Skip to main content

Advertisement

Log in

Examination of a role for metabotropic glutamate receptor 5 in the medial prefrontal cortex in cocaine sensitization in rats

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

Abstract

Rationale

Glutamatergic projection neurons in the medial prefrontal cortex (mPFC) are hyperexcitable in cocaine-sensitized animals, resulting in increased excitatory output to addiction-associated regions such as the ventral tegmental area (VTA) and nucleus accumbens. Evidence suggests that Group I metabotropic glutamate receptor 5 (mGluR5) is necessary for cocaine sensitization, and stimulation of this receptor in the mPFC potentially alters cell excitability directly through glutamate release or indirectly through downstream signaling cascades.

Objectives and methods

Experiments in this report examined the role of mPFC mGluR5 in behavioral sensitization to cocaine. Group I mGluR agonist dihydroxyphenylglycine (DHPG) (15 nmol/side), mGluR5 antagonist 3((2-methyl-4-thiazolyl)ethynyl)pyridine (MTEP) (15 nmol/side), mGluR1 antagonist YM298198 (15 nmol/side), AMPA receptor antagonist CNQX (1 nmol/side), and/or saline were administered through cannulae implanted 1 mm above the mPFC and/or VTA in male rats. Cocaine (15 mg/kg, i.p.) was systemically administered for four consecutive days to induce sensitization and/or once on test day immediately preceding locomotor monitoring.

Results

Intra-mPFC DHPG induced an mGluR5-mediated cross-sensitization to cocaine preventable through the prior administration of an AMPA receptor antagonist in the VTA. Furthermore, mGluR5 blockade in the mPFC failed to prevent the initiation of sensitization. However, intra-mPFC injections of the mGluR5 antagonist MTEP prevented the expression of cocaine sensitization at 21, but not 7, days following daily cocaine injections suggesting a possible role for mPFC mGluR5 in the persistence of the cocaine-sensitized state.

Conclusions

These data suggest that stimulation of mGluR5s in the mPFC is sufficient to induce cocaine sensitization and is necessary for the expression of this sensitized response.

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

Access this article

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
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  • Bandrowski AE, Huguenard JR, Prince DA (2003) Baseline glutamate levels affect group I and II mGluRs in layer V pyramidal neurons of rat sensorimotor cortex. J Neurophysiol 89:1308–1316

    Article  PubMed  CAS  Google Scholar 

  • Beyer CE, Steketee JD (2002) Cocaine sensitization: modulation by dopamine D2 receptors. Cereb Cortex 12:526–535

    Article  PubMed  Google Scholar 

  • Bowers MS, McFarland K, Lake RW, Peterson YK, Lapish CC, Gregory ML, Lanier SM, Kalivas PW (2004) Activator of G protein signaling 3: a gatekeeper of cocaine sensitization and drug seeking. Neuron 42:269–281

    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 

  • Cornish JL, Kalivas PW (2001) Repeated cocaine administration into the rat ventral tegmental area produces behavioral sensitization to a systemic cocaine challenge. Behav Brain Res 126:205–209

    Article  PubMed  CAS  Google Scholar 

  • D’Esposito M, Chen AJ (2006) Neural mechanisms of prefrontal cortical function: implications for cognitive rehabilitation. Prog Brain Res 157:123–139

    Article  PubMed  Google Scholar 

  • Dunn JM, Inderwies BR, Licata SC, Pierce RC (2005) Repeated administration of AMPA or a metabotropic glutamate receptor agonist into the rat ventral tegmental area augments the subsequent behavioral hyperactivity induced by cocaine. Psychopharmacology (Berl) 179:172–180

    Article  CAS  Google Scholar 

  • Fitzgerald LW, Ortiz J, Hamedani AG, Nestler EJ (1996) Drugs of abuse and stress increase the expression of GluR1 and NMDAR1 glutamate receptor subunits in the rat ventral tegmental area: common adaptations among cross-sensitizing agents. J Neurosci 16:274–282

    PubMed  CAS  Google Scholar 

  • Ford KA, Wolf ME, Hu XT (2009) Plasticity of L-type Ca2+ channels after cocaine withdrawal. Synapse 63:690–697

    Article  PubMed  CAS  Google Scholar 

  • Fukunaga I, Yeo CH, Batchelor AM (2007) Potent and specific actions of the mGlu1 antagonists YM298198 and JNJ16259685 on synaptic transmission in rat cerebellar slices. Br J Pharmacol 151:870–876

    Article  PubMed  CAS  Google Scholar 

  • Giorgetti M, Hotsenpiller G, Ward P, Teppen T, Wolf ME (2001) Amphetamine-induced plasticity of AMPA receptors in the ventral tegmental area: effects on extracellular levels of dopamine and glutamate in freely moving rats. J Neurosci 21:6362–6369

    PubMed  CAS  Google Scholar 

  • Homayoun H, Moghaddam B (2010) Group 5 metabotropic glutamate receptors: role in modulating cortical activity and relevance to cognition. Eur J Pharmacol 639:33–39

    Article  PubMed  CAS  Google Scholar 

  • Huang CC, Lin HJ, Hsu KS (2007) Repeated cocaine administration promotes long-term potentiation induction in rat medial prefrontal cortex. Cereb Cortex 17:1877–1888

    Article  PubMed  Google Scholar 

  • Kalivas PW, Alesdatter JE (1993) Involvement of N-methyl-d-aspartate receptor stimulation in the ventral tegmental area and amygdala in behavioral sensitization to cocaine. J Pharmacol Exp Ther 267:486–495

    PubMed  CAS  Google Scholar 

  • Kalivas PW, Duffy P (1998) Repeated cocaine administration alters extracellular glutamate in the ventral tegmental area. J Neurochem 70:1497–1502

    Article  PubMed  CAS  Google Scholar 

  • Kalivas PW, Pierce RC, Cornish J, Sorg BA (1998) A role for sensitization in craving and relapse in cocaine addiction. J Psychopharmacol 12:49–53

    Article  PubMed  CAS  Google Scholar 

  • Kenny PJ, Paterson NE, Boutrel B, Semenova S, Harrison AA, Gasparini F, Koob GF, Skoubis PD, Markou A (2003) Metabotropic glutamate 5 receptor antagonist MPEP decreased nicotine and cocaine self-administration but not nicotine and cocaine-induced facilitation of brain reward function in rats. Ann N Y Acad Sci 1003:415–418

    Article  PubMed  CAS  Google Scholar 

  • Kew JN, Kemp JA (2005) Ionotropic and metabotropic glutamate receptor structure and pharmacology. Psychopharmacology (Berl) 179:4–29

    Article  CAS  Google Scholar 

  • Kuhar MJ, Ritz MC, Boja JW (1991) The dopamine hypothesis of the reinforcing effects of cocaine. Trends Neurosci 14:299–302

    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 

  • Lea PM, Faden AL (2006) Metabotropic glutamate receptor subtype 5 antagonists MPEP and MTEP. CNS Drug Rev 12:149–166

    Google Scholar 

  • Li Y, Hu XT, Berney TG, Vartanian AJ, Stine CD, Wolf ME, White FJ (1999) Both glutamate receptor antagonists and prefrontal cortex lesions prevent induction of cocaine sensitization and associated neuroadaptations. Synapse 34:169–180

    Article  PubMed  CAS  Google Scholar 

  • Liu K, Steketee JD (2011) Repeated exposure to cocaine alters medial prefrontal cortex dopamine D(2)-like receptor modulation of glutamate and dopamine neurotransmission within the mesocorticolimbic system. J Neurochem 119:332–341

    Article  PubMed  CAS  Google Scholar 

  • Marek GJ, Zhang C (2008) Activation of metabotropic glutamate 5 (mGlu5) receptors induces spontaneous excitatory synaptic currents in layer V pyramidal cells of the rat prefrontal cortex. Neurosci Lett 442:239–243

    Article  PubMed  CAS  Google Scholar 

  • Melendez RI, Kalivas PW (2003) Metabotropic glutamate receptor regulation of extracellular glutamate levels in the prefrontal cortex. Ann N Y Acad Sci 1003:443–444

    Article  PubMed  Google Scholar 

  • Milliken GA, Johnson DE (1984) Analysis of messy data, vol. 1 Designed experiments. Lifetime Learning, Toronto, pp 326–337

    Google Scholar 

  • Nasif FJ, Hu XT, White FJ (2005) Repeated cocaine administration increases voltage-sensitive calcium currents in response to membrane depolarization in medial prefrontal cortex pyramidal neurons. J Neurosci 25:3674–3679

    Article  PubMed  CAS  Google Scholar 

  • Nestler EJ (2005) The neurobiology of cocaine addiction. Sci Pract Perspect 3:4–10

    Article  PubMed  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Paxinos G, Watson C (1997) The rat brain in stereotaxic coordiantes, 3rd edn. Academic Press, New York

    Google Scholar 

  • Pierce RC, Reeder DC, Hicks J, Morgan ZR, Kalivas PW (1998) Ibotenic acid lesions of the dorsal prefrontal cortex disrupt the expression of behavioral sensitization to cocaine. Neuroscience 82:1103–1114

    Article  PubMed  CAS  Google Scholar 

  • Robinson TE, Berridge KC (1993) The neural basis of drug craving: an incentive-sensitization theory of addiction. Brain Res Brain Res Rev 18:247–291

    Article  PubMed  CAS  Google Scholar 

  • Seamans JK, Yang CR (2004) The principal features and mechanisms of dopamine modulation in the prefrontal cortex. Prog Neurobiol 74:1–58

    Article  PubMed  CAS  Google Scholar 

  • Steketee JD (1998) Repeated injection of GBR 12909, but not cocaine or WIN 35,065-2, into the ventral tegmental area induces behavioral sensitization. Behav Brain Res 97:39–48

    Article  PubMed  CAS  Google Scholar 

  • Steketee JD (2005) Cortical mechanisms of cocaine sensitization. Crit Rev Neurobiol 17:69–86

    PubMed  CAS  Google Scholar 

  • Steketee JD, Beyer CE (2005) Injections of baclofen into the ventral medial prefrontal cortex block the initiation, but not the expression, of cocaine sensitization in rats. Psychopharmacology (Berl) 180:352–358

    Article  CAS  Google Scholar 

  • Steketee JD, Kalivas PW (2011) Drug wanting: behavioral sensitization and relapse to drug-seeking behavior. Pharmacol Rev 63:348–365

    Article  PubMed  CAS  Google Scholar 

  • Titley HK, Heskin-Sweezie R, Broussard DM (2010) The bidirectionality of motor learning in the vestibulo-ocular reflex is a function of cerebellar mGluR1 receptors. J Neurophysiol 104:3657–3666

    Article  PubMed  CAS  Google Scholar 

  • Torregrossa MM, Tang XC, Kalivas PW (2008) The glutamatergic projection from the prefrontal cortex to the nucleus accumbens core is required for cocaine-induced decreases in ventral pallidal GABA. Neurosci Lett 438:142–145

    Article  PubMed  CAS  Google Scholar 

  • Williams JM, Steketee JD (2004) Cocaine increases medial prefrontal cortical glutamate overflow in cocaine-sensitized rats: a time course study. Eur J Neurosci 20:1639–1646

    Article  PubMed  Google Scholar 

  • Williams JM, Steketee JD (2005) Time-dependent effects of repeated cocaine administration on dopamine transmission in the medial prefrontal cortex. Neuropharmacology 48:51–61

    Article  PubMed  CAS  Google Scholar 

  • Wisniewski K, Car H (2002) (S)-3,5-DHPG: a review. CNS Drug Rev 8:101–116

    Article  PubMed  CAS  Google Scholar 

  • Xie X, Steketee JD (2008) Repeated exposure to cocaine alters the modulation of mesocorticolimbic glutamate transmission by medial prefrontal cortex Group II metabotropic glutamate receptors. J Neurochem 107:186–196

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

All research efforts were financially supported by a grant from the National Institute on Drug Abuse (DA023215).

Conflicts of interest

The authors state no conflict of interest.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Kristin M. Timmer.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Timmer, K.M., Steketee, J.D. Examination of a role for metabotropic glutamate receptor 5 in the medial prefrontal cortex in cocaine sensitization in rats. Psychopharmacology 221, 91–100 (2012). https://doi.org/10.1007/s00213-011-2548-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-011-2548-1

Keywords

Navigation