Abstract
D-amphetamine (dAMPH) and methylphenidate (MPH) are stimulants used in the treatment of Attention Deficit Hyperactivity Disorder (ADHD). Preclinical studies have shown that in healthy animals, dAMPH induces dopamine (DA) dysfunction, as evidenced for instance by loss of DA levels and its transporters. It has also been suggested that DA plays an important role in emotional processing, and that altered DA-ergic intervention may modulate amygdala function. To explore the role of the DA system in emotional processing we examined emotional processing using functional magnetic resonance imaging (fMRI) in eight male recreational users of dAMPH and eight male healthy controls. We compared brain activation between both groups during an emotional face-processing task with and without an oral MPH challenge. All subjects were abstinent for at least 2 weeks during the baseline scan. The second scan was performed on the same day 1½ hours after receiving an oral dose of 35 mg MPH. A significant Valence*Group interaction (p = .037) indicated amygdala hyperreactivity to fearful facial expressions in dAMPH users that wasrobust against adjustment for age (p = .015). Furthermore, duration of amphetamine use in years was positively correlated with amygdala reactivity in dAMPH users (r = .76; p = .029). These exploratory findings are in line with previous findings suggesting that DA plays a role in emotional processing.
Similar content being viewed by others
References
Abercrombie, E. D., & Zigmond, M. J. (1989). Partial injury to central noradrenergic neurons: reduction of tissue norepinephrine content is greater than reduction of extracellular norepinephrine measured by microdialysis. The Journal of Neuroscience, 9(11), 4062–4067.
Bergman O., Åhs F., Furmark T., Appel L., Linnman C., Faria V., et al. (2014). Translational Psychiatry, 4(8), e420–6. doi:10.1038/tp.2014.50.
Blier, P. (2013). Neurotransmitter targeting in the treatment of depression. The Journal of Clinical Psychiatry, 74(2), 19–24. doi:10.4088/JCP.12084su1c.04.
Bolaños, C. A., Barrot, M., Berton, O., Wallace-Black, D., & Nestler, E. J. (2003). Methylphenidate treatment during pre- and periadolescence alters behavioral responses to emotional stimuli at adulthood. Biological Psychiatry, 54(12), 1317–1329. doi:10.1016/S0006-3223(03)00570-5.
Bolaños, C. A., Willey, M. D., Maffeo, M. L., Powers, K. D., Kinka, D. W., Grausam, K. B., & Henderson, R. P. (2008). Antidepressant treatment can normalize adult behavioral deficits induced by early-life exposure to methylphenidate. Biological Psychiatry, 63(3), 309–316. doi:10.1016/j.biopsych.2007.06.024.
Bonhomme, N., Cador, M., Stinus, L., Le Moal, M., & Spampinato, U. (1995). Short and long-term changes in dopamine and serotonin receptor binding sites in amphetamine-sensitized rats: a quantitative autoradiographic study. Brain Research, 675(1–2), 215–223.
Brotman, M. A., Rich, B. A., Guyer, A. E., Lunsford, J. R., Horsey, S. E., Reising, M. M., et al. (2010). Amygdala activation during emotion processing of neutral faces in children with severe mood dysregulation versus ADHD or bipolar disorder. The American Journal of Psychiatry, 167(1), 61–69. doi:10.1176/appi.ajp.2009.09010043.
Carlezon, W. A., Jr., Mague, S. D., & Andersen, S. L. (2003). Enduring behavioral effects of early exposure to methylphenidate in rats. BPS, 54(12), 1330–1337.
Conzelmann, A., Woidich, E., Mucha, R. F., Weyers, P., Jacob, C. P., Lesch, K. P., et al. (2011). Methylphenidate normalizes emotional processing in adult patients with attention-deficit/hyperactivity disorder: preliminary findings. Brain Research, 1381(24), 159–166.
Delaveau, P., Salgado-Pineda, P., Wicker, B., Micallef-Roll, J., & Blin, O. (2005). Effect of levodopa on healthy volunteers’ facial emotion perception: an FMRI study. Clinical Neuropharmacology, 28(6), 255–261.
Demenescu, L. R., Renken, R., Kortekaas, R., van Tol, M. J., Marsman, J. B. C., van Buchem, M. A., et al. (2011). Neural correlates of perception of emotional facial expressions in out-patients with mild-to-moderate depression and anxiety. A multicenter fMRI study. Psychological Medicine, 41(11), 2253–2264. doi:10.1017/S0033291711000596.
El-Mallakh, R. S. (2000). An open study of methylphenidate in bipolar depression. Bipolar Disorders, 2(1), 56–59. doi:10.1034/j.1399-5618.2000.020108.x.
Fadok, J. P., Dickerson, T. M. K., & Palmiter, R. D. (2009). Dopamine is necessary for cue-dependent fear conditioning. Journal of Neuroscience, 29(36), 11089–11097. doi:10.1523/JNEUROSCI. 1616-09.2009.
Geller, B., Harms, M. P., Wang, L., Tillman, R., DelBello, M. P., Bolhofner, K., et al. (2009). Effects of age, sex, and independent life events on amygdala and nucleus accumbens volumes in child bipolar I disorder. Biol Psychiatry 65(5), 432–437. doi:10.1016/j.biopsych.2008.09.033.
Guarraci, F. A., Frohardt, R. J., Young, S. L., & Kapp, B. S. (1999). A functional role for dopamine transmission in the amygdala during condtioned fear. Annals of the New York Academy of Sciences, 877(1), 732–736.
Hannestad, J., Gallezot, J. D., Planeta-Wilson, B., Lin, S. F., Williams, W. A., van Dyck, C. H., et al. (2010). Clinically relevant doses of methylphenidate significantly occupy norepinephrine transporters in humans in vivo. BPS, 68(9), 854–860. doi:10.1016/j.biopsych.2010.06.017.
Hariri, A. R., Mattay, V. S., Tessitore, A., Fera, F., Smith, W. G., & Weinberger, D. R. (2002). Dextroamphetamine modulates the response of the human amygdala. Neuropsychopharmacology, 27(6), 1036–1040. doi:10.1016/S0893-133X(02)00373-1.
Horvitz, J. C. (2000). Mesolimbocortical and nigrostriatal dopamine responses to salient non-reward events. NSC, 96(4), 651–656.
Hysek, C. M., Simmler, L. D., Schillinger, N., Meyer, N., Schmid, Y., Donzelli, M., et al. (2013). Pharmacokinetic and pharmacodynamic effects of methylphenidate and MDMA administered alone or in combination. The International Journal of Neuropsychopharmacology, 17(03), 371–381. doi:10.1017/S1461145713001132.
Kalivas, P. W., & Duffy, P. (1995). Selective activation of dopamine transmission in the shell of the nucleus accumbens by stress. Brain Research, 675(1–2), 325–328.
Lemon, N. (2006). Dopamine D1/D5 receptors gate the acquisition of novel information through Hippocampal long-term potentiation and long-term depression. Journal of Neuroscience, 26(29), 7723–7729. doi:10.1523/JNEUROSCI. 1454-06.2006.
Molina, B. S. G., Hinshaw, S. P., Swanson, J. M., Arnold, L. E., Vitiello, B., Jensen, P. S., et al. (2009). The MTA at 8 years: prospective follow-up of children treated for combined-type ADHD in a multisite study. Journal of the American Academy of Child and Adolescent Psychiatry, 48(5), 484–500. doi:10.1097/CHI.0b013e31819c23d0.
Musser, E. D., Galloway-Long, H. S., Frick, P. J., & Nigg, J. T. (2013). Emotion regulation and heterogeneity in attention-deficit/hyperactivity disorder. Journal of the American Academy of Child and Adolescent Psychiatry, 52(2), 163–171.e2. doi:10.1016/j.jaac.2012.11.009.
Posner, J., Nagel, B. J., Maia, T. V., Mechling, A., Oh, M., Wang, Z., & Peterson, B. S. (2011). Abnormal amygdalar activation and connectivity in adolescents with attention-deficit/hyperactivity disorder. Journal of the American Academy of Child and Adolescent Psychiatry, 50(8), 828–837.e3. doi:10.1016/j.jaac.2011.05.010.
Reneman, L., Booij, J., Lavalaye, J., de Bruin, K., Reitsma, J. B., Gunning, B. W., et al. (2001). Use of amphetamine by recreational users of ecstasy (MDMA) is associated with reduced striatal dopamine transporter densities: a [123I]β-CIT SPECT study – preliminary report. Psychopharmacology, 159(3), 335–340. doi:10.1007/s00213-001-0930-0.
Ricaurte, G. A. (2005). Amphetamine treatment similar to that used in the treatment of adult attention-deficit/hyperactivity disorder damages dopaminergic nerve endings in the striatum of adult nonhuman primates. Journal of Pharmacology and Experimental Therapeutics, 315(1), 91–98. doi:10.1124/jpet.105.087916.
Ruhé, H. G., Booij, J., Veltman, D. J., Michel, M. C., & Schene, A. H. (2011). Successful pharmacologic treatment of major depressive disorder attenuates amygdala activation to negative facial expressions. The Journal of Clinical Psychiatry, 73(04), 451–459. doi:10.4088/JCP.10m06584.
Scholl, J. L., Vuong, S. M., & Forster, G. L. (2010). Chronic amphetamine treatment enhances corticotropin-releasing factor-induced serotonin release in the amygdala. European Journal of Pharmacology, 644(1–3), 80–87. doi:10.1016/j.ejphar.2010.07.008.
Schouw, M. L. J., Kaag, A. M., Caan, M. W. A., Heijtel, D. F. R., Majoie, C. B. L. M., Nederveen, A. J., et al. (2013). Mapping the hemodynamic response in human subjects to a dopaminergic challenge with dextroamphetamine using ASL-based pharmacological MRI. NeuroImage, 72(C), 1–9. doi:10.1016/j.neuroimage.2012.12.056.
Schrantee A, Václavů L, Heijtel D.F., Caan M.W., Gsell W., Lucassen P.J., Nederveen A.J., Booij J., Reneman L. (2014). Dopaminergic System Dysfunction in Recreational Dexamphetamine Users. Neuropsychopharmacology,2014 (in press).
Shaw, P., Stringaris, A., Nigg, J., & Leibenluft, E. (2014). Emotion dysregulation in attention deficit hyperactivity disorder. American Journal of Psychiatry, 171(3), 276–293. doi:10.1176/appi.ajp.2013.13070966.
Tao, R., Calley, C. S., Hart, J., Mayes, T. L., Nakonezny, P. A., Lu, H., et al. (2012). Brain activity in adolescent major depressive disorder before and after fluoxetine treatment. The American Journal of Psychiatry, 169(4), 381–388. doi:10.1176/appi.ajp.2011.11040615.
Tessitore, A., Hariri, A. R., Fera, F., Smith, W. G., Chase, T. N., Hyde, T. M., et al. (2002). Dopamine modulates the response of the human amygdala: a study in Parkinson's disease. Journal of Neuroscience, 22(20), 9099–9103.
van den Bulk, B. G., Meens, P. H., van Lang, N. D., de Voogd, E. L., van der Wee, N. J., Rombouts, S. A., Crone, E. A., & Vermeiren, R. R. (2014). Amygdala activation during emotional face processing in adolescents with affective disorders: the role of underlying depression and anxiety symptoms. Frontiers in Human Neuroscience, 5(8), 393. doi:10.3389/fnhum.2014.00393.
Volkow, N. D., Wang G. J., Newcorn, J., Telang, F., Solanto, M. V., Fowler, J. S., et al. (2007). Depressed dopamine activity in caudate and preliminary evidence of limbic involvement in adults with attention-deficit/hyperactivity disorder. Archives of General Psychiatry 64, 932–940.
Williams, L. M., Hermens, D. F., Palmer, D., Kohn, M., Clarke, S., Keage, H., et al. (2008). Misinterpreting emotional expressions in attention-deficit/hyperactivity disorder: evidence for a neural marker and stimulant effects. Biological Psychiatry, 63(10), 917–926. doi:10.1016/j.biopsych.2007.11.022.
Acknowledgments
This work was financially supported by an AMC Fellowship Grant awarded to Dr. L. Reneman.
Conflict of interest
M. A. Bottelier, M. L. J. Schouw, M. B. de Ruiter, H. G. Ruhe, R. J. L. Lindauer, and L. Reneman declare that they have no conflicts of interest.
Informed consent
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, and the applicable revisions at the time of the investigation. Informed consent was obtained from all patients for being included in the study.
Author information
Authors and Affiliations
Corresponding author
Additional information
M. A. Bottelier and M. L. J. Schouw these authors contributed equally to the content of this paper
Rights and permissions
About this article
Cite this article
Bottelier, M.A., Schouw, M.L.J., de Ruiter, M.B. et al. Effects of methylphenidate during emotional processing in amphetamine users: preliminary findings. Brain Imaging and Behavior 9, 878–886 (2015). https://doi.org/10.1007/s11682-014-9350-8
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11682-014-9350-8