steven R. Goldberg

    2. Translational Addiction Research Laboratory, Centre for Addiction and Mental Health, University of Toronto, Toronto, ON, Canada

      Bernard Le Foll

    3. Alcohol Research and Treatment Clinic, Addiction Medicine Services, Ambulatory Care and Structured Treatments, Centre for Addiction and Mental Health, Toronto, ON, Canada

      Bernard Le Foll

    4. Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada

      Bernard Le Foll

    5. Department of Family and Community Medicine, University of Toronto, Toronto, ON, Canada

      Bernard Le Foll

    6. Department of Pharmacology, University of Toronto, Toronto, ON, Canada

      Bernard Le Foll

    7. Department of Psychiatry, Division of Brain and Therapeutics, University of Toronto, Toronto, ON, Canada

      Bernard Le Foll

    8. Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada

      Bernard Le Foll

    9. Department of Psychiatry, School of Medicine, University of California San Diego, La Jolla, CA, 92093, USA

      Athina Markou

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    1. Zuzana Justinova
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    2. Bernard Le Foll
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    3. Godfrey H. Redhi
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    4. Athina Markou
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    5. Steven R. Goldberg
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    Corresponding author

    Correspondence to Zuzana Justinova.

    Additional information

    Zuzana Justinova and Bernard Le Foll contributed equally to this work.

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    Justinova, Z., Le Foll, B., Redhi, G.H. et al. Differential effects of the metabotropic glutamate 2/3 receptor agonist LY379268 on nicotine versus cocaine self-administration and relapse in squirrel monkeys. Psychopharmacology 233, 1791–1800 (2016). https://doi.org/10.1007/s00213-015-3994-y

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