Skip to main content

Advertisement

SpringerLink
Log in

Attenuation of reinstatement of methamphetamine-, sucrose-, and food-seeking behavior in rats by fenobam, a metabotropic glutamate receptor 5 negative allosteric modulator

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

Abstract

Rationale

Methamphetamine (METH) is a highly potent and addictive psychostimulant with severe detrimental effects to the health of users. Currently, METH addiction is treated with a combination of cognitive and behavioral therapies, but these traditional approaches suffer from high relapse rates. Furthermore, there are currently no pharmacological treatment interventions approved by the FDA specifically for the treatment of METH addiction.

Objectives

Metabotropic glutamate receptor 5 (mGluR5) negative allosteric modulators (NAMs) have shown promise in significantly attenuating drug self-administration and drug-seeking in reinstatement paradigms. However, studies assessing the potential efficacy of mGluR5 NAMs that have been tested in human subjects are lacking. The current study sought to assess the effect of the mGluR5 NAM fenobam on METH-seeking behavior.

Methods

Rats were trained to self-administer METH (0.05 mg/kg i.v.), and following extinction, tested for effects of fenobam (5, 10, or 15 mg/kg intraperitoneal) on cue- and drug-induced reinstatement of METH-seeking. To determine if fenobam also alters reinstatement of seeking of natural reinforcers, separate groups of rats were trained to self-administer sucrose or food pellets and were tested for the effects of fenobam on cue-induced reinstatement of sucrose- and food-seeking.

Results

Fenobam attenuated drug- and cue-induced reinstatement of METH-seeking behavior at doses of 10 and 15 mg/kg. Fenobam also attenuated cue-induced reinstatement of sucrose- and food-seeking at all doses tested.

Conclusions

The mGluR5 NAM fenobam attenuates the reinstatement of METH-seeking behavior, but these effects may be due to nonspecific suppression of general appetitive behaviors.

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.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  • Anglin MD, Burke C, Perrochet B, Stamper E, Dawud-Noursi S (2000) History of the methamphetamine problem. J Psychoactive Drugs 32:137–141

    Article  PubMed  CAS  Google Scholar 

  • Backstrom P, Hyytia P (2007) Involvement of AMPA/kainate, NMDA, and mGlu5 receptors in the nucleus accumbens core in cue-induced reinstatement of cocaine seeking in rats. Psychopharmacology (Berl) 192:571–580

    Article  Google Scholar 

  • Berry-Kravis EM, Hessl D, Coffey S, Hervey C, Schneider A, Yuhas J, Hutchison J, Snape M, Tranfaglia M, Nguyen DV, Hagerman R (2009) A pilot open-label single-dose trial of fenobam in adults with fragile X syndrome. J Med Genet 46:266–271

    Article  PubMed  CAS  Google Scholar 

  • Bradbury MJ, Campbell U, Giracello D, Chapman D, King C, Tehrani L, Cosford ND, Anderson J, Varney MA, Strack AM (2005) Metabotropic glutamate receptor mGlu5 is a mediator of appetite and energy balance in rats and mice. J Pharmacol Exp Ther 313:395–402

    Article  PubMed  CAS  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 4:873–874

    Article  PubMed  CAS  Google Scholar 

  • Ciccarone D (2011) Stimulant abuse: pharmacology, cocaine, methamphetamine, treatment, attempts at pharmacotherapy. Prim Care 38:41–58

    Article  PubMed  Google Scholar 

  • Cleva RM, Watterson LR, Johnson MA, Olive MF (2012) Differential modulation of thresholds for intracranial self-stimulation by mGlu5 positive and negative allosteric modulators: implications for effects on drug self-administration. Front Pharmacol 2(1–7):93

    PubMed  Google Scholar 

  • Conn PJ, Pin J-P (1997) Pharmacology and functions of metabotropic glutamate receptors. Annu Rev Pharmacol Toxicol 37:205–237

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Cruickshank CC, Dyer KR (2009) A review of the clinical pharmacology of methamphetamine. Addiction 104:1085–1099

    Article  PubMed  Google Scholar 

  • Darke S, Kaye S, McKetin R, Duflou J (2008) Major physical and psychological harms of methamphetamine use. Drug Alcohol Rev 27:253–262

    Article  PubMed  Google Scholar 

  • Di Ciano P, Cardinal RN, Cowell RA, Little SJ, Everitt BJ (2001) Differential involvement of NMDA, AMPA/kainate, and dopamine receptors in the nucleus accumbens core in the acquisition and performance of Pavlovian approach behavior. J Neurosci 21:9471–9477

    PubMed  Google Scholar 

  • Duncan JR, Lawrence AJ (2012) The role of metabotropic glutamate receptors in addiction: evidence from preclinical models. Pharmacol Biochem Behav 100:811–824

    Article  PubMed  CAS  Google Scholar 

  • Eiler WJ 2nd, Baez M, Yu J, Witkin JM (2011) mGlu5 receptor deletion reduces relapse to food-seeking and prevents the anti-relapse effects of mGlu5 receptor blockade in mice. Life Sci 89:862–867

    Article  PubMed  CAS  Google Scholar 

  • Gass JT, Olive MF (2008) Glutamatergic substrates of drug addiction and alcoholism. Biochem Pharmacol 75:218–265

    Article  PubMed  CAS  Google Scholar 

  • Gass JT, Osborne MP, Watson NL, Brown JL, Olive MF (2009) mGluR5 antagonism attenuates methamphetamine reinforcement and prevents reinstatement of methamphetamine-seeking behavior in rats. Neuropsychopharmacology 34:820–833

    Article  PubMed  CAS  Google Scholar 

  • Gormley S, Rompre PP (2011) Blockade of mGluR5 receptors differentially alters amphetamine-induced enhancement of locomotor activity and of brain stimulation reward. J Psychopharmacol 25:393–401

    Article  PubMed  CAS  Google Scholar 

  • Hagerman R, Berry-Kravis E, Hessl D, Coffey S, Schneider A, Nguyen D, Hervey C, Hutchison J, Snape M (2008) Trial of fenobam, an mGluR5 antagonist, in adults with Fragile X syndrome. J Intellect Disabil Res 52:814

    Article  Google Scholar 

  • Harrison AA, Gasparini F, Markou A (2002) Nicotine potentiation of brain stimulation reward reversed by DHbE and SCH 23390, but not by eticlopride, LY 314582 or MPEP in rats. Psychopharmacology (Berl) 160:56–66

    Article  CAS  Google Scholar 

  • Itil TM, Seaman PA, Huque M, Mukhopadhyay S, Blasucci D, Tat K, Ciccone PE (1978) The clinical and quantitative EEG effects and plasma levels of fenobam (McN-3377) in subjects with anxiety: an open rising dose tolerance and efficacy study. Curr Ther Res 24:708–724

    Google Scholar 

  • Ito K, Abekawa T, Koyama T (2006) Relationship between development of cross-sensitization to MK-801 and delayed increases in glutamate levels in the nucleus accumbens induced by a high dose of methamphetamine. Psychopharmacology (Berl) 187:293–302

    Article  CAS  Google Scholar 

  • Jacob W, Gravius A, Pietraszek M, Nagel J, Belozertseva I, Shekunova E, Malyshkin A, Greco S, Barberi C, Danysz W (2009) The anxiolytic and analgesic properties of fenobam, a potent mGlu5 receptor antagonist, in relation to the impairment of learning. Neuropharmacology 57:97–108

    Article  PubMed  CAS  Google Scholar 

  • Jaeschke G, Porter R, Buttelmann B, Ceccarelli SM, Guba W, Kuhn B, Kolczewski S, Huwyler J, Mutel V, Peters JU, Ballard T, Prinssen E, Vieira E, Wichmann J, Spooren W (2007) Synthesis and biological evaluation of fenobam analogs as mGlu5 receptor antagonists. Bioorg Med Chem Lett 17:1307–1311

    Article  PubMed  CAS  Google Scholar 

  • Jaeschke G, Wettstein JG, Nordquist RE, Spooren W (2008) mGlu5 receptor antagonists and their therapeutic potential. Exp Opin Ther Patents 18:123–142

    Article  CAS  Google Scholar 

  • Kalivas PW, McFarland K (2003) Brain circuitry and the reinstatement of cocaine-seeking behavior. Psychopharmacology (Berl) 168:44–56

    Article  CAS  Google Scholar 

  • Kalivas PW, Volkow ND (2011) New medications for drug addiction hiding in glutamatergic neuroplasticity. Mol Psychiatry 16:974–986

    Article  PubMed  CAS  Google Scholar 

  • Kalivas PW, Volkow N, Seamans J (2005) Unmanageable motivation in addiction: a pathology in prefrontal-accumbens glutamate transmission. Neuron 45:647–650

    Article  PubMed  CAS  Google Scholar 

  • Karila L, Weinstein A, Aubin HJ, Benyamina A, Reynaud M, Batki SL (2010) Pharmacological approaches to methamphetamine dependence: a focused review. Br J Clin Pharmacol 69:578–592

    Article  PubMed  CAS  Google Scholar 

  • Kenny PJ, Markou A (2004) The ups and downs of addiction: role of metabotropic glutamate receptors. Trends Pharmacol Sci 25:265–272

    Article  PubMed  CAS  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 306:1068–1076

    Article  PubMed  CAS  Google Scholar 

  • Kenny PJ, Boutrel B, Gasparini F, Koob GF, Markou A (2005) Metabotropic glutamate 5 receptor blockade may attenuate cocaine self-administration by decreasing brain reward function in rats. Psychopharmacology (Berl) 179:247–254

    Article  CAS  Google Scholar 

  • Kish SJ (2008) Pharmacologic mechanisms of crystal meth. Can Med Assoc J 178:1679–1682

    Article  Google Scholar 

  • Knackstedt LA, Kalivas PW (2009) Glutamate and reinstatement. Curr Opin Pharmacol 9:59–64

    Article  PubMed  CAS  Google Scholar 

  • Kumaresan V, Yuan M, Yee J, Famous KR, Anderson SM, Schmidt HD, Pierce RC (2009) Metabotropic glutamate receptor 5 (mGluR5) antagonists attenuate cocaine priming- and cue-induced reinstatement of cocaine seeking. Behav Brain Res 202:238–244

    Article  PubMed  CAS  Google Scholar 

  • Lalumiere RT, Kalivas PW (2008) Glutamate release in the nucleus accumbens core is necessary for heroin seeking. J Neurosci 28:3170–3177

    Article  PubMed  CAS  Google Scholar 

  • Mark KA, Quinton MS, Russek SJ, Yamamoto BK (2007) Dynamic changes in vesicular glutamate transporter 1 function and expression related to methamphetamine-induced glutamate release. J Neurosci 27:6823–6831

    Article  PubMed  CAS  Google Scholar 

  • Maxwell JC, Brecht ML (2011) Methamphetamine: here we go again? Addict Behav 36:1168–1173

    Article  PubMed  Google Scholar 

  • Maxwell JC, Rutkowski BA (2008) The prevalence of methamphetamine and amphetamine abuse in North America: a review of the indicators, 1992–2007. Drug Alcohol Rev 27:229–235

    Article  PubMed  Google Scholar 

  • Mitrano DA, Smith Y (2007) Comparative analysis of the subcellular and subsynaptic localization of mGluR1a and mGluR5 metabotropic glutamate receptors in the shell and core of the nucleus accumbens in rat and monkey. J Comp Neurol 500:788–806

    Article  PubMed  CAS  Google Scholar 

  • Montana MC, Cavallone LF, Stubbert KK, Stefanescu AD, Kharasch ED, Gereau RW (2009) The metabotropic glutamate receptor subtype 5 antagonist fenobam is analgesic and has improved in vivo selectivity as compared to the prototypical antagonist 2-methyl-6-(phenylethynyl)-pyridine. J Pharmacol Exp Ther 330:834–843

    Article  PubMed  CAS  Google Scholar 

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

  • Olive MF (2009) Metabotropic glutamate receptor ligands as potential therapeutics for drug addiction. Curr Drug Abuse Rev 2:83–98

    Article  PubMed  CAS  Google Scholar 

  • Olive MF, Cleva RM, Kalivas PW, Malcolm RJ (2012) Glutamatergic medications for the treatment of drug and behavioral addictions. Pharmacol Biochem Behav 100:801–810

    Article  PubMed  CAS  Google Scholar 

  • Osborne MPH, Olive MF (2008) A role for mGluR5 receptors in intravenous methamphetamine self-administration. Ann N Y Acad Sci 1139:206–211

    Article  PubMed  CAS  Google Scholar 

  • Paterson NE, Markou A (2005) The metabotropic glutamate receptor 5 antagonist MPEP decreased break points for nicotine, cocaine and food in rats. Psychopharmacology (Berl) 179:255–261

    Article  CAS  Google Scholar 

  • Pecknold JC, McClure DJ, Appeltauer L (1980) Fenobam in anxious outpatients. Curr Ther Res 27:119–123

    Google Scholar 

  • Pecknold JC, McClure DJ, Appeltauer L, Wrzesinski L, Allan T (1982) Treatment of anxiety using fenobam (a nonbenzodiazepine) in a double-blind standard (diazepam) placebo-controlled study. J Clin Psychopharmacol 2:129–133

    Article  PubMed  CAS  Google Scholar 

  • Pin JP, Duvoisin R (1995) The metabotropic glutamate receptors: structure and functions. Neuropharmacology 34:1–26

    Article  PubMed  CAS  Google Scholar 

  • Porter RH, Jaeschke G, Spooren W, Ballard T, Buettelmann B, Kolczewski S, Peters JU, Prinssen E, Wichmann J, Vieira E, Muehlemann A, Gatti S, Mutel V, Malherbe P (2005) Fenobam: a clinically validated non-benzodiazepine anxiolytic is a potent, selective and non-competitive mGlu5 receptor antagonist with inverse agonist activity. J Pharmacol Exp Ther 315:711–721

    Article  PubMed  CAS  Google Scholar 

  • Rocher C, Gardier AM (2001) Effects of repeated systemic administration of d-fenfluramine on serotonin and glutamate release in rat ventral hippocampus: comparison with methamphetamine using in vivo microdialysis. Naunyn Schmiedeberg’s Arch Pharmacol 363:422–428

    Article  CAS  Google Scholar 

  • Romano C, Sesma MA, McDonald CT, O'Malley K, Van den Pol AN, Olney JW (1995) Distribution of metabotropic glutamate receptor mGluR5 immunoreactivity in rat brain. J Comp Neurol 355:455–469

    Article  PubMed  CAS  Google Scholar 

  • Rusyniak DE (2011) Neurologic manifestations of chronic methamphetamine abuse. Neurol Clin 29:641–655

    Article  PubMed  Google Scholar 

  • Scott JC, Woods SP, Matt GE, Meyer RA, Heaton RK, Atkinson JH, Grant I (2007) Neurocognitive effects of methamphetamine: a critical review and meta-analysis. Neuropsychol Rev 17:275–297

    Article  PubMed  Google Scholar 

  • Shigemoto R, Nomura S, Ohishi H, Sugihara H, Nakanishi S, Mizuno N (1993) Immunohistochemical localization of a metabotropic glutamate receptor, mGluR5, in the rat brain. Neurosci Lett 163:53–57

    Article  PubMed  CAS  Google Scholar 

  • Shoblock JR, Sullivan EB, Maisonneuve IM, Glick SD (2003) Neurochemical and behavioral differences between d-methamphetamine and d-amphetamine in rats. Psychopharmacology (Berl) 165:359–369

    CAS  Google Scholar 

  • Shrem MT, Halkitis PN (2008) Methamphetamine abuse in the United States: contextual, psychological and sociological considerations. J Health Psychol 13:669–679

    Article  PubMed  Google Scholar 

  • Sinclair CM, Cleva RM, Hood LE, Olive MF, Gass JT (2012) mGluR5 receptors in the basolateral amygdala and nucleus accumbens regulate cue-induced reinstatement of ethanol-seeking behavior. Pharmacol Biochem Behav 101:329–335

    Article  PubMed  CAS  Google Scholar 

  • Stephans SE, Yamamoto BY (1995) Effect of repeated methamphetamine administrations on dopamine and glutamate efflux in rat prefrontal cortex. Brain Res 700:99–106

    Article  PubMed  CAS  Google Scholar 

  • Sulzer D (2011) How addictive drugs disrupt presynaptic dopamine neurotransmission. Neuron 69:628–649

    Article  PubMed  CAS  Google Scholar 

  • Vocci FJ, Appel NM (2007) Approaches to the development of medications for the treatment of methamphetamine dependence. Addiction 102(suppl 1):96–106

    Article  PubMed  Google Scholar 

  • Zhang Y, Loonam TM, Noailles PA, Angulo JA (2001) Comparison of cocaine- and methamphetamine-evoked dopamine and glutamate overflow in somatodendritic and terminal field regions of the rat brain during acute, chronic, and early withdrawal conditions. Ann N Y Acad Sci 937:93–120

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by Public Health Service grant DA025606 from the National Institute on Drug Abuse. All experimental procedures conducted were performed in compliance with the current laws of USA.

Conflict of interest

All authors have no conflicts of interest to declare.

Author information

Authors and Affiliations

  1. Department of Psychology, Arizona State University, PO Box 871104, 950 S McAllister Avenue, Tempe, AZ, 85287, USA

    Lucas R. Watterson, Peter R. Kufahl, Natali E. Nemirovsky, Kaveish Sewalia, Lauren E. Hood & M. Foster Olive

Authors
  1. Lucas R. Watterson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Peter R. Kufahl
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Natali E. Nemirovsky
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kaveish Sewalia
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lauren E. Hood
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M. Foster Olive
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M. Foster Olive.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Watterson, L.R., Kufahl, P.R., Nemirovsky, N.E. et al. Attenuation of reinstatement of methamphetamine-, sucrose-, and food-seeking behavior in rats by fenobam, a metabotropic glutamate receptor 5 negative allosteric modulator. Psychopharmacology 225, 151–159 (2013). https://doi.org/10.1007/s00213-012-2804-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-012-2804-z

Keywords

Search

Navigation