Abstract
Dexamphetamine (dAMPH) is a stimulant drug that is widely used recreationally as well as for the treatment of attention-deficit hyperactivity disorder (ADHD). Although animal studies have shown neurotoxic effects of dAMPH on the dopaminergic system, little is known about such effects on the human brain. Here, we studied the dopaminergic system at multiple physiological levels in recreational dAMPH users and age, gender, and IQ-matched dAMPH-naïve healthy controls. We assessed baseline D2/3 receptor availability, in addition to changes in dopamine (DA) release using single-photon emission computed tomography and DA functionality using pharmacological magnetic resonance imaging, following a dAMPH challenge. Also, the subjective responses to the challenge were determined. dAMPH users displayed significantly lower striatal DA D2/3 receptor binding compared with healthy controls. In dAMPH users, we further observed a blunted DA release and DA functionality to an acute dAMPH challenge, as well as a blunted subjective response. Finally, the lower D2/3 availability, the more pleasant the dAMPH administration was experienced by control subjects, but not by dAMPH users. Thus, in agreement with preclinical studies, we show that the recreational use of dAMPH in human subjects is associated with dopaminergic system dysfunction. These findings warrant further (longitudinal) investigations and call for caution when using this drug recreationally and for ADHD.
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References
Ashburner J (2007). A fast diffeomorphic image registration algorithm. Neuroimage 38: 95–113.
Booij J, Korn P, Linszen DH, Royen van EA (1997). Assessment of endogenous dopamine release by methylphenidate challenge using iodine-123 iodobenzamide single-photon emission tomography. Eur J Nucl Med 24: 674–677.
Boot E, Booij J, Hasler G, Zinkstok JR, Haan de L, Linszen DH et al (2008). AMPT-induced monoamine depletion in humans: evaluation of two alternative [123I]IBZM SPECT procedures. Eur J Nucl Med Mol Imaging 35: 1350–1356.
Brodie MS, Pesold C, Appel SB (1999). Ethanol directly excites dopaminergic ventral tegmental area reward neurons. Alcohol Clin Exp Res 23: 1848–1852.
Bruns A, Künnecke B, Risterucci C, Moreau J-L, Kienlin von M (2009). Validation of cerebral blood perfusion imaging as a modality for quantitative pharmacological MRI in rats. Magn Reson Med 61: 1451–1458.
Cadet JL, Krasnova IN, Jayanthi S, Lyles J (2007). Neurotoxicity of substituted amphetamines: molecular and cellular mechanisms. Neurotox Res 11: 183–202.
Castner S, Al-Tikriti MS, Baldwin RM, Seibyl JP, Innis RB, Goldman-Rakic PS (2000). Behavioral changes and [123I]IBZM equilibrium SPECT measurement of amphetamine-induced dopamine release in rhesus monkeys exposed to subchronic amphetamine. Neuropsychopharmacology 22: 4–13.
Chen Y, Galpern WR, Brownell AL, Matthews RT, Bogdanov M, Isacson O et al (1997). Detection of dopaminergic neurotransmitter activity using pharmacologic MRI: correlation with PET, microdialysis, and behavioral data. Magn Reson Imaging 38: 389–398.
Di Chiara G, Imperato A (1988). Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proc Natl Acad Sci USA 85: 5274–5278.
Collins DL, Holmes CJ, Peters TM, Evans AC (1995). Automatic 3-D model-based neuroanatomical segmentation. Hum Brain Mapp 3: 190–208.
European Monitoring Centre for Drugs and Drug Addiction (2012). Statistical Bulletin. Online publication: http://www.emcdda.europa.eu/stats12.
Gill KE, Pierre PJ, Daunais J, Bennett AJ, Martelle S, Gage HD et al (2012). Chronic treatment with extended release methylphenidate does not alter dopamine systems or increase vulnerability for cocaine self-administration: a study in nonhuman primates. Neuropsychopharmacology 37: 2555–2565.
Ginovart N, Farde L, Halldin C, Swahn CG (1999). Changes in striatal D2-receptor density following chronic treatment with amphetamine as assessed with PET in nonhuman primates. Synapse 31: 154–162.
Groman SM, Morales AM, Lee B, London ED, Jentsch JD (2013). Methamphetamine-induced increases in putamen gray matter associate with inhibitory control. Psychopharmacology (Berl) 229: 527–538.
Hernandez-Lopez C (2002). 3,4-Methylenedioxymethamphetamine (Ecstasy) and alcohol interactions in humans: psychomotor performance, subjective effects, and pharmacokinetics. J Pharmacol Exp Ther 300: 236–244.
Jenkins BG, Sanchez-Pernaute R, Brownell AL, Chen YCI, Isacson O (2004). Mapping dopamine function in primates using pharmacologic magnetic resonance imaging. J Neurosci 24: 9553–9560.
Van Kammen DP, Murphy DL (1975). Attenuation of the euphoriant and activating effects of d- and l-amphetamine by lithium carbonate treatment. Psychopharmacologia 44: 215–224.
Kegeles LS, Zea-Ponce Y, Abi-Dargham A, Rodenhiser J, Wang T, Weiss R et al (1999). Stability of [123I]IBZM SPECT measurement of amphetamine-induced striatal dopamine release in humans. Synapse 31: 302–308.
Khalili-Mahani N, Osch MJP, van, Baerends E, Soeter RP, Kam de M, Zoethout RWM et al (2011). Pseudocontinuous arterial spin labeling reveals dissociable effects of morphine and alcohol on regional cerebral blood flow. J Cereb Blood Flow Metab 31: 1321–1333.
Koester P, Tittgemeyer M, Wagner D, Becker B, Gouzoulis-Mayfrank E, Daumann J (2012). Cortical thinning in amphetamine-type stimulant users. Neuroscience 221: 182–192.
Krasnova IN, Chiflikyan M, Justinova Z, McCoy MT, Ladenheim B, Jayanthi S et al (2013). CREB phosphorylation regulates striatal transcriptional responses in the self-administration model of methamphetamine addiction in the rat. Neurobiol Dis 58: 132–143.
Krasnova IN, Ladenheim B, Cadet JL (2005). Amphetamine induces apoptosis of medium spiny striatal projection neurons via the mitochondria-dependent pathway. FASEB J 19: 851–853.
Krasnova IN, Ladenheim B, Jayanthi S, Oyler J, Moran TH, Huestis MA et al (2001). Amphetamine-induced toxicity in dopamine terminals in CD-1 and C57BL/6J mice: complex roles for oxygen-based species and temperature regulation. Neuroscience 107: 265–274.
Mackey S, Stewart JL, Connolly CG, Tapert SF, Paulus MP (2014). A voxel-based morphometry study of young occasional users of amphetamine-type stimulants and cocaine. Drug Alcohol Depend 135: 104–111.
Marel K, van der, Klomp A, Meerhoff GF, Schipper P, Lucassen PJ, Homberg JR et al (2014). Long-term oral methylphenidate treatment in adolescent and adult rats: differential effects on brain morphology and function. Neuropsychopharmacology 39: 263–273.
Martinez D, Gil R, Slifstein M, Hwang D-R, Huang Y, Perez A et al (2005). Alcohol dependence is associated with blunted dopamine transmission in the ventral striatum. Biol Psychiatry 58: 779–786.
Martinez D, Greene K, Broft A, Kumar D, Liu F, Narendran R et al (2009). Lower level of endogenous dopamine in patients with cocaine dependence: findings from PET imaging of D(2)/D(3) receptors following acute dopamine depletion. Am J Psychiatry 166: 1170–1177.
Martinez D, Narendran R, Foltin RW, Slifstein M, Hwang D-R, Broft A et al (2007). Amphetamine-induced dopamine release: markedly blunted in cocaine dependence and predictive of the choice to self-administer cocaine. Am J Psychiatry 164: 622–629.
McCann UD, Ricaurte GA (2004). Amphetamine neurotoxicity: accomplishments and remaining challenges. Neurosci Biobehav Rev 27: 821–826.
Oberlin BG, Dzemidzic M, Tran SM, Soeurt CM, O’Connor SJ, Yoder KK et al (2014). Beer self-administration provokes lateralized nucleus accumbens dopamine release in male heavy drinkers. Psychopharmacology (Berl) doi:10.1007/s00213-014-3720-1.
Reneman L, Booij J, Lavalaye J, Bruin de K, Reitsma JB, Gunning WB et al (2002). Use of amphetamine by recreational users of ecstasy (MDMA) is associated with reduced striatal dopamine transporter densities: a [I-123] beta-CIT SPECT study-preliminary report. Psychopharmacology (Berl) 159: 335–340.
Ricaurte GA, Mechan AO, Yuan J, Hatzidimitriou G, Xie T, Mayne AH et al (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. J Pharmacol Exp Ther 315: 91–98.
Schmand B, Geerlings MI, Jonker C, Lindeboom J (1998). Reading ability as an estimator of premorbid intelligence: does it remain stable in emergent dementia? J Clin Exp Neuropsychol 20: 42–51.
Schouw M, Kaag A, Caan M (2013a). Mapping the hemodynamic response in human subjects to a dopaminergic challenge with dextroamphetamine using ASL-based pharmacological MRI. Neuroimage 72: 1–9.
Schouw MLJ, Caan MWA, Geurts HM, Schmand B, Booij J, Nederveen AJ et al (2013b). Monoaminergic dysfunction in recreational users of dexamphetamine. Eur Neuropsychopharmacol 23: 1491–1502.
Soto PL, Wilcox KM, Zhou Y, Kumar A, Ator NA, Riddle MA et al (2012). Long-term exposure to oral methylphenidate or dl-amphetamine mixture in peri-adolescent rhesus monkeys: effects on physiology, behavior, and dopamine system development. Neuropsychopharmacology 37: 2566–2579.
Strakowski SM, Sax KW, Setters MJ, Keck PE (1996). Enhanced response to repeated d-amphetamine challenge: evidence for behavioral sensitization in humans. Biol Psychiatry 40: 872–880.
Substance Abuse and Mental Health Services Administration (2012). National Survey on Drug Use and Health: Summary of National Findings, NSDUH Series H-46, HHS Publication No. (SMA) 13-4795. Rockville, MD: Substance Abuse and Mental Health Services Administration, 2013.
Urban NBL, Kegeles LS, Slifstein M, Xu X, Martinez D, Sakr E et al (2010). Sex differences in striatal dopamine release in young adults after oral alcohol challenge: a positron emission tomography imaging study with [11C]raclopride. Biol Psychiatry 68: 689–696.
Videbaek C, Toska K, Scheideler MA, Paulson OB, Moos Knudsen G (2000). SPECT tracer [(123)I]IBZM has similar affinity to dopamine D2 and D3 receptors. Synapse 38: 338–342.
Volkow ND, Chang L, Wang GJ, Fowler JS, Ding YS, Sedler MJ et al (2001). Low level of brain dopamine D2 receptors in methamphetamine abusers: association with metabolism in the orbitofrontal cortex. Am J Psychiatry 158: 2015–2021.
Volkow ND, Tomasi D, Wang G-J, Logan J, Alexoff DL, Jayne M et al (2014a). Stimulant-induced dopamine increases are markedly blunted in active cocaine abusers. Mol Psychiatry 19: 1037–1043.
Volkow ND, Wang G-J, Fowler JS, Logan J, Gatley SJ, Gifford A et al (1999). Prediction of reinforcing responses to psychostimulants in humans by brain dopamine D2 receptor levels. Am J Psychiatry 156: 1440–1443.
Volkow ND, Wang GJ, Fowler JS, Logan J, Gatley SJ, Hitzemann R et al (1997). Decreased striatal dopaminergic responsiveness in detoxified cocaine-dependent subjects. Nature 386: 830–833.
Volkow ND, Wang G-J, Telang F, Fowler JS, Alexoff D, Logan J et al (2014b). Decreased dopamine brain reactivity in marijuana abusers is associated with negative emotionality and addiction severity. Proc Natl Acad Sci USA 111: E3149–E3156.
Volkow ND, Wang G-J, Telang F, Fowler JS, Logan J, Jayne M et al (2007). Profound decreases in dopamine release in striatum in detoxified alcoholics: possible orbitofrontal involvement. J Neurosci 27: 12700–12706.
Wang G-J, Volkow ND, Wigal T, Kollins SH, Newcorn JH, Telang F et al (2013). Long-term stimulant treatment affects brain dopamine transporter level in patients with attention deficit hyperactive disorder. PLoS One 8: e63023.
Wang J, Alsop DC, Li L, Listerud J, Gonzalez-At JB, Schnall MD et al (2002). Comparison of quantitative perfusion imaging using arterial spin labeling at 1.5 and 4.0 Tesla. Magn Reson Med 48: 242–254.
Wilson JM, Kalasinsky KS, Levey AI, Bergeron C, Reiber G, Anthony RM et al (1996). Striatal dopamine nerve terminal markers in human, chronic methamphetamine users. Nat Med 2: 699–703.
Yu L, Cherng C-FG, Chen C (2002). Melatonin in concentrated ethanol and ethanol alone attenuate methamphetamine-induced dopamine depletions in C57BL/6J mice. J Neural Transm 109: 1477–1490.
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AS and LR were responsible for the study concept and design. In addition, DH, AN, and JB assisted in the setup of the experiments. AS and LV collected the data. AS, DH, and MC carried out ASL data processing and analysis. LV, DH, and AS conducted SPECT data processing and analysis. AS drafted the manuscript. All authors contributed to the interpretation and discussion of the data and edited the manuscript.
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Schrantee, A., Václavů, L., Heijtel, D. et al. Dopaminergic System Dysfunction in Recreational Dexamphetamine Users. Neuropsychopharmacol 40, 1172–1180 (2015). https://doi.org/10.1038/npp.2014.301
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DOI: https://doi.org/10.1038/npp.2014.301
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