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The motivational valence of nicotine in the rat ventral tegmental area is switched from rewarding to aversive following blockade of the α7-subunit-containing nicotinic acetylcholine receptor

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Abstract

Rationale

Within the mammalian ventral tegmental area (VTA), nicotine produces both aversive and rewarding motivational effects. However, the specific neuronal nicotinic acetylcholine receptor (nAChR) subtypes responsible for these effects are not clearly understood.

Objectives

In the present study, we challenged the motivational effects of nicotine directly in the VTA with nAChR subunit specific antagonists.

Methods

Using an unbiased place-conditioning procedure as a behavioural assay, we performed bilateral microinfusions of nicotine over a wide range of concentrations (0.008, 8, 24 and 48 nmol/0.5 μl) and challenged the aversive and reinforcing behavioural effects of these nicotine doses with co-administration of di-hydro-β-erythroidine (DHβE) (5 or 50 nmol/0.5 μl), a nAChR antagonist with higher relative affinity for the α4β2 nAChR subunit, methyllycaconitine citrate (MLA) (0.4 or 4 nmol/0.5 μl), a nAChR antagonist that displays greater relative affinity for the α7 nAChR, and the NMDA receptor antagonist, d-2-amino-7-phosphoheptanoic acid (AP-7; 18 nmol/0.5 μl).

Results

The α4β2 antagonist DHβE blocked both the rewarding and aversive properties of intra-VTA nicotine. However, the α7 antagonist MLA blocked nicotine reward and switched the motivational valence of higher doses of nicotine (8–48 nmol/0.5 μl) from rewarding to aversive. The NMDA antagonist AP-7 blocked both the aversive and rewarding effects of intra-VTA nicotine.

Conclusions

These results suggest a functional dissociation between nAChR neural substrates within the VTA that mediate the bivalent motivational properties of nicotine and further suggest that nicotine may produce its motivational effects through a glutamatergic mechanism.

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References

  • Barazangi N, Role LW (2001) Nicotine-induced enhancement of glutamatergic and GABAergic synaptic transmission in the mouse amygdala. J Neurophysiol 86:463–474

    CAS  PubMed  Google Scholar 

  • Corrigall WA, Coen KM (1994) Self-administered nicotine activates the mesolimbic dopamine system through the ventral tegmental area. Brain Res 653:278–284

    CAS  PubMed  Google Scholar 

  • Corrigall WA, Franklin KBJ, Coen KM, Clark PBS (1992) The mesolimbic dopaminergic system is implicated in the reinforcing effects of nicotine. Psychopharmacology 107:285–289

    CAS  PubMed  Google Scholar 

  • Corrigall WA, Coen KM, Adamson KL, Chow BLC, Zhang J (2000) Response of nicotine self-administration in the rat to manipulations of mu-opioid and γ-aminobuutyric acid receptors in the ventral tegmental area. Psychopharmacology 149:107–114

    CAS  PubMed  Google Scholar 

  • Chavez-Noriega LE, Crona JH, Washburn MS, Urrutia A, Elliot KJ, Johnson EC (1997) Pharmacological characterization of recombinant human neuronal nicotinic acetylcholine receptors α2β2, α2β4, α3β2, α3β4, α4β2, α4β4 and α7 expressed in Xenopus oocytes. J Pharmacol Exp Ther 280:346–356

    PubMed  Google Scholar 

  • Drasdo A, Caulfield M, Betrand D, Wonnacott S (1992) Methyllycaconitine: a novel nicotinic antagonist. Mol Cell Neurosci 3:237–243

    CAS  Google Scholar 

  • Fisher JL, Pidoplichko VI, Dani JA (1998) Nicotine modifies the activity of ventral tegmental area dopaminergic neurons and hippocampal GABAergic neurons. J Physiol 92:209–213

    Article  CAS  Google Scholar 

  • Gommans J, Stolerman IP, Shoaib M (2000) Antagonism of the discriminative and aversive stimulus properties of nicotine in C57BL/6J mice. Neuropharmacology 39:2840–2847

    Article  CAS  PubMed  Google Scholar 

  • Grottick AJ, Trube G, Corrigall WA, Huwyler J, Malherbe P, Wyler R, Higgins GA (2000) Evidence that nicotinic α7 receptors are not involved in the hyperlocomotor and rewarding effects of nicotine. J Pharmacol Exp Ther 294:1112–1119

    CAS  PubMed  Google Scholar 

  • Jones S, Sudweeks S, Yakel JL (1999) Nicotinic receptors in the brain: correlating physiology with function. Trends Neurosci 22:555–561

    Article  CAS  PubMed  Google Scholar 

  • Jorenby DE, Steinpreis RE, Sherman JE, Baker TB (1990) Aversion instead of preference learning indicated by nicotine place conditioning in rats. Psychopharmacology 101:533–538

    CAS  PubMed  Google Scholar 

  • Klink R, de Kerchove d'Exaerde A, Zoli M, Changeux JP (2002) Molecular and physiological diversity of nicotinic acetylcholine receptors in midbrain dopaminergic nuclei. J Neurosci 21:1452–1463

    Google Scholar 

  • Laviolette SR, van der Kooy D (2001) GABAA receptors in the ventral tegmental area control bidirectional reward signaling between dopaminergic and non-dopaminergic neural motivational systems. Eur J Neurosci 13:1009–1015

    Article  CAS  PubMed  Google Scholar 

  • Laviolette SR, van der Kooy D (2003) Blockade of mesolimbic dopamine transmission dramatically potentiates nicotine reward sensitivity in the ventral tegmental area. Mol Psychol (in press)

  • Lundahl LH, Henningfield JE, Lukas SE (2000) Mecamylamine blockade of both positive and negative effects of IV nicotine in human volunteers. Pharmacol Biochem Behav 66:637–643

    CAS  PubMed  Google Scholar 

  • Marks MJ, Whiteaker P, Calcaterra J, Stitzel JA, Bullock AE, Grady SR, Picciotto MR, Changeux JP, Collins AC (1999) Two pharmacologically distinct components of nicotinic receptor-mediated rubidium efflux in mouse brain require the β2 subunit. J Pharmacol Exp Ther 289:1090–1103

    CAS  PubMed  Google Scholar 

  • Markou A, Paterson NE (2001) The nicotinic antagonist methyllycaconitine has differential effects on nicotine self-administration and nicotine withdrawal in the rat. Nicotine Tob Res 3:361–373

    Article  CAS  PubMed  Google Scholar 

  • McGehee DS, Heath MJS, Gelber S, Devay P, Role LW (1995) Nicotine enhancement of fast excitatory synaptic transmission in CNS by presynaptic receptors. Science 269:1692–1696

    CAS  PubMed  Google Scholar 

  • Nader K, van der Kooy D (1997) Deprivation state switches the neurobiological substrates mediating opiate reward in the ventral tegmental area. J Neurosci 17:383–390

    CAS  PubMed  Google Scholar 

  • Paxinos G, Watson C (1986) The rat brain in stereotaxic coordinates, 2nd edn. Academic Press, New York

  • Picciotto MR, Zoli M, Rimodini R, Lena C, Marubio LM, Pich EM, Fuxe K, Changeux JP (1998) Acetylcholine receptors containing the β2 subunit are involved in the reinforcing properties of nicotine. Nature 391:173–177

    CAS  PubMed  Google Scholar 

  • Rose JE, Corrigall WA (1997) Nicotine self-administration in animals and humans: similarities and differences. Psychopharmacology 130:28–40

    Article  CAS  PubMed  Google Scholar 

  • Schilstrom B, Nomikos GG, Nisell M, Hertel P, Svensson TH (1998) N-methyl-d-aspartate receptor antagonism in the ventral tegmental area diminishes the systemic nicotine-induced dopamine release in the nucleus accumbens. Neuroscience 82:781–789

    Google Scholar 

  • Schilstrom B, Fagerquist MV, Zhang X, Hertel P, Panagis G, Nomikos GG, Svensson TH (2000) Putative role of presynaptic α7 nicotinic receptors in nicotine stimulated increases of extracellular levels of glutamate and aspartate in the ventral tegmental area. Synapse 38:375–383

    Article  CAS  PubMed  Google Scholar 

  • Shoaib M, Gommans J, Morley A, Stolerman IP, Grailhe R, Changeux JP (2002) The role of nicotinic receptor beta-2 subunits in nicotine discrimination and conditioned taste aversion. Neuropharmacology 42:530–539

    Article  CAS  PubMed  Google Scholar 

  • Yin R, French ED (2000) A comparison of the effects of nicotine on dopamine and non-dopamine neurons in the rat ventral tegmental area: an in vitro electrophysiological study. Brain Res Bull 51:507–514

    Article  CAS  PubMed  Google Scholar 

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Acknowledgement

This research was supported by C.I.H.R.

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Laviolette, S.R., van der Kooy, D. The motivational valence of nicotine in the rat ventral tegmental area is switched from rewarding to aversive following blockade of the α7-subunit-containing nicotinic acetylcholine receptor. Psychopharmacology 166, 306–313 (2003). https://doi.org/10.1007/s00213-002-1317-6

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  • DOI: https://doi.org/10.1007/s00213-002-1317-6

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