Skip to main content
SpringerLink
Log in

The metabotropic glutamate receptor 5 antagonist MPEP decreased break points for nicotine, cocaine and food in rats

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Rationale

The metabotropic glutamate (mGlu5) receptor subtype 5 antagonist MPEP attenuates self-administration of numerous drugs of abuse.

Objectives

The purpose of the present study was to explore whether MPEP-induced decreases in nicotine and cocaine self-administration reflect attenuation of the reinforcing and incentive motivational effects of nicotine and cocaine. The effects of MPEP on breaking points maintained by nicotine, cocaine or food were assessed using a progressive ratio schedule of reinforcement. Breaking points obtained under such schedules are postulated to reflect both the reinforcing and incentive motivational properties of reinforcers.

Methods

Rats were allowed to respond for nicotine (0.05 mg/kg per infusion, free base), cocaine (0.18 mg/kg per infusion, salt), or food (45 mg pellets) under a progressive ratio schedule of reinforcement. After establishing stable and equivalent levels of responding for all three reinforcers, rats underwent one test session where no rewards were presented to assess the effects of 1-day extinction, similar to 1-day pharmacological-induced extinction, on performance in this schedule. Subsequently, rats were again allowed to respond for nicotine, cocaine or food until reestablishment of stable levels of responding. Then, MPEP (1–9 mg/kg) was administered intraperitoneally according to a within-subjects Latin square design, 30 min prior to the testing sessions.

Results

Responding in the absence of a primary reinforcer was significantly decreased compared to responding under baseline conditions. Further, MPEP decreased break points maintained by nicotine, cocaine and food.

Conclusions

The mGlu5 receptor is implicated in mediating the reinforcing and incentive motivational properties of nicotine, cocaine and food.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  • Arnold JM, Roberts DCS (1997) A critique of fixed and progressive-ratio schedules used to examine the neural substrates of drug reinforcement. Pharmacol Biochem Behav 57(3):441–447

    Article  CAS  PubMed  Google Scholar 

  • Backstrom P, Bachteler D, Koch S, Hyytia P, Spanagel R (2004) mGluR5 antagonist MPEP reduces ethanol-seeking and relapse behavior. Neuropsychopharmacology [Epub ahead of print Jan 21]

  • Balfour DJ, Wright AE, Benwell ME, Birrell CE (2000) The putative role of extra-synaptic mesolimbic dopamine in the neurobiology of nicotine dependence. Behav Brain Res 113(1–2):73–83

    Article  Google Scholar 

  • Bindra D (1976) A theory of intelligent behavior. Wiley, New York

    Google Scholar 

  • Brebner K, Froestl W, Andrews M, Phelan R, Roberts DCS (1999) The GABAB agonist CGP44532 decreases cocaine self-administration in rats: demonstration using a progressive-ratio and a discrete trials procedure. Neuropharmacology 38:1797–1804

    Article  CAS  PubMed  Google Scholar 

  • Caggiula AR, Donny EC, White AR, Chaudhri N, Booth S, Gharib MA, Hoffman A, Perkins KA, Sved AF (2001) Cue dependency of nicotine self-administration and smoking. Pharmacol Biochem Behav 70:515–530

    Article  CAS  PubMed  Google Scholar 

  • Caine SB, Koob GF (1994) Effects of dopamine D-1 and D-2 antagonists on cocaine self-administration under different schedules of reinforcement in the rat. J Pharmacol Exp Ther 270(1):209–218

    CAS  PubMed  Google Scholar 

  • Caine SB, Koob GF (1995) Pretreatment with the dopamine agonist 7-OH-DPAT shifts the cocaine self-administration dose–effect function to the left under different schedules in the rat. Behav Pharmacol 6(4):333–347

    Google Scholar 

  • Chiamulera C, Epping-Jordan MP, Zocchi A, Marcon C, Cottiny C, Tacconi S, Corsi M, Orzi F, Conquet F (2001) Reinforcing and locomotor stimulant effects of cocaine are absent in mGluR5 null mutant mice. Nat Neurosci 4(9):873–874

    Article  CAS  PubMed  Google Scholar 

  • Corrigall WA, Coen KM (1991) Selective dopamine antagonists reduce nicotine self-administration. Psychopharmacology 104:171–176

    Google Scholar 

  • de Wit H, Stewart J (1981) Reinstatement of cocaine-reinforced responding in the rat. Psychopharmacology 75(2):134–143

    CAS  PubMed  Google Scholar 

  • Dews PB (1955) Studies on behavior. I. Differential sensitivity to pentobarbital of pecking performance in pigeons depending on the schedule of reward. J Pharmacol Exp Ther 138:393–401

    Google Scholar 

  • Donny EC, Caggiula AR, Mielke MM, Booth S, Gharib MA, Hoffman A, Maldovan V, Shupenko C, McCallum SE (1999) Nicotine self-administration in rats on a progressive-ratio schedule of reinforcement. Psychopharmacology 147:135–142

    Article  CAS  PubMed  Google Scholar 

  • Donny EC, Caggiula AR, Rose C, Jacobs KS, Mielke MM, Sved AF (2000) Differential effects of response-contingent and response-independent nicotine in rats. Eur J Pharmacol 402(3):231–240

    Google Scholar 

  • Droungas A, Ehrman RN, Childress AR, O’Brien CP (1995) Effects of smoking cues and cigarette availability on craving and smoking behavior. Addict Behav 20:657–673

    Article  Google Scholar 

  • Due DL, Huettel SA, Hall WG, Rubin DC (2002) Activation in mesolimbic and visuospatial neural circuits elicited by smoking cues: evidence from functional magnetic resonance imaging. Am J Psychiatry 159:954–960

    Article  Google Scholar 

  • Dworkin SI, Mirkis S, Smith JE (1995) Response-dependent versus response-independent presentation of cocaine: differences in the lethal effects of the drug. Psychopharmacology 117(3):262–266

    Google Scholar 

  • Fattore L, Cossu G, Martellotta MC, Fratta W (2002) Baclofen antagonizes intravenous self-administration of nicotine in mice and rats. Alcohol Alcohol 37(5):495–498

    Article  CAS  PubMed  Google Scholar 

  • Gardner EL (2000) What we have learned about addiction from animal models of drug self-administration. Am J Addict 9(4):285–313

    Article  Google Scholar 

  • Gasparini F, Lingenhohl K, Stoehr N, Flor PJ, Heinrich M, Vranesic I, Biollaz M, Allgeier H, Heckendorn R, Urwyler S, Varney MA, Johnson EC, Hess SD, Rao SP, Sacaan AI, Santori EM, Velicelebi G, Kuhn R (1999) 2-Methyl-6-(phenylethynyl)-pyridine (MPEP), a potent, selective and systemically active mGlu5 receptor antagonist. Neuropharmacology 38:1493–1503

    Article  CAS  PubMed  Google Scholar 

  • Harrison AA, Parsons LH, Koob GF, Markou A (1999) RU 24969, a 5-HT1A/1B agonist, elevates brain stimulation reward thresholds: an effect reversed by GR127935, a selective 5-HT1B/1D antagonist. Psychopharmacology 141:242–250

    Article  CAS  PubMed  Google Scholar 

  • Harrison AA, Gasparini F, Markou A (2002) Nicotine potentiation of brain stimulation reward reversed by DHβE and SCH23390, but not by eticlopride, LY 314582 or MPEP in rats. Psychopharmacology 160:56–66

    Google Scholar 

  • Henry SA, Lehmann-Masten V, Gasparini F, Geyer MA, Markou A (2002) The mGluR5 antagonist MPEP, but not the mGluR2/3 agonist LY314582, augments PCP effects on prepulse inhibition and locomotor activity. Neuropharmacology 43(8):1199–1209

    Article  Google Scholar 

  • Kalivas PW, Duffy P (1995) D1 receptors modulate glutamate transmission in the ventral tegmental area. J Neurosci 15(7 Pt 2):5379–5388

    Google Scholar 

  • Kenny PJ, Gasparini F, Markou A (2003) Group II metabotropic and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA)/kainate glutamate receptors regulate the deficit in brain reward function associated with nicotine withdrawal in rats. J Pharmacol Exp Ther 306(3):1068–1076

    Article  CAS  PubMed  Google Scholar 

  • Koob GF (2003) Neuroadaptive mechanisms of addiction: studies on the extended amygdala. Eur Neuropsychopharmacol 13:442–452

    Google Scholar 

  • Levin ED, Mead T, Rezvani AH, Rose JE, Gallivan C, Gross R (2000) The nicotinic antagonist mecamylamine preferentially inhibits cocaine vs. food self-administration in rats. Physiol Behav 71(5):565–570

    Article  Google Scholar 

  • Markou A, Weiss F, Gold LH, Caine SB, Schulteis G, Koob GF (1993) Animal models of drug craving. Psychopharmacology 112:163–182

    CAS  PubMed  Google Scholar 

  • Markou A, Arroyo M, Everitt BJ (1999) Effects of contingent and non-contingent cocaine on drug-seeking behavior measured using a second-order schedule of cocaine reinforcement in rats. Neuropsychopharmacology 20:542–555

    Article  Google Scholar 

  • McGeehan AJ, Olive MF (2003) The mGluR5 antagonist MPEP reduces the conditioned rewarding effects of cocaine but not other drugs of abuse. Synapse 47(3):240–242

    CAS  PubMed  Google Scholar 

  • McMillan DE, Katz JL (2002) Continuing implications of the early evidence against the drive reduction hypothesis of the behavioral effects of drugs. Psychopharmacology 163(3–4):251–264

    Article  Google Scholar 

  • National Institutes of Health (1996) Guide for the care and use of laboratory animals. National Academy Press, Washington D.C.

    Google Scholar 

  • Paterson NE, Markou A (2003) Increased motivation for self-administered cocaine after escalated cocaine intake. NeuroReport 14(17):2229–2232

    Article  CAS  PubMed  Google Scholar 

  • Paterson NE, Semenova S, Gasparini F, Markou A (2003) The mGluR5 antagonist MPEP decreased nicotine self-administration in rats and mice. Psychopharmacology 167(3):257–264

    Google Scholar 

  • Paterson NE, Froestl W, Markou A (2004a) The GABA(B) receptor agonists baclofen and CGP44532 decreased nicotine self-administration in the rat. Psychopharmacology 172(2):179–186

    Article  CAS  PubMed  Google Scholar 

  • Paterson NE, Froestl W, Markou A (2004b) Repeated administration of the GABA(B) receptor agonist CGP44532 decreased nicotine self-administration, and acute administration decreased cue-induced reinstatement of nicotine-seeking in rats. Neuropsychopharmacology. Online publication Jul 21 2004. DOI:10.1038/sj.npp.1300524

  • Picciotto MR, Zoli M, Rimondini R, Lena C, Marubio LM, Pich EM, Fuxe K, Changeux JP (1998) Acetylcholine receptors containing the beta2 subunit are involved in the reinforcing properties of nicotine. Nature 391(6663):173–177

    Article  CAS  PubMed  Google Scholar 

  • Popik P, Wrobel M (2002) Morphine conditioned reward is inhibited by MPEP, the mGluR5 antagonist. Neuropharmacology 43(8):1210–1217

    CAS  PubMed  Google Scholar 

  • Reid MS, Hsu K Jr, Berger SP (1997) Cocaine and amphetamine preferentially stimulate glutamate release in the limbic system: studies on the involvement of dopamine. Synapse 27(2):95–105

    Google Scholar 

  • Reid MS, Fox L, Ho LB, Berger SP (2000) Nicotine stimulation of extracellular glutamate levels in the nucleus accumbens: neuropharmacological characterization. Synapse 35(2):129–136

    Article  Google Scholar 

  • Rothman RB, Baumann MH, Dersch CM, Romero DV, Rice KC, Carroll FI, Partilla JS (2001) Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin. Synapse 39(1):32–41

    Article  CAS  PubMed  Google Scholar 

  • Schilstrom B, Fagerquist MV, Zhang X, Hertel P, Panagis G, Nomikos GG, Svensson TH (2000) Putative role of presynaptic alpha*7 nicotinic receptors in nicotine stimulated increases of extracellular levels of glutamate and aspartate in the ventral tegmental area. Synapse 38(4):375–383

    Article  Google Scholar 

  • Stafford D, LeSAge MG, Glowa JR (1999) Effects of phentermine on responding maintained by progressive ratio schedules of cocaine and food delivery in rhesus monkeys. Behav Pharmacol 10(8):775–784

    Google Scholar 

  • Tatarczynska E, Klodzinska A, Chojnacka-Wojcik E, Palucha A, Gasparini F, Kuhn R, Pilc A (2001) Potential anxiolytic- and anti-depressant-like effects of MPEP, a potent, selective and systemically active mGlu5 receptor antagonist. Br J Pharmacol 132:1423–1430

    CAS  PubMed  Google Scholar 

  • Watkins SS, Epping-Jordan MP, Koob GF, Markou A (1999) Blockade of nicotine self-administration with nicotinic antagonists in rats. Pharmacol Biochem Behav 62(4):743–751

    Article  Google Scholar 

  • Winer BJ (1971) Statistical principles in experimental design, 2nd edn. McGraw-Hill, New York

    Google Scholar 

  • Wojnicki FH, Rothman RB, Rice KC, Glowa JR (1999) Effect of phentermine on responding maintained under multiple fixed-ratio schedules of food and cocaine presentation in the rhesus monkey. J Pharmacol Exp Ther 288(2):550–560

    Google Scholar 

  • Woolverton WL (1986) Effects of a D1 and a D2 dopamine antagonist on the self-administration of cocaine and pirebedil by rhesus monkeys. Pharmacol Biochem Behav 24(3):531–535

    Article  Google Scholar 

Download references

Acknowledgements

This is publication number 16539-NP from The Scripps Research Institute. The authors thank Michael Arends for editorial assistance. This work was supported by NIDA grant DA11946 and a Novartis Research Grant to A.M.

Author information

Authors and Affiliations

  1. Department of Neuropharmacology, CVN-7, The Scripps Research Institute, 10550 North Torrey Pines Rd., La Jolla, CA, 92037, USA

    Neil E. Paterson & Athina Markou

Authors
  1. Neil E. Paterson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Athina Markou
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Athina Markou.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Paterson, N.E., Markou, A. The metabotropic glutamate receptor 5 antagonist MPEP decreased break points for nicotine, cocaine and food in rats. Psychopharmacology 179, 255–261 (2005). https://doi.org/10.1007/s00213-004-2070-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-004-2070-9

Keywords

Search

Navigation