, Volume 203, Issue 1, pp 23–32 | Cite as

Effects of a cannabinoid receptor (CB) 1 antagonist AM251 on behavioral sensitization to nicotine in a rat model of novelty-seeking behavior: correlation with hippocampal 5HT

  • Amrinder S. Bhatti
  • Cigdem Aydin
  • Ozge Oztan
  • Zhiyuan Ma
  • Penny Hall
  • Rui Tao
  • Ceylan IsgorEmail author
Original Investigation



There are marked individual differences in the efficacy of mainstream nicotine cessation agents in preventing relapse. A rat model of novelty-seeking phenotype was reported to have predictive value for psychostimulant taking behavior where locomotor reactivity to novelty is used to rank high (HR, highest 1/3) versus low (LR, lowest 1/3) responsiveness to novelty in outbred rats. We tested the hypothesis that a cannabinoid receptor (CB) 1 antagonist that is in clinical trials for smoking cessation may reverse behaviorally sensitizing effects of nicotine in HRs and repeated nicotine-induced elevations in hippocampal 5HT.

Materials and methods

Adolescent LRHR rats underwent intermittent behavioral sensitization to nicotine regimen with or without a CB1 receptor antagonist AM251 or bupropion treatment following nicotine training during 1 week of nicotine-free period. Expression of behavioral sensitization to nicotine was assessed in response to a low-dose nicotine challenge. Using the same sensitization regimen and therapeutic treatments, hippocampal 5HT levels were measured via in vivo microdialysis in response to the nicotine challenge.


HR but not LR animals showed behavioral sensitization to a low-dose nicotine challenge following intermittent nicotine training and 1 week of injection-free period. AM251 (5 mg/kg, i.p.) but not bupropion administration during injection-free period successfully reversed locomotor sensitization to nicotine challenge in HRs. AM251 treatment also reversed nicotine-induced elevations in extracellular 5HT in the HR hippocampal hilus.


These data suggest that CB1 antagonists may prevent locomotor sensitization to nicotine and reverse nicotine-induced elevations in hippocampal 5HT in high novelty seekers.


Cannabinoid receptor Hippocampus Novelty seeking Nicotine sensitization Bupropion Serotonin 



This work is entirely supported by the Florida Department of Health grant 05NIR-5194 awarded to Dr. Isgor.


  1. Balfour DJK, Ridley DL (2000) The effects of nicotine on neural pathways implicated in depression: a factor in nicotine addiction? Pharmacol Biochem Behav 66:79–85PubMedCrossRefGoogle Scholar
  2. Ballaz S, Akil H, Watson SJ (2007) Analysis of 5HT6 and 5HT7 receptor gene expression in rats showing differences in novelty-seeking behavior. Neuroscience 147:428–438PubMedCrossRefGoogle Scholar
  3. Bhatti AS, Hall P, Ma Z, Tao R, Isgor C (2007) Hippocampus modulates the behaviorally-sensitizing effects of nicotine in a rat model of novelty-seeking: potential role for mossy fibers. Hippocampus 17:922–933PubMedCrossRefGoogle Scholar
  4. Brody AL, Mandelkern MA, Lee G, Smith E, Sadeghi M, Saxena S et al (2004) Attenuation of cue-induced cigarette craving and anterior cingulate cortex activation in bupropion-treated smokers: a preliminary study. Psychiatry Res 130:269–281PubMedCrossRefGoogle Scholar
  5. Brog JS, Salyapongse A, Deutch AY, Zahm DS (1993) The patterns of afferent innervation of the core and shell in the “accumbens” part of the ventral striatum: immunohistochemical detection of retrogradely transported Fluoro-Gold. J Comp Neurol 338:255–278PubMedCrossRefGoogle Scholar
  6. Castane A, Valjent E, Ledent C, Parmentier M, Maldonado R, Valverde O (2002) Lack of CB1 cannabinoid receptors modifies nicotine behavioral responses, but not nicotine abstinence. Neuropharmacology 43:857–867PubMedCrossRefGoogle Scholar
  7. Cohen C, Perrault G, Voltz C, Steinberg R, Soubrie P (2002) SR141716, a central cannabinoid (CB(1)) receptor antagonist, blocks the motivational and dopamine-releasing effects of nicotine in rats. Behav Pharmacol 13:451–463PubMedGoogle Scholar
  8. Covey LS (1999) Tobacco cessation among patients with depression. Prim Care 26:691–706PubMedGoogle Scholar
  9. Cryan JF, Gasparini F, van Heeke G. Markou A (2003) Non-nicotinic neuropharmacological strategies for nicotine dependence: beyond bupropion. DDT 8:1025–1034PubMedGoogle Scholar
  10. Dwoskin LP, Rauhut AS, King-Pospisil KA, Bardo MT (2006) Review of the pharmacology and clinical profile of bupropion, an antidepressant and tobacco use cessation agent. CNS Drug Rev 12:178–207PubMedCrossRefGoogle Scholar
  11. Egertova M, Elphick MR (2000) Localization of cannabinoid receptors in the rat brain using antibodies to the intracellular C-terminal tail of CB1. J Comp Neurol 422:159–171PubMedCrossRefGoogle Scholar
  12. Fabian-Fine R, Skehel P, Errington ML, Davies HA, Sher E, Stewart MG et al (2001) Ultrastructural distribution of the alpha7 nicotinic acetylcholine receptor subunit in rat hippocampus. J Neurosci 21:7993–8003PubMedGoogle Scholar
  13. File SE, Kenny PJ, Ouagazzal A-M (1998) Anxiolytic and anxiogenic effects of nicotine in the social interaction test: role of the dorsal hippocampus. Behav Neurosci 112:1423–1429PubMedCrossRefGoogle Scholar
  14. Gobbi G, Bambico FR, Mangieri R, Bortolato M, Campologno P, Solinas M et al (2005) Antidepressant-like activity and modulation of brain monoaminergic transmission by blockade of anandamide hydrolysis. Proc Natl Acad Sci USA 102:18620–18625PubMedCrossRefGoogle Scholar
  15. Haring M, Marsicano G, Lutz B, Monory K (2007) Identification of the cannabinoid receptor type 1 in serotonergic cells of raphe nuclei in mice. Neuroscience 146:1212–19PubMedCrossRefGoogle Scholar
  16. Hooks MS, Jones GH, Smith AD, Neill DB, Justice JB Jr (1991) Response to novelty predicts the locomotor and nucleus accumbens dopamine response to cocaine. Synapse 9:121–128PubMedCrossRefGoogle Scholar
  17. Hurt RD, Sachs DP, Glover ED, Offord KP, Johnston JA, Dale LC et al (1997) A comparison of sustained-release bupropion and placebo for smoking cessation. N Engl J Med 337:1195–1202PubMedCrossRefGoogle Scholar
  18. Kabbaj M, Isgor C, Watson SJ, Akil H (2002) Stress during adolescence alters behavioral sensitization to amphetamine. Neuroscience 113(2):395–400PubMedCrossRefGoogle Scholar
  19. Kenny PJ, Cheetah S, File SE (2000a) Anxiogenic effects of nicotine in the dorsal hippocampus are mediated by 5HT1A and not by muscarinic M1. Neuropsychopharmacology 39:300–307Google Scholar
  20. Kenny PJ, File SE, Neal MJ (2000b) Evidence for complex influence of nicotinic acetylcholine receptors on hippocampal serotonin release. J Neurochem 75:2409–14PubMedCrossRefGoogle Scholar
  21. Kenny PJ, File SE, Rattray M (2001) Nicotine regulates 5HT1A receptor gene expression in the cerebral cortex and dorsal hippocampus. Eur J Neurosci 13:1267–1271PubMedCrossRefGoogle Scholar
  22. Le Foll B, Goldberg SR (2004) Rimonabant, a CB1 antagonist, blocks nicotine-conditioned place preferences. Neuroreport 15:2139–2143PubMedCrossRefGoogle Scholar
  23. Lerman C, Berrettini W (2003) Elucidating the role of genetic factors in smoking behavior and nicotine dependence. Am J Med Genet 118B:48–54CrossRefPubMedGoogle Scholar
  24. Maldonado R, Valverde O, Berrendero F (2006) Involvement of the endocannabinoid system in drug addiction. Trends Neurosci 29:225–232PubMedCrossRefGoogle Scholar
  25. Mansvelder HD, McGehee D (2002) Cellular and synaptic mechanisms of nicotine addiction. J Neurobiol 53:606–617PubMedCrossRefGoogle Scholar
  26. Markou A, Kenny PJ (2002) Neuroadaptations to chronic exposure to drugs of abuse: relevance to depressive symptomatology seen across psychiatric diagnostic categories. Neurotox Res 4:297–313PubMedCrossRefGoogle Scholar
  27. Miller DK, Wilkins LH, Bardo MT, Crooks PA, Dwoskin LP (2001) Once weekly administration of nicotine produces long-lasting locomotor sensitization in rats via a nicotinic receptor-mediated mechanism. Psychopharmacology (Berl) 156:469–476CrossRefGoogle Scholar
  28. Mokler DJ, Lariviere D, Johnson DW, Theriault NL, Bronzino JD, Dixon M et al (1998) Serotonin neuronal release from dorsal hippocampus following electrical stimulation of the dorsal and median raphe nuclei in conscious rats. Hippocampus 8:262–273PubMedCrossRefGoogle Scholar
  29. Murray RP, Voelker HT, Rakos RT, Nides MA, McCutcheon VJ, Bjornson W (1997) Intervention for relapse to smoking: the Lung Health Study restart programs. Addict Behav 22:281–286PubMedCrossRefGoogle Scholar
  30. Nestler E (2002) Common molecular and cellular substrates of addiction and memory. Neurobiol Learn Mem 78:637–647PubMedCrossRefGoogle Scholar
  31. Olausson P, Engel JA, Soderpalm B (2002) Involvement of serotonin in nicotine dependence: processes relevant to positive and negative regulation of drug intake. Pharmacol Biochem Behav 71:757–771PubMedCrossRefGoogle Scholar
  32. Paxinos G, Watson C (1982) The rat brain in stereotaxic coordinates, 2nd edn. Academic, New YorkGoogle Scholar
  33. Pertwee RG (1997) Pharmacology of cannabinoid CB1 and CB2 receptors. Pharmacol Ther 74:129–180PubMedCrossRefGoogle Scholar
  34. Piazza PV, Deminiere JM, Le Moal M, Simon H (1989) Factors that predict individual vulnerability to amphetamine self-administration. Science 245:1511–1513PubMedCrossRefGoogle Scholar
  35. 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 82:1103–1114PubMedCrossRefGoogle Scholar
  36. Robbe D, Kopf M, Remaury A, Bockaert J, Manzoni OJ (2002) Endogenous cannabinoids mediate long-term synaptic depression in the nucleus accumbens. Proc Natl Acad Sci USA 99:8384–8388PubMedCrossRefGoogle Scholar
  37. Robinson TE, Becker JB (1986) Enduring changes in brain and behavior produced by chronic amphetamine: a review and evaluation of animal models of amphetamine psychosis. Brain Res 396:157–198PubMedCrossRefGoogle Scholar
  38. Saito M, O’Brien D, Kovacs KM, Wang R, Zavadil J, Vadasz C (2005) Nicotine-induced sensitization in mice: changes in locomotor activity and mesencephalic gene expression. Neurochem Res 30:1027–1035PubMedCrossRefGoogle Scholar
  39. Seth P, Cheeta S, Tucci S, File SE (2002) Nicotinic–serotonergic interactions in brain and behaviour. Pharmacol Biochem Behav 71:795–805PubMedCrossRefGoogle Scholar
  40. Shiffman S, Johnston JA, Khayrallah M, Elash CA, Gwaltney CJ, Paty JA et al (2000) The effect of bupropion on nicotine craving and withdrawal. Psychopharmacology 148:33–40PubMedCrossRefGoogle Scholar
  41. Shoaib M, Sidhpura N, Shafait S (2003) Investigating the actions of bupropion on dependence-related effects of nicotine in rats. Psychopharmacology (Berl) 165:405–412Google Scholar
  42. Suto N, Austin JD, Vezina P (2001) Locomotor response to novelty predicts a rat’s propensity to self-administer nicotine. Psychopharmacology (Berl) 158:175–180CrossRefGoogle Scholar
  43. Vezina P, Queen AL (2000) Induction of locomotor sensitization by amphetamine regulates the activation of NMDA receptors in the rat ventral tegmental area. Psychopharmacol (Berl) 151:184–191CrossRefGoogle Scholar
  44. Wilson RI, Nicoll RA (2002) Endocannabinoid signaling in the brain. Science 296:678–682PubMedCrossRefGoogle Scholar
  45. Wing VC, Shoaib M (2007) Examining the clinical efficacy of bupropion and nortriptyline as smoking cessation agents in a rodent model of nicotine withdrawal. Psychopharmacology (Berl) 195:303–313CrossRefGoogle Scholar
  46. Wise RA, Bozarth MA (1987) A psychomotor stimulant theory of addiction. Psychol Rev 94:469–92PubMedCrossRefGoogle Scholar
  47. Wright CI, Groenewegen HJ (1995) Patterns of convergence and segregation in the medial nucleus accumbens of the rat: relationships of prefrontal cortical, midline thalamic, and basal amygdaloid afferents. J Comp Neurol 361:383–403PubMedCrossRefGoogle Scholar
  48. Xi ZX, Spiller K, Pak AC, Gilbert J, Dillon C, Li X, Peng XQ, Gardner EL (2008) Cannabinoid CB1 receptor antagonist attenuate cocaine’s rewarding effects: experiments with self-administration and brain-stimulation reward in rats. Neuropsychopharmacology 33:1735–1745PubMedCrossRefGoogle Scholar
  49. Zuckerman M (1984) Sensation-seeking: a comparative approach to a human trait. Behav Brain Sci 7:413–471CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Amrinder S. Bhatti
    • 1
  • Cigdem Aydin
    • 1
  • Ozge Oztan
    • 1
  • Zhiyuan Ma
    • 1
  • Penny Hall
    • 1
  • Rui Tao
    • 1
  • Ceylan Isgor
    • 1
    Email author
  1. 1.Department of Basic Biomedical Sciences, Charles E. Schmidt College of ScienceFlorida Atlantic UniversityBoca RatonUSA

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