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Bupropion and nicotine enhance responding for nondrug reinforcers via dissociable pharmacological mechanisms in rats

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Abstract

Rationale

Nicotine serves as a primary reinforcer but also potently enhances responding for nonnicotine stimuli with reinforcing properties. One of the most successful pharmacotherapies for smoking cessation, bupropion, also increases responding for nondrug reinforcers such as food and brain stimulation rewards.

Objective

The present studies investigated whether treatment with bupropion and nicotine had similar effects on responding for a reinforcing visual stimulus (VS). They also investigated whether the effects of bupropion and nicotine depended on common pharmacological substrates.

Results

Nicotine (0.4 mg/kg base) enhanced responding for the VS, and this enhancing effect increased across testing sessions, replicating our previous findings. Bupropion (3, 10, and 30 mg/kg salt) dose-dependently increased responding for the VS. Treatment with 10 and 30 mg/kg bupropion resulted in a profile similar to nicotine; operant responding increased over repeated drug treatments. The reinforcement enhancing effect of nicotine, but not bupropion, was blocked by pretreatment with the nicotinic acetylcholine receptor antagonist mecamylamine. In contrast, the reinforcement enhancing effect of bupropion, but not nicotine, was blocked by pretreatment with the alpha noradrenergic antagonist prazosin.

Conclusion

The reinforcement enhancing effects of nicotine and bupropion increased over time and repeated treatments suggesting a shared mechanism of action. However, the reinforcement enhancing effects of nicotine are mediated by nicotinic acetylcholine receptors, whereas the reinforcement enhancing effects of bupropion were mediated by alpha noradrenergic receptors.

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References

  • Balfour DJ, Wright AE, Benwell ME, Birrell CE (2000) The putative role of extra-synaptic mesolimbic dopamine in the neurobiology of nicotine dependence. Behav Brain Res 113:73–83

    Article  CAS  PubMed  Google Scholar 

  • Benwell ME, Balfour DJ (1992) The effects of acute and repeated nicotine treatment on nucleus accumbens dopamine and locomotor activity. Br J Pharmacol 105:849–856

    CAS  PubMed  Google Scholar 

  • Besheer J, Palmatier MI, Metschke DM, Bevins RA (2004) Nicotine as a signal for the presence or absence of sucrose reward: a Pavlovian drug appetitive conditioning preparation in rats. Psychopharmacology 172:108–117

    Article  CAS  PubMed  Google Scholar 

  • Bevins RA, Palmatier MI (2003) Nicotine-conditioned locomotor sensitization in rats: assessment of the US-preexposure effect. Behav Brain Res 143:65–74

    Article  CAS  PubMed  Google Scholar 

  • Blanc G, Trovero F, Vezina P, Herve D, Godeheu AM, Glowinski J, Tassin JP (1994) Blockade of prefronto-cortical alpha 1-adrenergic receptors prevents locomotor hyperactivity induced by subcortical d-amphetamine injection. Eur J Neurosci 6:293–298

    Article  CAS  PubMed  Google Scholar 

  • Borges V, Yang E, Dunn J, Henion J (2004) High-throughput liquid chromatography-tandem mass spectrometry determination of bupropion and its metabolites in human, mouse and rat plasma using a monolithic column. J Chromatogr, B, Analytical Technologies in the Biomedical and Life Sciences 804:277–287

    Article  CAS  Google Scholar 

  • Bruijnzeel AW, Markou A (2003) Characterization of the effects of bupropion on the reinforcing properties of nicotine and food in rats. Synapse 50:20–28

    Article  CAS  PubMed  Google Scholar 

  • Burns LH, Everitt BJ, Kelley AE, Robbins TW (1994) Glutamate-dopamine interactions in the ventral striatum: role in locomotor activity and responding with conditioned reinforcement. Psychopharmacology (Berl) 115:516–528

    Article  CAS  Google Scholar 

  • Chaudhri N, Caggiula AR, Donny EC, Booth S, Gharib M, Craven L, Palmatier MI, Liu X, Sved AF (2006a) Operant responding for conditioned and unconditioned reinforcers in rats is differentially enhanced by the primary reinforcing and reinforcement-enhancing effects of nicotine. Psychopharmacology 189:27–36

    Article  CAS  PubMed  Google Scholar 

  • Chaudhri N, Caggiula AR, Donny EC, Palmatier MI, Liu X, Sved AF (2006b) Complex interactions between nicotine and nonpharmacological stimuli reveal multiple roles for nicotine in reinforcement. Psychopharmacology 184:353–366

    Article  CAS  PubMed  Google Scholar 

  • Chu B, Kelley AE (1992) Potentiation of reward-related responding by psychostimulant infusion into nucleus accumbens: role of dopamine receptor subtypes. Psychobiology 20:153–162

    CAS  Google Scholar 

  • Coen K, Adamson KL, Corrigall W (2009) Medication-related pharmacological manipulations of nicotine self-administration in the rat maintained on fixed- and progressive-ratio schedules of reinforcement. Psychopharmacology 201:557–568

    Article  CAS  PubMed  Google Scholar 

  • Cousins MS, Stamat HM, de Wit H (2001) Acute doses of d-amphetamine and bupropion increase cigarette smoking. Psychopharmacology 157:243–253

    Article  CAS  PubMed  Google Scholar 

  • Cryan JF, Bruijnzeel AW, Skjei KL, Markou A (2003) Bupropion enhances brain reward function and reverses the affective and somatic aspects of nicotine withdrawal in the rat. Psychopharmacology (Berl) 168: 347–58

    Article  CAS  Google Scholar 

  • Dani JA (2003) Roles of dopamine signaling in nicotine addiction. Mol Psychiatry 8:255–256

    Article  CAS  PubMed  Google Scholar 

  • Dani JA, Ji D, Zhou FM (2001) Synaptic plasticity and nicotine addiction. Neuron 31:349–352

    Article  CAS  PubMed  Google Scholar 

  • Darracq L, Blanc G, Glowinski J, Tassin JP (1998) Importance of the noradrenaline–dopamine coupling in the locomotor activating effects of d-amphetamine. J Neurosci 18:2729–2739

    CAS  PubMed  Google Scholar 

  • Dhatt RK, Gudehithlu KP, Wemlinger TA, Tejwani GA, Neff NH, Hadjiconstantinou M (1995) Preproenkephalin mRNA and methionine-enkephalin content are increased in mouse striatum after treatment with nicotine. J Neurochem 64:1878–1883

    Article  CAS  PubMed  Google Scholar 

  • Dickinson SL, Gadie B, Tulloch IF (1988) Alpha 1- and alpha 2-adrenoreceptor antagonists differentially influence locomotor and stereotyped behaviour induced by d-amphetamine and apomorphine in the rat. Psychopharmacology 96:521–527

    Article  CAS  PubMed  Google Scholar 

  • Donny EC, Caggiula AR, Knopf S, Brown C (1995) Nicotine self-administration in rats. Psychopharmacology 122:390–394

    Article  CAS  PubMed  Google Scholar 

  • Donny EC, Chaudhri N, Caggiula AR, Evans-Martin FF, Booth S, Gharib MA, Clements LA, Sved AF (2003) Operant responding for a visual reinforcer in rats is enhanced by noncontingent nicotine: implications for nicotine self-administration and reinforcement. Psychopharmacology 169:68–76

    Article  CAS  PubMed  Google Scholar 

  • 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 12:178–207

    Article  PubMed  Google Scholar 

  • Exley R, Clements MA, Hartung H, McIntosh JM, Cragg SJ (2008) Alpha6-containing nicotinic acetylcholine receptors dominate the nicotine control of dopamine neurotransmission in nucleus accumbens. Neuropsychopharmacology 33:2158–2166

    Article  CAS  PubMed  Google Scholar 

  • Fryer JD, Lukas RJ (1999) Noncompetitive functional inhibition at diverse, human nicotinic acetylcholine receptor subtypes by bupropion, phencyclidine, and ibogaine. J Pharmacol Exp Ther 288:88–92

    CAS  PubMed  Google Scholar 

  • Fu Y, Matta SG, James TJ, Sharp BM (1998) Nicotine-induced norepinephrine release in the rat amygdala and hippocampus is mediated through brainstem nicotinic cholinergic receptors. J Pharmacol Exp Ther 284:1188–1196

    CAS  PubMed  Google Scholar 

  • Fu Y, Matta SG, Kane VB, Sharp BM (2003) Norepinephrine release in amygdala of rats during chronic nicotine self-administration: an in vivo microdialysis study. Neuropharmacology 45:514–523

    Article  CAS  PubMed  Google Scholar 

  • Glow PH, Russell A (1973) Effects of dexamphetamine, amylobarbitone sodium and their mixture on sensory contingent bar pressing behaviour in the rat. Psychopharmacologia 31:239–251

    Article  CAS  PubMed  Google Scholar 

  • Hahn B, Stolerman IP (2005) Modulation of nicotine-induced attentional enhancement in rats by adrenoceptor antagonists. Psychopharmacology 177:438–447

    Article  CAS  PubMed  Google Scholar 

  • Henningfield JE, Griffiths RR (1981) Cigarette smoking and subjective response: effects of d-amphetamine. Clin Pharmacol Ther 30:497–505

    CAS  PubMed  Google Scholar 

  • Hurt RD, Sachs DP, Glover ED, Offord KP, Johnston JA, Dale LC, Khayrallah MA, Schroeder DR, Glover PN, Sullivan CR, Croghan IT, Sullivan PM (1997) A comparison of sustained-release bupropion and placebo for smoking cessation. New Engl J Med 337:1195–1202

    Article  CAS  PubMed  Google Scholar 

  • Jorenby DE, Leischow SJ, Nides MA, Rennard SI, Johnston JA, Hughes AR, Smith SS, Muramoto ML, Daughton DM, Doan K, Fiore MC, Baker TB (1999) A controlled trial of sustained-release bupropion, a nicotine patch, or both for smoking cessation. New Engl J Med 340:685–691

    Article  CAS  PubMed  Google Scholar 

  • Laviolette SR, van der Kooy D (2004) The neurobiology of nicotine addiction: bridging the gap from molecules to behaviour. Nat Rev Neurosci 5:55–65

    Article  CAS  PubMed  Google Scholar 

  • Li SX, Perry KW, Wong DT (2002) Influence of fluoxetine on the ability of bupropion to modulate extracellular dopamine and norepinephrine concentrations in three mesocorticolimbic areas of rats. Neuropharmacology 42:181–190

    Article  CAS  PubMed  Google Scholar 

  • Liu X, Caggiula AR, Palmatier MI, Booth S, Gharib M, Craven L, Donny EC, Sved AF (2006) Reinforcement enhancing effect of nicotine and its attenuation by nicotinic and dopaminergic antagonists. Proceedings of the Society for Research on Nicotine and Tobacco

  • Liu X, Palmatier MI, Caggiula AR, Donny EC, Booth S, Gharib M, Craven L, Sved AF (2007) Cholinergic substrates of the reinforcement enhancing effects of nicotine. Psychopharmacology Submitted

  • Liu X, Caggiula AR, Palmatier MI, Donny EC, Sved AF (2008) Cue-induced reinstatement of nicotine-seeking behavior in rats: effect of bupropion, persistence over repeated tests, and its dependence on training dose. Psychopharmacology 196:365–375

    Article  CAS  PubMed  Google Scholar 

  • Martin P, Massol J, Colin JN, Lacomblez L, Puech AJ (1990) Antidepressant profile of bupropion and three metabolites in mice. Pharmacopsychiatry 23:187–194

    Article  CAS  PubMed  Google Scholar 

  • McGehee DS (2006) Nicotinic and opioid receptor interactions in nicotine addiction. Mol Interv 6:311–314

    Article  CAS  PubMed  Google Scholar 

  • McGehee DS (2007) Nicotine and synaptic plasticity in prefrontal cortex. Sci STKE 2007: pe44

  • Mehta NB (1983) The chemistry of bupropion. J Clin Psychiatry 44:56–59

    CAS  PubMed  Google Scholar 

  • Nahorski SR (1976) Association of high affinity stereospecific binding of 3H-propranolol to cerebral membranes with beta adrenoceptors. Nature 259:488–489

    Article  CAS  PubMed  Google Scholar 

  • Nichols D, Selken J (2007) Alpha1-adrenergic receptors mediate the locomotor response to systemic administration of ()-3, 4-methylenedioxymethamphetamine (MDMA) in rats. Pharmacol Biochem Behav 86:622–630

    Article  PubMed  CAS  Google Scholar 

  • O'Dell TJ, Christensen BN (1988) Mecamylamine is a selective non-competitive antagonist of N-methyl-D-aspartate- and aspartate-induced currents in horizontal cells dissociated from the catfish retina. Neurosci Lett 94:93–98

    Article  PubMed  Google Scholar 

  • Ordway GA, Jaconetta SM, Halaris AE (1993) Characterization of subtypes of alpha-2 adrenoceptors in the human brain. J Pharmacol Exp Ther 264:967–976

    CAS  PubMed  Google Scholar 

  • Palmatier MI, Evans-Martin FF, Hoffman A, Caggiula AR, Chaudhri N, Donny EC, Liu X, Booth S, Gharib M, Craven L, Sved AF (2006) Dissociating the primary reinforcing and reinforcement-enhancing effects of nicotine using a rat self-administration paradigm with concurrently available drug and environmental reinforcers. Psychopharmacology 184:391–400

    Article  CAS  PubMed  Google Scholar 

  • Palmatier MI, Liu X, Caggiula AR, Donny EC, Sved AF (2007a) The role of nicotinic acetylcholine receptors in the primary reinforcing and reinforcement-enhancing effects of nicotine. Neuropsychopharmacology 32:1098–1108

    Article  CAS  PubMed  Google Scholar 

  • Palmatier MI, Liu X, Matteson GL, Donny EC, Caggiula AR, Sved AF (2007b) Conditioned reinforcement in rats established with self-administered nicotine and enhanced by noncontingent nicotine. Psychopharmacology 195:235–243

    Article  CAS  PubMed  Google Scholar 

  • Palmatier MI, Matteson GL, Black JJ, Liu X, Caggiula AR, Craven L, Donny EC, Sved AF (2007c) The reinforcement enhancing effects of nicotine depend on the incentive value of non-drug reinforcers and increase with repeated drug injections. Drug Alcohol Depend

  • Paterson N, Balfour D, Markou A (2007) Chronic bupropion attenuated the anhedonic component of nicotine withdrawal in rats via inhibition of dopamine reuptake in the nucleus accumbens shell. Eur J Neurosci 25:3099–3108

    Article  PubMed  Google Scholar 

  • Paterson NE, Balfour DJ, Markou A (2008) Chronic bupropion differentially alters the reinforcing, reward-enhancing and conditioned motivational properties of nicotine in rats. Nicotine Tob Res 10:995–1008

    Article  CAS  PubMed  Google Scholar 

  • Phillips GD, Robbins TW, Everitt BJ (1994) Mesoaccumbens dopamine-opiate interactions in the control over behaviour by a conditioned reinforcer. Psychopharmacology (Berl) 114:345–359

    Article  CAS  Google Scholar 

  • Picciotto MR, Addy NA, Mineur YS, Brunzell DH (2008) It is not "either/or": activation and desensitization of nicotinic acetylcholine receptors both contribute to behaviors related to nicotine addiction and mood. Prog Neurobiol 84:329–342

    Article  CAS  PubMed  Google Scholar 

  • Ranaldi R, Beninger RJ (1993) Dopamine D1 and D2 antagonists attenuate amphetamine-produced enhancement of responding for conditioned reward in rats. Psychopharmacology (Berl) 113:110–118

    Article  CAS  Google Scholar 

  • Rauhut AS, Mullins SN, Dwoskin LP, Bardo MT (2002) Reboxetine: attenuation of intravenous nicotine self-administration in rats. J Pharmacol Exp Ther 303:664–672

    Article  CAS  PubMed  Google Scholar 

  • Rauhut AS, Neugebauer N, Dwoskin LP, Bardo MT (2003) Effect of bupropion on nicotine self-administration in rats. Psychopharmacology 169:1–9

    Article  CAS  PubMed  Google Scholar 

  • Rice ME, Cragg SJ (2004) Nicotine amplifies reward-related dopamine signals in striatum. Nat Neurosci 7:583–584

    Article  CAS  PubMed  Google Scholar 

  • Robbins TW (1976) Relationship between reward-enhancing and stereotypical effects of psychomotor stimulant drugs. Nature 264:57–59

    Article  CAS  PubMed  Google Scholar 

  • Robbins TW (1977) Reward enhancement by psychomotor stimulant drugs. Neuropharmacology 16:529–530

    Article  CAS  PubMed  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  CAS  PubMed  Google Scholar 

  • Rose JE, Behm FM, Westman EC, Bates JE, Salley A (2003) Pharmacologic and sensorimotor components of satiation in cigarette smoking. Pharmacol Biochem Behav 76:243–250

    Article  CAS  PubMed  Google Scholar 

  • Rothman RB, Baumann MH, Dersch CM, Romero DV, Rice KC, Carroll FI, Partilla JS (2001) Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin. Synapse 39:32–41

    Article  CAS  PubMed  Google Scholar 

  • Schuster CR, Lucchesi BR, Emley GS (1979) The effects of d-amphetamine, meprobamate, and lobeline on the cigarette smoking behavior of normal human subjects. NIDA Res Monogr: 91–99

  • Shoaib M, Sidhpura N, Shafait S (2003) Investigating the actions of bupropion on dependence-related effects of nicotine in rats. Psychopharmacology 165:405–412

    CAS  PubMed  Google Scholar 

  • Slemmer JE, Martin BR, Damaj MI (2000) Bupropion is a nicotinic antagonist. J Pharmacol Exp Ther 295:321–327

    CAS  PubMed  Google Scholar 

  • Stairs DJ, Dworkin SI (2008) Rate-dependent effects of bupropion on nicotine self-administration and food-maintained responding in rats. Pharmacol Biochem Behav

  • Tassin J-P, Glowinski J, Lanteri C, Salomon L (2006) Behavioral sensitization to amphetamine results from an uncoupling between noradrenergic and serotonergic neurons. Proc Natl Acad Sci U S A 103:7476–7481

    Article  PubMed  CAS  Google Scholar 

  • Tella SR, Ladenheim B, Cadet JL (1997) Differential regulation of dopamine transporter after chronic self-administration of bupropion and nomifensine. J Pharmacol Exp Ther 281:508–513

    CAS  PubMed  Google Scholar 

  • Thanos PK, Michaelides M, Ho CW, Wang GJ, Newman AH, Heidbreder CA, Ashby CR Jr, Gardner EL, Volkow ND (2008) The effects of two highly selective dopamine D3 receptor antagonists (SB-277011A and NGB-2904) on food self-administration in a rodent model of obesity. Pharmacol Biochem Behav 89:499–507

    Article  CAS  PubMed  Google Scholar 

  • Ventura R, Cabib S, Alcaro A, Orsini C, Puglisi-Allegra S (2003) Norepinephrine in the prefrontal cortex is critical for amphetamine-induced reward and mesoaccumbens dopamine release. J Neurosci 23:1879–1885

    CAS  PubMed  Google Scholar 

  • Villegier AS, Lotfipour S, Belluzzi JD, Leslie FM (2007) Involvement of alpha1-adrenergic receptors in tranylcypromine enhancement of nicotine self-administration in rat. Psychopharmacology 193:457–465

    Article  CAS  PubMed  Google Scholar 

  • Warner C, Shoaib M (2005) How does bupropion work as a smoking cessation aid? Addict Biol 10:219–231

    Article  CAS  PubMed  Google Scholar 

  • Wewers ME, Dhatt RK, Snively TA, Tejwani GA (1999) The effect of chronic administration of nicotine on antinociception, opioid receptor binding and met-enkelphalin levels in rats. Brain Res 822:107–113

    Article  CAS  PubMed  Google Scholar 

  • Wilkinson JL, Bevins RA (2007) Bupropion hydrochloride produces conditioned hyperactivity in rats. Physiol Behav 90:790–796

    Article  CAS  PubMed  Google Scholar 

  • Wolterink G, Phillips G, Cador M, Donselaar-Wolterink I, Robbins TW, Everitt BJ (1993) Relative roles of ventral striatal D1 and D2 dopamine receptors in responding with conditioned reinforcement. Psychopharmacology 110:355–364

    Article  CAS  PubMed  Google Scholar 

  • Wooltorton JR, Pidoplichko VI, Broide RS, Dani JA (2003) Differential desensitization and distribution of nicotinic acetylcholine receptor subtypes in midbrain dopamine areas. J Neurosci 23:3176–3185

    CAS  PubMed  Google Scholar 

  • Yokel RA, Wise RA (1976) Attenuation of intravenous amphetamine reinforcement by central dopamine blockade in rats. Psychopharmacology 48:311–318

    Article  CAS  PubMed  Google Scholar 

  • Zhang XY, Kosten TA (2005) Prazosin, an alpha-1 adrenergic antagonist, reduces cocaine-induced reinstatement of drug-seeking. Biol Psychiatry 57:1202–1204

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

All experiments followed the “Principles of laboratory animal care” (NIH #85-23, revised 1985) and were approved by the University of Pittsburgh Institutional Animal Care and Use Committee (Assurance # A3187-01). This research was supported by NIH grants, DA-24801, DA-10464, and DA-19278.

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Authors and Affiliations

  1. Department of Psychology, Kansas State University, 469 Bluemont Hall, Manhattan, KS, 66502, USA

    Matthew I. Palmatier

  2. Department of Psychology, University of Pittsburgh, Pittsburgh, PA, 15260, USA

    Melissa E. Levin, Eric C. Donny & Anthony R. Caggiula

  3. Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA, 15260, USA

    Kara L. Mays & Alan F. Sved

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  1. Matthew I. Palmatier
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  2. Melissa E. Levin
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  6. Alan F. Sved
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Correspondence to Matthew I. Palmatier.

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Palmatier, M.I., Levin, M.E., Mays, K.L. et al. Bupropion and nicotine enhance responding for nondrug reinforcers via dissociable pharmacological mechanisms in rats. Psychopharmacology 207, 381–390 (2009). https://doi.org/10.1007/s00213-009-1666-5

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