Bupropion increases activation in nucleus accumbens during anticipation of monetary reward
Bupropion is used for major depressive disorder, smoking cessation aid, and obesity. It blocks reuptake of dopamine and noradrenaline and antagonizes nicotinic acetylcholine receptor. Animal studies showed that bupropion enhanced rewarding effects. In addition, bupropion has the potential to treat patients with reward processing dysfunction. However, neural substrates underlying the bupropion effects on reward function in human subjects are not fully understood.
We investigated single-dose administration of bupropion on neural response of reward anticipation in healthy subjects using a monetary incentive delay (MID) task by functional magnetic resonance imaging (fMRI), especially focusing on nucleus accumbens (NAc) activity to non-drug reward stimuli under bupropion treatment.
We used a randomized placebo-controlled within-subject crossover design. Fifteen healthy adults participated in two series of an fMRI study, taking either placebo or bupropion. The participants performed the MID task during the fMRI scanning. The effects of bupropion on behavioral performance and blood oxygenation level-dependent (BOLD) signal in NAc during anticipation of monetary gain were analyzed.
We found that bupropion significantly increased BOLD responses in NAc during monetary reward anticipation. The increased BOLD responses in NAc were observed with both low and high reward incentive cues. There was no significant difference between placebo and bupropion in behavioral performance.
Our findings provide support for the notion that bupropion enhances non-drug rewarding effects, suggesting a possible mechanism underlying therapeutic effects for patients with motivational deficit.
KeywordsBupropion Reward fMRI Nucleus accumbens Monetary incentive delay task
We are thankful to the Clinical Imaging Center for Healthcare, Nippon Medical School, for their support. In particular, we thank Koji Nagaya, Megumi Hongo, Koji Kanaya, Masaya Suda, and Minoru Sakurai for their technical assistance with the MRI examinations and Michiyo Tamura for research assistance. We also thank Arndt Gerz for his English editing of the manuscript and Brian Knutson and Hidehiko Takahashi for their advice on the MID task.
This study was supported by a Grant-in-Aid for Encouragement of Young Scientists (B) (24791237 to Y.I.) and a grant (S0801035 to H.S.) from the Ministry of Education, Culture, Sports, Science and Technology, Japan.
Compliance with ethical standards
All participants gave written informed consent, and the study was approved by the ethics committee of Nippon Medical School (approval number 223035).
Conflict of interest
The authors declare that they have no conflicts of interest.
The authors are entirely responsible for the scientific content of this paper.
- Balodis IM, Grilo CM, Kober H, Worhunsky PD, White MA, Stevens MC, Pearlson GD, Potenza MN (2014) A pilot study linking reduced fronto-striatal recruitment during reward processing to persistent bingeing following treatment for binge-eating disorder. Int J Eat Disord 47:376–384. https://doi.org/10.1002/eat.22204 CrossRefGoogle Scholar
- Beck AT, Steer RA, Brown GK (1996) Manual for the Beck Depression Inventory, 2nd edn. Pearson, TexasGoogle Scholar
- Bischoff S, Bittiger H, Krauss J, Vassout A, Waldmeier P (1984) Affinity changes of rat striatal dopamine receptors in vivo after acute bupropion treatment. Eur J Pharmacol 104:173–176. https://doi.org/10.1016/0014-2999(84)90386-8
- Bond A, Lader M (1974) The use of analogue scales in rating subjective feelings. Br J Med Psychol 47:211–218. https://doi.org/10.1111/j.2044-8341.1974.tb02285.x CrossRefGoogle Scholar
- Bray GA, Frühbeck G, Ryan DH, Wilding JP (2016) Management of obesity. Lancet 387:1947–1956. https://doi.org/10.1016/S0140-6736(16)00271-3
- Bruijnzeel AW, Alexander JC, Perez PD, Bauzo-Rodriguez R, Hall G, Klausner R, Guerra V, Zeng H, Igari M, Febo M (2014) Acute nicotine administration increases BOLD fMRI signal in brain regions involved in reward signaling and compulsive drug intake in rats. Int J Neuropsychopharmacol 18:pyu011. https://doi.org/10.1093/ijnp/pyu011 CrossRefGoogle Scholar
- Buckholtz JW, Treadway MT, Cowan RL, Woodward ND, Benning SD, Li R, Ansari MS, Baldwin RM, Schwartzman AN, Shelby ES, Smith CE, Cole D, Kessler RM, Zald DH (2010) Mesolimbic dopamine reward system hypersensitivity in individuals with psychopathic traits. Nat Neurosci 13:419–421. https://doi.org/10.1038/nn.2510 CrossRefGoogle Scholar
- Cheetham SC, Kettle CJ, Martin KF, Heal DJ (1995) D1 receptor binding in rat striatum: modification by various D1 and D2 antagonists, but not by sibutramine hydrochloride, antidepressants or treatments which enhance central dopaminergic function. J Neural Transm Gen Sect 102:35–46. https://doi.org/10.1007/BF01276563 CrossRefGoogle Scholar
- Chevassus H, Farret A, Gagnol JP, Ponçon CA, Costa F, Roux C, Galtier F, Petit P (2013) Psychological and physiological effects of bupropion compared to methylphenidate after prolonged administration in healthy volunteers (NCT00285155). Eur J Clin Pharmacol 69:779–787. https://doi.org/10.1007/s00228-012-1418-z CrossRefGoogle Scholar
- Conners CK, Casat CD, Gualtieri CT, Weller E, Reader M, Reiss A, Weller RA, Khayrallah M, Ascher J (1996) Bupropion hydrochloride in attention deficit disorder with hyperactivity. J Am Acad Child Adolesc Psychiatry 35:1314–1321. https://doi.org/10.1097/00004583-199610000-00018 CrossRefGoogle 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 168: 347–358. https://doi.org/10.1007/s00213-003-1445-7
- Damaj MI, Carroll FI, Eaton JB, Navarro HA, Blough BE, Mirza S, Lukas RJ, Martin BR (2004) Enantioselective effects of hydroxy metabolites of bupropion on behavior and on function of monoamine transporters and nicotinic receptors. Mol Pharmacol 66:675–682. https://doi.org/10.1124/mol.104.001313 CrossRefGoogle Scholar
- David SP, Munafò MR, Johansen-Berg H, Smith SM, Rogers RD, Matthews PM, Walton RT (2005) Ventral striatum/nucleus accumbens activation to smoking-related pictorial cues in smokers and nonsmokers: a functional magnetic resonance imaging study. Biol Psychiatry 58:488–494. https://doi.org/10.1016/j.biopsych.2005.04.028 CrossRefGoogle Scholar
- Egerton A, Shotbolt JP, Stokes PR, Hirani E, Ahmad R, Lappin JM, Reeves SJ, Mehta MA, Howes OD, Grasby PM (2010) Acute effect of the anti-addiction drug bupropion on extracellular dopamine concentrations in the human striatum: an [11C]raclopride PET study. Neuroimage 50:260–266. https://doi.org/10.1016/j.neuroimage.2009.11.077 CrossRefGoogle 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 288:88–92Google Scholar
- Gobbi G, Slater S, Boucher N, Debonnel G, Blier P (2003) Neurochemical and psychotropic effects of bupropion in healthy male subjects. J Clin Psychopharmacol 23:233–239. https://doi.org/10.1097/01.jcp.0000084023.22282.03 Google Scholar
- Hall BJ, Pearson LS, Buccafusco JJ (2010) Effect of administration of the nicotinic acetylcholine receptor antagonist BTMPS, during nicotine self-administration, on lever responding induced by context long after withdrawal. Neuropharmacology 58:429–435. https://doi.org/10.1016/j.neuropharm.2009.09.009 CrossRefGoogle Scholar
- Hamilton M (1959) The assessment of anxiety states by rating. Br J Med Psychol 32:50–55. https://doi.org/10.1111/j.2044-8341.1959.tb00467.x CrossRefGoogle Scholar
- Hamilton MJ, Bush M, Smith P, Peck AW (1982) The effects of bupropion, a new antidepressant drug, and diazepam, and their interaction in man. Br J Clin Pharmacol 14:791–797. https://doi.org/10.1111/j.1365-2125.1982.tb02038.x CrossRefGoogle Scholar
- Herrera-Guzmán I, Gudayol-Ferré E, Lira-Mandujano J, Herrera-Abarca J, Herrera-Guzmán D, Montoya-Pérez K, Guardia-Olmos J (2008) Cognitive predictors of treatment response to bupropion and cognitive effects of bupropion in patients with major depressive disorder. Psychiatry Res 160:72–82. https://doi.org/10.1016/j.psychres.2007.04.012 CrossRefGoogle Scholar
- Høiseth G, Haslemo T, Uthus LH, Molden E (2015) Effect of CYP2B6*6 on steady-state serum concentrations of bupropion and hydroxybupropion in psychiatric patients: a study based on therapeutic drug monitoring data. Ther Drug Monit 37:589–593. https://doi.org/10.1097/FTD.0000000000000183 CrossRefGoogle Scholar
- Knutson B, Adams CM, Fong GW, Hommer D (2001) Anticipation of increasing monetary reward selectively recruits nucleus accumbens. J Neurosci 21:RC159. https://doi.org/10.1523/JNEUROSCI.21-16-j0002.2001 CrossRefGoogle Scholar
- Learned-Coughlin SM, Bergström M, Savitcheva I, Ascher J, Schmith VD, Långstrom B (2003) In vivo activity of bupropion at the human dopamine transporter as measured by positron emission tomography. Biol Psychiatry 54:800–805. https://doi.org/10.1016/S0006-3223(02)01834-6
- 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. https://doi.org/10.1016/S0028-3908(01)00160-5
- Martin KF, Phillips I, Cheetham SC, Heal DJ (1995) Dopamine D2 receptors: a potential pharmacological target for nomifensine and tranylcypromine but not other antidepressant treatments. Pharmacol Biochem Behav 51:565–569. https://doi.org/10.1016/0091-3057(95)00095-E
- McNair DM, Lorr M, Droppleman LF (1971) Manual for the Profile of Mood States. Educational and Industrial Testing Service, CaliforniaGoogle Scholar
- Oldfield RC (1971) The assessment and analysis of handedness: the Edinburgh inventory. Neuropsychologia 9:97–113. https://doi.org/10.1016/0028-3932(71)90067-4
- Ossewaarde L, Verkes RJ, Hermans EJ, Kooijman SC, Urner M, Tendolkar I, van Wingen GA, Fernández G (2011) Two-week administration of the combined serotonin-noradrenaline reuptake inhibitor duloxetine augments functioning of mesolimbic incentive processing circuits. Biol Psychiatry 70:568–574. https://doi.org/10.1016/j.biopsych.2011.03.041 CrossRefGoogle Scholar
- Peters J, Bromberg U, Schneider S, Brassen S, Menz M, Banaschewski T, Conrod PJ, Flor H, Gallinat J, Garavan H, Heinz A, Itterman B, Lathrop M, Martinot JL, Paus T, Poline JB, Robbins TW, Rietschel M, Smolka M, Ströhle A, Struve M, Loth E, Schumann G, Büchel C, IMAGEN Consortium (2011) Lower ventral striatal activation during reward anticipation in adolescent smokers. Am J Psychiatry 168:540–549. https://doi.org/10.1176/appi.ajp.2010.10071024 CrossRefGoogle Scholar
- Pizzagalli DA, Holmes AJ, Dillon DG, Goetz EL, Birk JL, Bogdan R, Dougherty DD, Iosifescu DV, Rauch SL, Fava M (2009) Reduced caudate and nucleus accumbens response to rewards in unmedicated individuals with major depressive disorder. Am J Psychiatry 166:702–710. https://doi.org/10.1176/appi.ajp.2008.08081201 CrossRefGoogle Scholar
- Rahman S, Neugebauer NM, Zhang Z, Crooks PA, Dwoskin LP, Bardo MT (2008) The novel nicotinic receptor antagonist N,N’-dodecane-1,12-diyl-bis-3-picolinium dibromide decreases nicotine-induced dopamine metabolism in rat nucleus accumbens. Eur J Pharmacol 601:103–105. https://doi.org/10.1016/j.ejphar.2008.10.037
- Randall PA, Lee CA, Podurgiel SJ, Hart E, Yohn SE, Jones M, Rowland M, López-Cruz L, Correa M, Salamone JD (2014) Bupropion increases selection of high effort activity in rats tested on a progressive ratio/chow feeding choice procedure: implications for treatment of effort-related motivational symptoms. Int J Neuropsychopharmacol 18:pyu017. https://doi.org/10.1093/ijnp/pyu017 CrossRefGoogle Scholar
- Sagara H, Kitamura Y, Yae T, Shibata K, Suemaru K, Sendo T, Araki H, Gomita Y (2008) Nicotinic acetylcholine α4β2 receptor regulates the motivational effect of intracranial self stimulation behavior in the runway method. J Pharmacol Sci 108:455–461. https://doi.org/10.1254/jphs.08168FP CrossRefGoogle Scholar
- Saji K, Ikeda Y, Kim W, Shingai Y, Tateno A, Takahashi H, Okubo Y, Fukayama H, Suzuki H (2013) Acute NK1 receptor antagonist administration affects reward incentive anticipation processing in healthy volunteers. Int J Neuropsychopharmacol 16:1461–1471. https://doi.org/10.1017/S1461145712001678 CrossRefGoogle Scholar
- Schott BH, Minuzzi L, Krebs RM, Elmenhorst D, Lang M, Winz OH, Seidenbecher CI, Coenen HH, Heinze HJ, Zilles K, Düzel E, Bauer A (2008) Mesolimbic functional magnetic resonance imaging activations during reward anticipation correlate with reward-related ventral striatal dopamine release. J Neurosci 28:14311–14319. https://doi.org/10.1523/JNEUROSCI.2058-08.2008 CrossRefGoogle Scholar
- Slemmer JE, Martin BR, Damaj MI (2000) Bupropion is a nicotinic antagonist. J Pharmacol Exp Ther 295:321–327Google Scholar
- Spielberger CD (1983) Manual for the State-Trait Anxiety Inventory, STAI-form Y. Consulting Psychologists Press, CaliforniaGoogle Scholar
- Takamura M, Okamoto Y, Okada G, Toki S, Yamamoto T, Ichikawa N, Mori A, Minagawa H, Takaishi Y, Fujii Y, Kaichi Y, Akiyama Y, Awai K, Yamawaki S (2017) Patients with major depressive disorder exhibit reduced reward size coding in the striatum. Prog Neuro-Psychopharmacol Biol Psychiatry 79:317–323. https://doi.org/10.1016/j.pnpbp.2017.07.006 CrossRefGoogle Scholar
- Talairach J, Tournoux P (1988) Co-planar stereotaxic atlas of the human brain: 3-dimensional proportional system—an approach to cerebral imaging. Thieme Medical Publishers, New YorkGoogle Scholar
- Tobey KM, Walentiny DM, Wiley JL, Carroll FI, Damaj MI, Azar MR, Koob GF, George O, Harris LS, Vann RE (2012) Effects of the specific α4β2 nAChR antagonist, 2-fluoro-3-(4-nitrophenyl) deschloroepibatidine, on nicotine reward-related behaviors in rats and mice. Psychopharmacology 223:159–168. https://doi.org/10.1007/s00213-012-2703-3 CrossRefGoogle Scholar
- Versace F, Engelmann JM, Deweese MM, Robinson JD, Green CE, Lam CY, Minnix JA, Karam-Hage MA, Wetter DW, Schembre SM, Cinciripini PM (2017) Beyond cue reactivity: non-drug-related motivationally relevant stimuli are necessary to understand reactivity to drug-related cues. Nicotine Tob Res 19:663–669. https://doi.org/10.1093/ntr/ntx002 CrossRefGoogle Scholar
- Wilson RP, Colizzi M, Bossong MG, Allen P, Kempton M; MTAC, Bhattacharyya S (2018) The neural substrate of reward anticipation in health: a meta-analysis of fMRI findings in the monetary incentive delay task. Neuropsychol Rev 28:496–506. https://doi.org/10.1007/s11065-018-9385-5