Abstract
Release of dopamine in the nucleus accumbens (NAcc) is essential for acute drug reward. The present study was designed to trace the reinforcing effect of dopamine release by measuring the functional connectivity (FC) between the NAcc and brain regions involved in a limbic cortical–subcortical circuit during a dopaminergic challenge. Twenty healthy volunteers received single doses of methylphenidate (40 mg) and placebo on separate test days according to a double-blind, cross-over study design. Resting state functional magnetic resonance imaging (fMRI) was measured between 1.5 and 2 h postdosing. FC between regions of interest (ROI) in the NAcc, the medial dorsal nucleus (MDN) of the thalamus and remote areas within the limbic circuit was explored. Methylphenidate significantly reduced FC between the NAcc and the basal ganglia (i.e., subthalamic nucleus and ventral pallidum (VP)), relative to placebo. Methylphenidate also decreased FC between the NAcc and the medial prefrontal cortex (mPFC) as well as the temporal cortex. Methylphenidate did not affect FC between MDN and the limbic circuit. It is concluded that methylphenidate directly affects the limbic reward circuit. Drug-induced changes in FC of the NAcc may serve as a useful marker of drug activity in in the brain reward circuit.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Achard S, Bullmore E (2007) Efficiency and cost of economical brain functional networks. PLoS Comput Biol 3:e17
Alexander GE, DeLong MR, Strick PL (1986) Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Annu Rev Neurosci 9:357–381
Bechara A (2005) Decision making, impulse control and loss of willpower to resist drugs: a neurocognitive perspective. Nat Neurosci 8:1458–1463
Bonelli RM, Cummings JL (2007) Frontal–subcortical circuitry and behavior. Dialogues Clin Neurosci 9:141–151
Carboni E, Silvagni A, Valentini V, Di Chiara G (2003) Effect of amphetamine, cocaine and depolarization by high potassium on extracellular dopamine in the nucleus accumbens shell of SHR rats. An in vivo microdyalisis study. Neurosci Biobehav Rev 27:653–659
Cauda F, Cavanna AE, D'Agata F, Sacco K, Duca S, Geminiani GC (2011) Functional connectivity and coactivation of the nucleus accumbens: a combined functional connectivity and structure-based meta-analysis. J Cogn Neurosci 23:2864–2877
Chao-Gan Y, Yu-Feng Z (2010) DPARSF: a MATLAB toolbox for “pipeline” data analysis of resting-state fMRI. Front Syst Neurosci 4:13
Chong SL, Claussen CM, Dafny N (2012) Nucleus accumbens neuronal activity in freely behaving rats is modulated following acute and chronic methylphenidate administration. Brain Res Bull 87:445–456
Cole DM, Oei NY, Soeter RP, Both S, van Gerven JM, Rombouts SA, Beckmann CF (2012) Dopamine-dependent architecture of cortico-subcortical network connectivity. Cerebr Cortex. doi:10.1093/cercor/bhs136
Cummings JL (1993) Frontal–subcortical circuits and human behavior. Arch Neurol 50:873–880
Dagher A, Robbins TW (2009) Personality, addiction, dopamine: insights from Parkinson's disease. Neuron 61:502–510
Di Martino A, Scheres A, Margulies DS, Kelly AM, Uddin LQ, Shehzad Z, Biswal B, Walters JR, Castellanos FX, Milham MP (2008) Functional connectivity of human striatum: a resting state FMRI study. Cerebr Cortex 18:2735–2747
Faure A, Richard JM, Berridge KC (2010) Desire and dread from the nucleus accumbens: cortical glutamate and subcortical GABA differentially generate motivation and hedonic impact in the rat. PLoS One 5:e11223
Goldstein RZ, Volkow ND (2011a) Dysfunction of the prefrontal cortex in addiction: neuroimaging findings and clinical implications. Nat Rev Neurosci 12:652–669
Goldstein RZ, Volkow ND (2011b) Oral methylphenidate normalizes cingulate activity and decreases impulsivity in cocaine addiction during an emotionally salient cognitive task. Neuropsychopharmacol Off Publ Am Coll Neuropsychopharmacol 36:366–367
Gu H, Salmeron BJ, Ross TJ, Geng X, Zhan W, Stein EA, Yang Y (2010) Mesocorticolimbic circuits are impaired in chronic cocaine users as demonstrated by resting-state functional connectivity. NeuroImage 53:593–601
Honey GD, Suckling J, Zelaya F, Long C, Routledge C, Jackson S, Ng V, Fletcher PC, Williams SC, Brown J, Bullmore ET (2003) Dopaminergic drug effects on physiological connectivity in a human cortico-striato-thalamic system. Brain J Neurol 126:1767–1781
Hong LE, Gu H, Yang Y, Ross TJ, Salmeron BJ, Buchholz B, Thaker GK, Stein EA (2009) Association of nicotine addiction and nicotine's actions with separate cingulate cortex functional circuits. Arch Gen Psychiatry 66:431–441
Kalivas PW, Volkow N, Seamans J (2005) Unmanageable motivation in addiction: a pathology in prefrontal–accumbens glutamate transmission. Neuron 45:647–650
Kalivas PW, Volkow ND (2005) The neural basis of addiction: a pathology of motivation and choice. Am J Psychiatry 162:1403–1413
Kalivas PW, Volkow ND (2011) New medications for drug addiction hiding in glutamatergic neuroplasticity. Mol Psychiatry 16:974–986
Kelly C, de Zubicaray G, Di Martino A, Copland DA, Reiss PT, Klein DF, Castellanos FX, Milham MP, McMahon K (2009) l-Dopa modulates functional connectivity in striatal cognitive and motor networks: a double-blind placebo-controlled study. J Neurosci Off J Soc Neurosci 29:7364–7378
Kollins SH, English J, Robinson R, Hallyburton M, Chrisman AK (2009) Reinforcing and subjective effects of methylphenidate in adults with and without attention deficit hyperactivity disorder (ADHD). Psychopharmacology 204:73–83
Lee L, Kepple J, Wang Y, Freestone S, Bakhtiar R, Hossain M (2003) Bioavailability of modified-release methylphenidate: influence of high-fat breakfast when administered intact and when capsule content sprinkled on applesauce. Biopharm Drug Dispos 24:233–243
McMahon K, Copland DA, De Zubicaray G, MB (2006) Effects of levodopa administration on cerebral functional connectivity 12th Annual Meeting of the Organization for Human Brain Mapping. . Florence, Italy
Murphy K, Birn RM, Handwerker DA, Jones TB, Bandettini PA (2009) The impact of global signal regression on resting state correlations: are anti-correlated networks introduced? NeuroImage 44:893–905
Nestler EJ (2005) Is there a common molecular pathway for addiction? Nat Neurosci 8:1445–1449
Parasrampuria DA, Schoedel KA, Schuller R, Silber SA, Ciccone PE, Gu J, Sellers EM (2007) Do formulation differences alter abuse liability of methylphenidate? A placebo-controlled, randomized, double-blind, crossover study in recreational drug users. J Clin Psychopharmacol 27:459–467
Perreault ML, Hasbi A, O'Dowd BF, George SR (2011) The dopamine d1–d2 receptor heteromer in striatal medium spiny neurons: evidence for a third distinct neuronal pathway in Basal Ganglia. Front Neuroanat 5:31
Pierce RC, Kumaresan V (2006) The mesolimbic dopamine system: the final common pathway for the reinforcing effect of drugs of abuse? Neurosci Biobehav Rev 30:215–238
Podet A, Lee MJ, Swann AC, Dafny N (2010) Nucleus accumbens lesions modulate the effects of methylphenidate. Brain Res Bull 82:293–301
Spencer TJ, Biederman J, Ciccone PE, Madras BK, Dougherty DD, Bonab AA, Livni E, Parasrampuria DA, Fischman AJ (2006) PET study examining pharmacokinetics, detection and likeability, and dopamine transporter receptor occupancy of short- and long-acting oral methylphenidate. Am J Psychiatry 163:387–395
Tomasi D, Volkow ND, Wang R, Carrillo JH, Maloney T, Alia-Klein N, Woicik PA, Telang F, Goldstein RZ (2010) Disrupted functional connectivity with dopaminergic midbrain in cocaine abusers. PLoS One 5:e10815
Volkow ND, Fowler JS, Wang G, Ding Y, Gatley SJ (2002) Mechanism of action of methylphenidate: insights from PET imaging studies. J Atten Disord 6(Suppl 1):S31–S43
Volkow ND, Fowler JS, Wang GJ, Swanson JM, Telang F (2007) Dopamine in drug abuse and addiction: results of imaging studies and treatment implications. Arch Neurol 64:1575–1579
Volkow ND, Wang GJ, Fowler JS, Ding YS (2005a) Imaging the effects of methylphenidate on brain dopamine: new model on its therapeutic actions for attention-deficit/hyperactivity disorder. Biol Psychiatry 57:1410–1415
Volkow ND, Wang GJ, Fowler JS, Hitzemann R, Gatley SJ, Dewey SS, Pappas N (1998) Enhanced sensitivity to benzodiazepines in active cocaine-abusing subjects: a PET study. Am J Psychiatry 155:200–206
Volkow ND, Wang GJ, Fowler JS, Logan J, Gatley SJ, Gifford A, Hitzemann R, Ding YS, Pappas N (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, Tomasi D, Telang F (2011) Addiction: beyond dopamine reward circuitry. Proc Natl Acad Sci USA 108:15037–15042
Volkow ND, Wang GJ, Ma Y, Fowler JS, Wong C, Ding YS, Hitzemann R, Swanson JM, Kalivas P (2005b) Activation of orbital and medial prefrontal cortex by methylphenidate in cocaine-addicted subjects but not in controls: relevance to addiction. J Neurosci Off J Soc Neurosci 25:3932–3939
Author information
Authors and Affiliations
Corresponding author
Additional information
Trial registration: http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2033.
Rights and permissions
About this article
Cite this article
Ramaekers, J.G., Evers, E.A., Theunissen, E.L. et al. Methylphenidate reduces functional connectivity of nucleus accumbens in brain reward circuit. Psychopharmacology 229, 219–226 (2013). https://doi.org/10.1007/s00213-013-3105-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00213-013-3105-x