Skip to main content
SpringerLink
Log in

Intra-median raphe nucleus (MRN) infusions of muscimol, a GABA-A receptor agonist, reinstate alcohol seeking in rats: role of impulsivity and reward

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

An Erratum to this article was published on 13 November 2007

Abstract

Rationale and objectives

We previously found that the inhibition of median raphe nucleus (MRN) 5-HT transmission by local injections of a 5-HT1A agonist 8-OH-DPAT or corticotrophin-releasing factor (CRF) mimic the effect of foot shock stress to reinstate alcohol seeking. In this study, we further explored the role of the MRN by examining the effect of inhibition of MRN neurons, by injecting the GABA-A receptor agonist muscimol, on the reinstatement of alcohol seeking.

Materials and methods

Male rats were trained to lever press for 12% alcohol. Cannulae were implanted aimed at the MRN; some rats were also given intra-MRN injections of 5,7-DHT to destroy ascending 5-HT neurons. After retraining, alcohol responding was extinguished for 14 days. Subsequently, we tested the effect of muscimol injections into the MRN (0, 12.5, 25, 50 ng) on reinstatement. We also tested the effect of MRN muscimol injections on a measure of reward, conditioned place preference (CPP) and performance in the five-choice serial reaction time task (5-CSRTT), which tests a variety of psychological processes including sustained attention and impulsivity.

Results

MRN muscimol injections strongly reinstated alcohol seeking and this effect was not reversed by the depletion of 5-HT with 5,7-DHT. MRN muscimol injections did not induce a CPP, but did significantly impair multiple aspects of performance on the 5-CSRTT, including a marked increase in premature, or impulsive, responding.

Conclusions

Together with our previous findings, these results suggest that the inhibition of MRN projection neurons provokes alcohol seeking. Results from the 5-CSRTT suggest that increased impulsivity may contribute to these effects.

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

  • Amitai N, Semenova S, Markou A (2007) Cognitive-disruptive effects of the psychotomimetic phencyclidine and attenuation by atypical antipsychotic medications in rats. Psychopharmacology (Berl) 193:521–537

    Article  CAS  Google Scholar 

  • Aznar S, Qian ZX, Knudsen GM (2004) Non-serotonergic dorsal and median raphe projection onto parvalbumin- and calbindin-containing neurons in hippocampus and septum. Neuroscience 124:573–581

    Article  PubMed  CAS  Google Scholar 

  • Carli M, Samanin R (2000) The 5-HT(1A) receptor agonist 8-OH-DPAT reduces rats’ accuracy of attentional performance and enhances impulsive responding in a five-choice serial reaction time task: role of presynaptic 5-HT(1A) receptors. Psychopharmacology (Berl) 149:259–268

    Article  CAS  Google Scholar 

  • Currie PJ, Fletcher PJ, Coscina DV (1994) Administration of 8-OH-DPAT into the midbrain raphe nuclei: effects on medial hypothalamic NE-induced feeding. Am J Physiol 266:R1645–R1651

    PubMed  CAS  Google Scholar 

  • Fletcher PJ (1991) Dopamine receptor blockade in nucleus accumbens or caudate nucleus differentially affects feeding induced by 8-OH-DPAT injected into dorsal or median raphe. Brain Res 552:181–189

    Article  PubMed  CAS  Google Scholar 

  • Fletcher PJ (1993) A comparison of the effects of dorsal and median raphe injections of 8-OH-DPAT in three operant tasks measuring response inhibition. Behav Brain Res 54:187–197

    Article  PubMed  CAS  Google Scholar 

  • Fletcher PJ (1994) Effects of 8-OH-DPAT, 5-CT and muscimol on behaviour maintained by a DRL20 schedule of reinforcement, following microinjection into the dorsal or median raphe nuclei. Behav Pharmacol 5:326–336

    Article  PubMed  CAS  Google Scholar 

  • Fletcher PJ (1995) Effects of combined or separate 5,7-dihydroxytryptamine lesions of the dorsal and median raphe nuclei on responding maintained by a DRL 20 s schedule of food reinforcement. Brain Res 675:45–54

    Article  PubMed  CAS  Google Scholar 

  • Fletcher PJ, Ming ZH, Higgins GA (1993) Conditioned place preference induced by microinjection of 8-OH-DPAT into the dorsal or median raphe nucleus. Psychopharmacology (Berl) 113:31–36

    Article  CAS  Google Scholar 

  • Funk D, Li Z, Fletcher PJ, Le AD (2005) Effects of injections of 8-hydroxy-2-(di-n-propylamino)tetralin or muscimol in the median raphe nucleus on c-fos mRNA in the rat brain. Neuroscience 131:475–479

    Article  PubMed  CAS  Google Scholar 

  • Gobert A, Lejeune F, Rivet JM, Audinot V, Newman-Tancredi A, Millan MJ (1995) Modulation of the activity of central serotoninergic neurons by novel serotonin1A receptor agonists and antagonists: a comparison to adrenergic and dopaminergic neurons in rats. J Pharmacol Exp Ther 273:1032–1046

    PubMed  CAS  Google Scholar 

  • Harrison AA, Everitt BJ, Robbins TW (1997) Central 5-HT depletion enhances impulsive responding without affecting the accuracy of attentional performance: interactions with dopaminergic mechanisms. Psychopharmacology (Berl) 133:329–342

    Article  CAS  Google Scholar 

  • Higgins GA, Enderlin M, Haman M, Fletcher PJ (2003) The 5-HT2A receptor antagonist M100,907 attenuates motor and ‘impulsive-type’ behaviours produced by NMDA receptor antagonism. Psychopharmacology (Berl) 170:309–319

    Article  CAS  Google Scholar 

  • Highfield D, Clements A, Shalev U, McDonald R, Featherstone R, Stewart J, Shaham Y (2000) Involvement of the medial septum in stress-induced relapse to heroin seeking in rats. Eur J Neurosci 12:1705–1713

    Article  PubMed  CAS  Google Scholar 

  • Hjorth S, Sharp T (1991) Effect of the 5-HT1A receptor agonist 8-OH-DPAT on the release of 5-HT in dorsal and median raphe-innervated rat brain regions as measured by in vivo microdialysis. Life Sci 48:1779–1786

    Article  PubMed  CAS  Google Scholar 

  • Klitenick MA, Wirtshafter D (1988) Comparative studies of the ingestive behaviors produced by microinjections of muscimol into the midbrain raphe nuclei of the ventral tegmental area of the rat. Life Sci 42:775–782

    Article  PubMed  CAS  Google Scholar 

  • Klitenick MA, Wirtshafter D (1989) Elicitation of feeding, drinking, and gnawing following microinjections of muscimol into the median raphe nucleus of rats. Behav Neural Biol 51:436–441

    Article  PubMed  CAS  Google Scholar 

  • Le A, Shaham Y (2002) Neurobiology of relapse to alcohol in rats. Pharmacol Ther 94:137–156

    Article  PubMed  CAS  Google Scholar 

  • Le AD, Quan B, Juzytsch W, Fletcher PJ, Joharchi N, Shaham Y (1998) Reinstatement of alcohol-seeking by priming injections of alcohol and exposure to stress in rats. Psychopharmacology (Berl) 135:169–174

    Article  CAS  Google Scholar 

  • Le AD, Poulos CX, Harding S, Watchus J, Juzytsch W, Shaham Y (1999) Effects of naltrexone and fluoxetine on alcohol self-administration and reinstatement of alcohol seeking induced by priming injections of alcohol and exposure to stress. Neuropsychopharmacology 21:435–444

    Article  PubMed  CAS  Google Scholar 

  • Le AD, Harding S, Juzytsch W, Shaham Y (2000a) Median raphe infusions of the 5-HT1a receptor agonist, 8-OH-DPAT, reinstate alcohol seeking in rats. Soc Neurosci Abstr 26:786

    Google Scholar 

  • Le AD, Harding S, Juzytsch W, Watchus J, Shalev U, Shaham Y (2000b) The role of corticotrophin-releasing factor in stress-induced relapse to alcohol-seeking behavior in rats. Psychopharmacology (Berl) 150:317–324

    Article  CAS  Google Scholar 

  • Le AD, Harding S, Juzytsch W, Fletcher PJ, Shaham Y (2002) The role of corticotropin-releasing factor in the median raphe nucleus in relapse to alcohol. J Neurosci 22:7844–7849

    PubMed  CAS  Google Scholar 

  • Linseman MA (1987) Alcohol consumption in free feeding rats: procedure, genetic and pharmacokinetic factors. Psychopharmacology (Berl) 92:254–261

    Article  CAS  Google Scholar 

  • Liu X, Weiss F (2002) Additive effect of stress and drug cues on reinstatement of ethanol seeking: exacerbation by history of dependence and role of concurrent activation of corticotropin-releasing factor and opioid mechanisms. J Neurosci 22:7856–7861

    PubMed  CAS  Google Scholar 

  • Liu ZH, Ikemoto S (2007) The midbrain raphe nuclei mediate primary reinforcement via GABA(A) receptors. Eur J Neurosci 25:735–743

    Article  PubMed  CAS  Google Scholar 

  • Martin-Fardon R, Ciccocioppo R, Massi M, Weiss F (2000) Nociceptin prevents stress-induced ethanol- but not cocaine-seeking behavior in rats. Neuroreport 11:1939–1943

    Article  PubMed  CAS  Google Scholar 

  • Paxinos G, Watson C (1998) The rat brain in stereotaxic coordinates, 4th edn. Academic, New York

    Google Scholar 

  • Prusky GT, Harker KT, Douglas RM, Whishaw IQ (2002) Variation in visual acuity within pigmented, and between pigmented and albino rat strains. Behav Brain Res 136:339–348

    Article  PubMed  Google Scholar 

  • Robbins TW (2002) The 5-choice serial reaction time task: behavioural pharmacology and functional neurochemistry. Psychopharmacology 163:362–380

    Article  PubMed  CAS  Google Scholar 

  • Semenova S, Markou A (2007) The effects of the mGluR5 antagonist MPEP and the mGluR2/3 antagonist LY341495 on rats’ performance in the 5-choice serial reaction time task. Neuropharmacology 52:863–872

    Article  PubMed  CAS  Google Scholar 

  • Sharp T, Bramwell SR, Hjorth S, Grahame-Smith DG (1989) Pharmacological characterization of 8-OH-DPAT-induced inhibition of rat hippocampal 5-HT release in vivo as measured by microdialysis. Br J Pharmacol 98:989–997

    PubMed  CAS  Google Scholar 

  • Shim I, Javaid J, Wirtshafter D (1997) Dissociation of hippocampal serotonin release and locomotor activity following pharmacological manipulations of the median raphe nucleus. Behav Brain Res 89:191–198

    Article  PubMed  CAS  Google Scholar 

  • Stratford TR, Wirtshafter D (2000) Forebrain lesions differentially affect drinking elicited by dipsogenic challenges and injections of muscimol into the median raphe nucleus. Behav Neurosci 114:760–771

    Article  PubMed  CAS  Google Scholar 

  • Tomkins DM, Sellers EM, Fletcher PJ (1994) Median and dorsal raphe injections of the 5-HT1A agonist, 8-OH-DPAT, and the GABAA agonist, muscimol, increase voluntary ethanol intake in Wistar rats. Neuropharmacology 33:349–358

    Article  PubMed  CAS  Google Scholar 

  • Wirtshafter D, Klitenick MA (1989) Comparative studies of locomotor behavior following microinjections of muscimol into various sites in the paramedian tegmentum. Pharmacol Biochem Behav 32:625–628

    Article  PubMed  CAS  Google Scholar 

  • Wirtshafter D, Klitenick MA, Asin KE (1987) Evidence against serotonin involvement in the hyperactivity produced by injections of muscimol into the median raphe nucleus. Pharmacol Biochem Behav 27:45–52

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by a grant from the NIAAA (AA13108) to A.D. Lê. The authors would like to thank Dr. Yavin Shaham for his expert comments on an earlier version of this manuscript.

Author information

Authors and Affiliations

  1. Department of Neuroscience, Centre for Addiction and Mental Health, 33 Russell Street, Toronto, ON, M5S 2S1, Canada

    Anh Lê Dzung, Douglas Funk, Stephen Harding, Walter Juzytsch, Zhaoxia Li & Paul J. Fletcher

  2. Department of Pharmacology, University of Toronto, Toronto, Canada

    Anh Lê Dzung

  3. Department of Psychiatry, University of Toronto, Toronto, Canada

    Anh Lê Dzung & Paul J. Fletcher

  4. Department of Psychology, University of Toronto, Toronto, Canada

    Paul J. Fletcher

Authors
  1. Anh Lê Dzung
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Douglas Funk
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Stephen Harding
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Walter Juzytsch
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zhaoxia Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Paul J. Fletcher
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Anh Lê Dzung.

Additional information

An erratum to this article can be found at http://dx.doi.org/10.1007/s00213-007-0997-3

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lê Dzung, A., Funk, D., Harding, S. et al. Intra-median raphe nucleus (MRN) infusions of muscimol, a GABA-A receptor agonist, reinstate alcohol seeking in rats: role of impulsivity and reward. Psychopharmacology 195, 605–615 (2008). https://doi.org/10.1007/s00213-007-0943-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-007-0943-4

Keywords

Search

Navigation