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Psychopharmacology

, Volume 231, Issue 18, pp 3745–3755 | Cite as

Enhanced alcohol-seeking behavior by nicotine in the posterior ventral tegmental area of female alcohol-preferring (P) rats: modulation by serotonin-3 and nicotinic cholinergic receptors

  • Sheketha R. HauserEmail author
  • Gerald A. DeehanJr
  • Jamie E. Toalston
  • Richard L. Bell
  • William J. McBride
  • Zachary A. Rodd
Original Investigation

Abstract

Rationale

Alcohol and nicotine co-use can reciprocally promote self-administration and drug-craving/drug-seeking behaviors. To date, the neurocircuitry in which nicotine influences ethanol (EtOH) seeking has not been elucidated. Clinical and preclinical research has suggested that the activation of the mesolimbic dopamine system is involved in the promotion of drug seeking. Alcohol, nicotine, and serotonin-3 (5-HT3) receptors interact within the posterior ventral tegmental area (pVTA) to regulate drug reward. Recently, our laboratory has reported that systemic administration of nicotine can promote context-induced EtOH seeking.

Objectives

The goals of the current study were to (1) determine if microinjections of pharmacologically relevant levels of nicotine into the pVTA would enhance EtOH seeking, (2) determine if coadministration of nicotinic cholinergic receptor antagonist (nACh) or 5-HT3 receptor antagonists would block the ability of nicotine microinjected into the pVTA to promote EtOH seeking, and (3) determine if 5-HT3 receptors in the pVTA can modulate EtOH seeking.

Results

Nicotine (100 and 200 μM) microinjected into the pVTA enhanced EtOH seeking. Coinfusion with 200 μM mecamylamine (nACh antagonist) or 100 and 200 μM zacopride (5-HT3 receptor antagonist) blocked the observed nicotine enhancement of EtOH seeking. The data also indicated that microinjection of 1 μM CPBG (5-HT3 receptor agonist) promotes context-induced EtOH seeking; conversely, microinjection of 100 and 200 μM zacopride alone reduced context-induced EtOH seeking.

Conclusions

Overall, the results show that nicotine-enhanced EtOH-seeking behavior is modulated by 5-HT3 and nACh receptors within the pVTA and that the 5-HT3 receptor system within pVTA may be a potential pharmacological target to inhibit EtOH-seeking behaviors.

Keywords

Alcohol-seeking behavior Serotonin-3 receptors Nicotinic cholinergic receptors Alcohol-preferring P rat Pavlovian Spontaneous Recovery Zacopride Mecamylamine 

Notes

Acknowledgments

The skillful technical assistance of Tylene Pommer and Victoria McQueen is gratefully acknowledged. This project was supported by research grants AA07611, AA022287, AA020908, AA07462, and AA019366 from NIAAA. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the NIAAA or NIH.

Conflict of interest

I certify that there is no actual or potential conflict of interest in relation to this article.

References

  1. Abrams DB, Rohsenow DJ, Niaura RS, Pedraza M, Longbaugh R, Beatties MC, Binkoff JA, Noel NE, Monti PM (1992) Smoking and treatment outcome for alcoholics: effects on coping skills, urge to drink and drinking rats. Behav Ther 23:283–297CrossRefGoogle Scholar
  2. Albuquerque EX, Pereira EFR, Alkondon M, Rogers SW (2009) Mammalian nicotinic acetylcholine receptors: from structure to function. Physiol Rev 89:73–120PubMedCentralPubMedCrossRefGoogle Scholar
  3. Alen F, Gomez R, Gonzalez-Cuevas G, Navarro M, Lopez-Moreno JA (2009) Nicotine causes opposite effects on alcohol intake: Evidence in an animal experimental model of abstinence and relapse from alcohol. Nicotine Tob Res 11:1304–1311PubMedCrossRefGoogle Scholar
  4. Bianchi C, Ferraro L, Tanganelli S, Morari M, Spalluto G, Simonato M, Beani L (1995) 5-Hydroxytryptamine-mediated effects of nicotine on endogenous GABA efflux from guinea-pig slices. Br J Pharmacol 116:2724–2728PubMedCentralPubMedCrossRefGoogle Scholar
  5. Blomqvist O, Ericson M, Johnson DH, Engel JA, Soderpalm B (1996) Voluntary ethanol intake in the rat: Effects of nicotinic acetylcholine receptor blockade or subchronic nicotine treatment. Eur J Pharmacol 314:257–267PubMedCrossRefGoogle Scholar
  6. Breitinger H-G A, Geetha N, Hess GP (2001) Inhibition of the serotonin 5-HT3 receptor by nicotine, cocaine and fluoxetine investigated by rapid chemical kinetic techniques. Biochem 40:8419–8429CrossRefGoogle Scholar
  7. Brodie MS, Shefner SA, Dunwiddie TV (1990) Ethanol increases the firing rate of dopamine neurons of the rat ventral tegmental area in vitro. Brain Res 508:65–69PubMedCrossRefGoogle Scholar
  8. Brodie MS, Pesold C, Appel SB (1999) Ethanol directly excites dopaminergic ventral tegmental area reward neurons. Alcohol Clin Exp Res 23:1848–1852PubMedCrossRefGoogle Scholar
  9. Brooks DC (2000) Recent and remote extinction cues reduce spontaneous recovery. Q. J. Exp Psychol 153:25–58CrossRefGoogle Scholar
  10. Calabresi P, Lacey MG, North RA (1989) Nicotinic excitation of rat ventral tegmental neurones in vitro studied by intracellular recording. Br J Pharmacol 98:135–140PubMedCentralPubMedCrossRefGoogle Scholar
  11. Campbell AD, Kohl RR, McBride WJ (1996) Serotonin-3 receptor and ethanol-stimulated somatodendritic dopamine release. Alcohol 13:569–574PubMedCrossRefGoogle Scholar
  12. Carboni E, Acquas E, Frau R, Di Chiara G (1989) Differential inhibitory effects of a 5-HT3 antagonist on drug-induced stimulation of dopamine release. Eur J Pharmacol 164:515–519PubMedCrossRefGoogle Scholar
  13. Corrigall WA, Coen KM (1994) Nicotine self-administration and locomotor activity are not modified by the 5-HT3 antagonists ICS 205-930 and MDL 72222. Pharmacol Biochem Behav 49:67–71PubMedCrossRefGoogle Scholar
  14. Corrigall WA, Coen KM, Adamson KL (1994) Self-administered nicotine activates the mesolimbic dopamine system through the ventral tegmental area. Brain Res 653:278–284PubMedCrossRefGoogle Scholar
  15. Daeppen JB, Smith TL, Danko GP, Gordon L, Landi NA, Nurnberger JI Jr, Bucholz KK, Raimo E, Schuckit MA (2000) Clinical correlates of cigarette smoking and nicotine dependence in alcohol-dependent men and women. The Collaborative Study Group on the Genetics of Alcoholism. Alcohol Alcohol 35:171–175PubMedCrossRefGoogle Scholar
  16. Dhaher R, Hauser SR, Getachew B, Bell RL, McBride WJ, McKinzie DL, Rodd ZA (2010) The orexin-1 receptor antagonist SB-334867 reduces alcohol relapse drinking, but not alcohol-seeking, in Alcohol-Preferring (P) rats. J Addict Med 4:153–159PubMedCentralPubMedCrossRefGoogle Scholar
  17. Ding Z-M, Katner SN, Rodd ZA, Truitt W, Hauser SR, Deehan GA Jr, Engleman EA, McBride WJ (2012) Repeated exposure of the posterior ventral tegmental area to nicotine increases the sensitivity of local dopamine neurons to the stimulating effects of ethanol. Alcohol 46:217–223PubMedCentralPubMedCrossRefGoogle Scholar
  18. Dong L, Zhu Y, Dong Y, Yang J, Zhao Y, Qi Y, Wu P, Zhu Y, Zheng P (2009) Neuroactive steroid dehydroepiandrosterone sulfate inhibits 5 hydroxytryptamine (5-HT)-evoked glutamate release via activation of sigma-1 receptors and then inhibition of 5-HT3 receptors in rat prelimbic cortex. J Pharmacol Exp Ther 330:494–501PubMedCrossRefGoogle Scholar
  19. Dougherty JJ, Nichols RA (2009) Cross-regulation between colocalized nicotinic acetylcholine and 5-HT3 serotonin receptors on presynaptic nerve terminals. Acta Pharmacol Sin 30:788–794PubMedCrossRefGoogle Scholar
  20. Drisdel RC, Sharp D, Henderson T, Hales TG, Green WN (2008) High affinity binding of epibatidine to serotonin type 3 receptors. J Biol Chem 283:9659–9665PubMedCentralPubMedCrossRefGoogle Scholar
  21. Ericson M, Blomqvist O, Engel JA, Soderpalm B (1998) Voluntary ethanol intake in the rat and the associated accumbal dopamine overflow are blocked by ventral tegmental mecamylamine. Eur J Pharmacol 358:189–196PubMedCrossRefGoogle Scholar
  22. Ericson M, Molander A, Lof E, Engel JA, Soderpalm B (2003) Ethanol elevates accumbal dopamine levels via indirect activation of ventral tegmental nicotinic acetylcholine receptors. Eur J Pharmacol 467:85–93PubMedCrossRefGoogle Scholar
  23. Ford MM, Fretwell AM, Nickel JD, Mark GP, Strong MN, Yoneyama N, Finn DA (2009) The influence of mecamylamine on ethanol and sucrose self-administration. Neuropharmacology 57:250–258PubMedCentralPubMedCrossRefGoogle Scholar
  24. Gotti C, Clementi F (2004) Neuronal nicotinic receptors: from structure to pathology. Prog Neurobiol 74:363–396PubMedCrossRefGoogle Scholar
  25. Gotti C, Guiducci S, Tedesco V, Corbioli S, Zanetti L, Moretti M, Zanardi A, Rimondini R, Mugnaini M, Clementi F, Chiamulera C, Zoli M (2010) Nicotinic acetylcholine receptors in the mesolimbic pathway: primary role of ventral tegmental area alpha6beta2* receptors in mediating systemic nicotine effects on dopamine release, locomotion, and reinforcement. J Neurosci 30:5311–5325PubMedCrossRefGoogle Scholar
  26. Gulliver SB, Rohsenow DJ, Colby SM, Dey AN, Abrams DB, Niaura RS, Monti PM (1995) Interrelationship of smoking and alcohol dependence, use and urges to use. J Stud Alcohol 56:202–206PubMedGoogle Scholar
  27. Gurley DA, Lanthorn TH (1998) Nicotinic agonists competitively antagonize serotonin at mouse 5-HT3 receptors expressed in Xenopus oocytes. Neurosci Lett 247:107–110PubMedCrossRefGoogle Scholar
  28. Hauser SR, Ding ZM, Getachew B, Toalston JE, Oster SM, McBride WJ, Rodd ZA (2011) The posterior ventral tegmental area mediates alcohol-seeking behavior in alcohol-preferring rats. J Pharmacol Exp Ther 336:857–865PubMedCentralPubMedCrossRefGoogle Scholar
  29. Hauser SR, Getachew B, Oster SM, Dhaher R, Ding ZM, Bell RL, McBride WJ, Rodd ZA (2012a) Nicotine modulates alcohol-seeking and relapse by alcohol-preferring (P) rats in a time-dependent manner. Alcohol Clin Exp Res 36:43–54PubMedCrossRefGoogle Scholar
  30. Hauser SR, Katner SN, Deehan GA Jr, Ding ZM, Toalston JE, Scott BJ, Bell RL, McBride WJ, Rodd ZA (2012b) Development of an oral operant nicotine/ethanol co-use model in alcohol-preferring (P) rats. Alcohol Clin Exp Res 36:43–54PubMedCrossRefGoogle Scholar
  31. Hauser SR, Bracken AL, Deehan GA Jr, Toalston JE, Ding ZM, Truitt WA, Bell RL, McBride WJ, Rodd ZA (2013) Selective breeding for high alcohol preference increases the sensitivity of the posterior VTA to the reinforcing effects of nicotine. Addict Biol. In PressGoogle Scholar
  32. Hendrickson LM, Zhao-Shea R, Tapper AR (2009) Modulation of ethanol drinking-in-the-dark by mecamylamine and nicotinic acetylcholine receptor agonists in C57BL/6 J mice. Psychopharmacology (Berlin) 204:563–572CrossRefGoogle Scholar
  33. Herve D, Pickel VM, Joh TH, Beaudet A (1987) Serotonin axon terminals in the ventral tegmental area of the rat: fine structure and synaptic input to dopaminergic neurons. Brain Res 435:71–83PubMedCrossRefGoogle Scholar
  34. Ikemoto S, Qin M, Liu Z-H (2006) Primary reinforcing effects of nicotine are triggered from multiple regions both inside and outside the ventral tegmental area. J Neurosci 26:723–730PubMedCentralPubMedCrossRefGoogle Scholar
  35. Ivanová S, Greenshaw AJ (1997) Nicotine-induced decreases in VTA electrical self-stimulation thresholds: blockade by haloperidol and mecamylamine but not scopolamine or ondansetron. Psychopharmacology (Berlin) 134:187–192CrossRefGoogle Scholar
  36. Jackson MB, Yakel JL (1995) The 5-HT3 receptor channel. Ann Rev Physiol 57:447–468CrossRefGoogle Scholar
  37. Johnson BA (2004) Role of the serotonergic system in the neurobiology of alcoholism: implications for treatment. CNS Drugs 18:1105–1118PubMedCrossRefGoogle Scholar
  38. Johnson BA, Roache JD, Ait-Daoud N, Zanca NA, Velazquez M (2002) Ondansetron reduces the craving of biologically predisposed alcoholics. Psychopharmacology (Berlin) 160:408–413CrossRefGoogle Scholar
  39. Kidd FJ, Levy JC, Nielsen M, Hamon M, Gozlan H (1993) Characterisation of the non-5-HT3 high-affinity ‘R’ binding site for (R)-zacopride in brain and other tissues. Eur J Pharmacol 247:45–56PubMedCrossRefGoogle Scholar
  40. Le AD, Corrigall WA, Harding JW, Juzytsch W, Li TK (2000) Involvement of nicotinic receptors in alcohol self-administration. Alcohol Clin Exp Res 24:155–163PubMedCrossRefGoogle Scholar
  41. Le AD, Wang A, Harding S, Juzytsch W, Shaham Y (2003) Nicotine increases alcohol self-administration and reinstates alcohol seeking in rats. Psychopharmacology (Berlin) 168:216–221CrossRefGoogle Scholar
  42. Le AD, Li Z, Funk D, Shram M, Li TK, Shaham Y (2006a) Increased vulnerability to nicotine self-administration and relapse in alcohol-naïve offspring of rats selectively bred for high alcohol intake. J Neurosci 26:1872–1879PubMedCrossRefGoogle Scholar
  43. Le AD, Funk D, Harding S, Juzytsch W, Fletcher PJ, Shaham Y (2006b) Effects of dexfenfluramine and 5-HT3 receptor antagonists on stress-induced reinstatement of alcohol seeking in rats. Psychopharmacology (Berlin) 186:82–92CrossRefGoogle Scholar
  44. Liu W, Thielen RJ, Rodd ZA, McBride WJ (2006) Activation of serotonin-3 receptors increases dopamine release within the ventral tegmental area of Wistar and alcohol-preferring (P) rats. Alcohol 40:167–176PubMedCentralPubMedCrossRefGoogle Scholar
  45. Lof E, Olausson P, deBejczy A, Stomberg R, McIntosh JM, Taylor JR, Söderpalm B (2007) Nicotinic acetylcholine receptors in the ventral tegmental area mediate the dopamine activating and reinforcing properties of ethanol cues. Psychopharmacology (Berlin) 195:333–343CrossRefGoogle Scholar
  46. Lopez-Moreno JA, Trigo-Diaz JM, de Rodriguez FF, Gonzalez CG, de Gomez HR, Crespo GI, Navarro M (2004) Nicotine in alcohol deprivation increases alcohol operant self-administration during reinstatement. Neuropharmacology 47:1036–1044PubMedCrossRefGoogle Scholar
  47. Lummis SC, Thompson AJ, Bencherif M, Lester HA (2011) Varenicline is a potent agonist of the human 5-hydroxytryptamine3 receptor. J Pharmacol Exp Ther 339:125–131PubMedCentralPubMedCrossRefGoogle Scholar
  48. Mascia MP, Trudell JR, Harris RA (2000) Specific binding sites for alcohols and anesthetics on ligand-gated ion channels. Proc Natl Acad Sci U S A 97:9305–9310PubMedCentralPubMedCrossRefGoogle Scholar
  49. Nayak SV, Ronde P, Spier AD, Lummis SCR, Nichols RA (2000) Nicotinic receptors co-localize with 5-HT3 serotonin receptors on striatal nerve terminals. Neuropharmacology 39:2681–2690PubMedCrossRefGoogle Scholar
  50. Nisell M, Nomikos GG, Svensson TH (1994) Systemic nicotine-induced dopamine release in the rat nucleus accumbens is regulated by nicotinic receptors in the ventral tegmental area. Synapse 16:36–44PubMedCrossRefGoogle Scholar
  51. Paxinos G, Watson C (1998) The rat brain in stereotaxic coordinates, 4th edn. Academic Press, New YorkGoogle Scholar
  52. Peters JA, Carland JE, Cooper MA, Livesey MR, Deeb TZ, Hales TG, Lambert JJ (2006) Novel structural determinants of single-channel conductance in nicotinic acetylcholine and 5-hydroxytryptamine type-3 receptors. Biochem Soc Trans 34:882–886PubMedCrossRefGoogle Scholar
  53. Pidoplichko VI, Noguchi J, Areola OO, Liang Y, Peterson J, Zhang T, Dani JA (2004) Nicotinic cholinergic synaptic mechanisms in the ventral tegmental area contribute to nicotine addiction. Learn Mem 11:60–69PubMedCentralPubMedCrossRefGoogle Scholar
  54. Rahman S, Zhang J, Corrigall WA (2004) Local perfusion of nicotine differentially modulates somatodendritic dopamine release in the rat ventral tegmental area after nicotine pre-exposure. Neurochem Res 29:1687–1693PubMedCrossRefGoogle Scholar
  55. Robbins SJ (1990) Mechanisms underlying spontaneous recovery in authoshaping. J Exp Psychol Anim Behav Process 16:235–249CrossRefGoogle Scholar
  56. Rodd ZA, McKinzie DL, Bell RL, McQueen VK, Murphy JM, Schoepp DD, McBride WJ (2006) The metabotropic glutamate 2/3 receptor agonist LY404039 reduces alcohol-seeking but not alcohol self-administration in alcohol-preferring (P) rats. Behav Brain Res 171:207–215PubMedCrossRefGoogle Scholar
  57. Rodd ZA, Gryszowka VE, Toalston JE, Oster SM, Ji D, Bell RL, McBride WJ (2007) The reinforcing actions of a serotonin-3 receptor agonist within the ventral tegmental area: evidence for subregional and genetic differences and involvement of dopamine neurons. J Pharmacol Exp Ther 321:1003–1012PubMedCrossRefGoogle Scholar
  58. Rodd ZA, Bell RL, Oster SM, Toalston JE, Pommer TJ, McBride WJ, Murphy JM (2010) Serotonin-3 receptors in the posterior ventral tegmental area regulate ethanol self-administration of alcohol-preferring (P) rats. Alcohol 44:245–255PubMedCrossRefGoogle Scholar
  59. Rodd-Henricks ZA, McKinzie DL, Crile RS, Murphy JM, McBride WJ (2000) Regional heterogeneity for the intracranial self-administration of ethanol within the ventral tegmental area of female Wistar rats. Psychopharmacology 149:217–224PubMedCrossRefGoogle Scholar
  60. Rodd-Henricks ZA, Bell RL, Kuc KA, Murphy JM, McBride WJ, Lumeng L, Li TK (2002a) Effects of ethanol exposure on subsequent acquisition and extinction of ethanol self-administration and expression of alcohol-seeking behavior in adult alcohol-preferring (P) rats: I. Periadolescent exposure. Alcohol Clin Exp Res 26:1632–1641PubMedCrossRefGoogle Scholar
  61. Rodd-Henricks ZA, Bell RL, Kuc KA, Murphy JM, McBride WJ, Lumeng L, Li TK (2002b) Effects of ethanol exposure on subsequent acquisition and extinction of ethanol self-administration and expression of alcohol-seeking behavior in adult alcohol-preferring (P) rats: II. Adult exposure. Alcohol Clin Exp Res 26:1642–1652PubMedCrossRefGoogle Scholar
  62. Rodd-Henricks ZA, McKinzie DL, Melendez RI, Berry N, Murphy JM, McBride WJ (2003) Effects of serotonin-3 receptor antagonists on the intracranial self-administration of ethanol within the ventral tegmental area of Wistar rats. Psychopharmacology 165:252–259PubMedGoogle Scholar
  63. Sajja RK, Rahman S (2012) Neuronal nicotinic receptor ligands modulate chronic nicotine-induced ethanol consumption in C57BL/6 J mice. Pharmacol Biochem Behav 102:36–43PubMedCrossRefGoogle Scholar
  64. Sellers EM, Toneatto T, Romach MK, Somer GR, Sobell LC, Sobell MB (1994) Clinical efficacy of the 5-HT3 antagonist ondansetron in alcohol abuse and dependence. Alcohol Clin Exp Res 18:879–885PubMedCrossRefGoogle Scholar
  65. Smith BR, Horan JT, Gaskin S, Amit Z (1999) Exposure to nicotine enhances acquisition of ethanol drinking by laboratory rats in a limited access paradigm. Psychopharmacology (Berlin) 142:408–412CrossRefGoogle Scholar
  66. Sobell MB, Sobell LC, Kozolowski LT (1995) Dual recoveries from alcohol and smoking problems. In: Fertig JB, Allen JS (eds) Alcohol and tobacco: from basic science to clinical practice. NIAAA, BethesdaGoogle Scholar
  67. Soderpalm B, Ericson M, Olausson P, Blomqvist O, Engel JA (2000) Nicotinic mechanisms involved in the dopamine activating and reinforcing properties of ethanol. Behav Brain Res 113:85–96PubMedCrossRefGoogle Scholar
  68. Steensland P, Simms JA, Holgate J, Richards JK, Bartlett SE (2007) Varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, selectively decreases ethanol consumption and seeking. Proc Natl Acad Sci U S A 104:12518–12523PubMedCentralPubMedCrossRefGoogle Scholar
  69. Wonnacott S (1997) Presynaptic nicotinic ACh receptors. Trends Neurosci 20:92–98PubMedCrossRefGoogle Scholar
  70. Zhao-Shea R, Liu L, Soll LG, Improgo MR, Meyers EE, McIntosh JM, Grady SR, Marks MJ, Gardner PD, Tapper AR (2011) Nicotine-mediated activation of dopaminergic neurons in distinct regions of the ventral tegmental area. Neuropsychopharmacology 36:1021–1032PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Sheketha R. Hauser
    • 1
    Email author
  • Gerald A. DeehanJr
    • 1
  • Jamie E. Toalston
    • 1
  • Richard L. Bell
    • 1
  • William J. McBride
    • 1
  • Zachary A. Rodd
    • 1
  1. 1.Institute of Psychiatric Research, Department of PsychiatryIndiana University School of MedicineIndianapolisUSA

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