, Volume 185, Issue 4, pp 479–486 | Cite as

Hemodynamic and metabolic changes induced by cocaine in anesthetized rat observed with multimodal functional MRI

  • Karl F. Schmidt
  • Marcelo Febo
  • Qiang Shen
  • Feng Luo
  • Kenneth M. Sicard
  • Craig F. Ferris
  • Elliot A. Stein
  • Timothy Q. DuongEmail author
Original Investigation



Physiological changes (such as heart rate and respiration rate) associated with strong pharmacological stimuli could change the blood-oxygenation-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) mapping signals, independent of neural activity.


This study investigates whether the physiological changes per se associated with systemic cocaine administration (1 mg/kg) contaminate the BOLD fMRI signals by measuring BOLD and cerebral blood flow (CBF) fMRI and estimating the cerebral metabolic rate of oxygen (CMRO2) changes.

Materials and methods

BOLD and CBF fMRI was performed, and changes in CMRO2 were estimated using the BOLD biophysical model.


After systemic cocaine administration, blood pressure, heart rate, and respiration rate increased, fMRI signals remained elevated after physiological parameters had returned to baseline. Cocaine induced changes in the BOLD signal within regions of the reward pathway that were heterogeneous and ranged from −1.2 to 5.4%, and negative changes in BOLD were observed along the cortical surface. Changes in CBF and estimated CMRO2 were heterogeneous and positive throughout the brain, ranging from 14 to 150% and 10 to 55%, respectively.


This study demonstrates a valuable tool to investigate the physiological and biophysical basis of drug action on the central nervous system, offering the means to distinguish the physiological from neural sources of the BOLD fMRI signal.


Multimodal imaging CMRO2 BOLD CBF Pharmacological fMRI Biophysical model Arterial spin labeling Hypercapnic calibration 



This work was supported in part by research grants from the National Institute of Neurological Disorders and Stroke (NINDS, R01 NS045879), the American Heart Association (SDG 0430020N), and the National Institute on Drug Abuse (NIDA, R01DA13517). All experiments were performed in accordance with guidelines for the care and use of mammals in neuroscience and behavioral research (National Research Council 2003) and in compliance with the laws of the United States.


  1. American Psychiatric Association (1994) Diagnostic and statistical manual of mental disorders: DSM-IV, 4th edn. American Psychiatric Association, Washington, District of ColumbiaGoogle Scholar
  2. Bardo MT (1998) Neuropharmacological mechanisms of drug reward: beyond dopamine in the nucleus accumbens. Crit Rev Neurobiol 12:37–67PubMedGoogle Scholar
  3. Boxerman JL, Bandettini PA, Kwong KK, Baker JR, Davis TL, Rosen BR, Weisskoff RM (1995) The intravascular contribution to fMRI signal change: Monte Carlo modeling and diffusion-weighted studies in vivo. Magn Reson Med 34:4–10PubMedCrossRefGoogle Scholar
  4. Breiter HC, Gollub RL, Weisskoff RM, Kennedy DN, Makris N, Berke JD, Goodman JM, Kantor HL, Gastfriend DR, Riorden JP, Mathew RT, Rosen BR, Hyman SE (1997) Acute effects of cocaine on human brain activity and emotion. Neuron 19:591–611CrossRefPubMedGoogle Scholar
  5. Chen YC, Mandeville JB, Nguyen TV, Talele A, Cavagna F, Jenkins BG (2001) Improved mapping of pharmacologically induced neuronal activation using the IRON technique with superparamagnetic blood pool agents. J Magn Reson Imaging 14:517–524CrossRefPubMedGoogle Scholar
  6. Davis TL, Kwong KK, Weisskoff RM, Rosen BR (1998) Calibrated functional MRI: mapping the dynamics of oxidative metabolism. Proc Natl Acad Sci USA 95:1834–1839CrossRefPubMedGoogle Scholar
  7. Duong TQ, Kim DS, Ugurbil K, Kim SG (2000a) Spatiotemporal dynamics of the BOLD fMRI signals: toward mapping submillimeter cortical columns using the early negative response. Magn Reson Med 44:231–242CrossRefPubMedGoogle Scholar
  8. Duong TQ, Silva AC, Lee SP, Kim SG (2000b) Functional MRI of calcium-dependent synaptic activity: cross correlation with CBF and BOLD measurements. Magn Reson Med 43:383–392CrossRefPubMedGoogle Scholar
  9. Fox PT, Raichle ME, Mintun MA, Dence C (1988) Nonoxidative glucose consumption during focal physiologic neural activity. Science 241:462–464PubMedCrossRefGoogle Scholar
  10. Gollub RL, Breiter HC, Kantor H, Kennedy D, Gastfriend D, Mathew RT, Makris N, Guimaraes A, Riorden J, Campbell T, Foley M, Hyman SE, Rosen B, Weisskoff R (1998) Cocaine decreases cortical cerebral blood flow but does not obscure regional activation in functional magnetic resonance imaging in human subjects. J Cereb Blood Flow Metab 18:724–734CrossRefPubMedGoogle Scholar
  11. Grubb RL, Jr., Raichle ME, Eichling JO, Ter-Pogossian MM (1974) The effects of changes in PaCO2 on cerebral blood volume, blood flow, and vascular mean transit time. Stroke 5:630–639PubMedGoogle Scholar
  12. Hafkenshiel J, Friedland C (1952) Physiology of the cerebral circulation in essential hypertension: The effects of 5% carbon dioxide mixtures on cerebral hemodynamics and oxygen metabolism. J Pharmacol Exp Ther 34:391–392Google Scholar
  13. Hoge RD, Atkinson J, Gill B, Crelier GR, Marrett S, Pike GB (1999a) Investigation of BOLD signal dependence on cerebral blood flow and oxygen consumption: the deoxyhemoglobin dilution model. Magn Reson Med 42:849–863CrossRefPubMedGoogle Scholar
  14. Hoge RD, Atkinson J, Gill B, Crelier GR, Marrett S, Pike GB (1999b) Linear coupling between cerebral blood flow and oxygen consumption in activated human cortex. Proc Natl Acad Sci USA 96:9403–9408CrossRefPubMedGoogle Scholar
  15. Honey G, Bullmore E (2004) Human pharmacological MRI. Trends Pharmacol Sci 25:366–374CrossRefPubMedGoogle Scholar
  16. Hyder F (2004) Neuroimaging with calibrated FMRI. Stroke 35:2635–2641CrossRefPubMedGoogle Scholar
  17. Hyder F, Chase JR, Behar KL, Mason GF, Siddeek M, Rothman DL, Shulman RG (1996) Increased tricarboxylic acid cycle flux in rat brain during forepaw stimulation detected with 1H[13C]NMR. Proc Natl Acad Sci USA 93:7612–7617CrossRefPubMedGoogle Scholar
  18. Jones M, Hewson-Stoate N, Martindale J, Redgrave P, Mayhew J (2004) Nonlinear coupling of neural activity and CBF in rodent barrel cortex. Neurolmage 22:956–965CrossRefGoogle Scholar
  19. Kasischke KA, Vishwasrao HD, Fisher PJ, Zipfel WR, Webb WW (2004) Neural activity triggers neuronal oxidative metabolism followed by astrocytic glycolysis. Science 305:99–103CrossRefPubMedGoogle Scholar
  20. Kaufman MJ, Levin JM, Maas LC, Kukes TJ, Villafuerte RA, Dostal K, Lukas SE, Mendelson JH, Cohen BM, Renshaw PF (2001) Cocaine-induced cerebral vasoconstriction differs as a function of sex and menstrual cycle phase. Biol Psychiatry 49:774–781CrossRefPubMedGoogle Scholar
  21. Kelley AE (2004) Memory and addiction; shared neural circuitry and molecular mechanisms. Neuron 44:161–179CrossRefPubMedGoogle Scholar
  22. Kennedy C, Des Rosiers MH, Sakurada O, Shinohara M, Reivich M, Jehle JW, Sokoloff L (1976) Metabolic mapping of the primary visual system of the monkey by means of the autoradiographic [14C]deoxyglucose technique. Proc Natl Acad Sci USA 73:4230–4234PubMedCrossRefGoogle Scholar
  23. Kety S, Schmidt C (1948) The effects of altered arterial tensions of carbon dioxide and oxygen on cerebral blood flow and cerebral oxygen consumption of normal young men. Jouranl of Clinical Investigations 27:484–491CrossRefGoogle Scholar
  24. Kim SG, Rostrup E, Larsson HB, Ogawa S, Paulson OB (1999) Determination of relative CMRO2 from CBF and BOLD changes: significant increase of oxygen consumption rate during visual stimulation. Magn Reson Med 41:1152–1161CrossRefPubMedGoogle Scholar
  25. Krings T, Erberich SG, Roessler F, Reul J, Thron A (1999) MR blood oxygenation level-dependent signal differences in parenchymal and large draining vessels: implications for functional MR imaging. AJNR Am J Neuroradiol 20:1907–1914PubMedGoogle Scholar
  26. Liu ZM, Schmidt KF, Sicard KM, Duong TQ (2004) Imaging oxygen consumption in forepaw somatosensory simulation in rats under isoflurane anesthesia. Magn Reson Med 52:277–285CrossRefPubMedGoogle Scholar
  27. Luo F, Wu G, Li Z, Li SJ (2003) Characterization of effects of mean arterial blood pressure induced by cocaine and cocaine methiodide on BOLD signals in rat brain. Magn Reson Med 49:264–270CrossRefPubMedGoogle Scholar
  28. Madsen PL, Linde R, Hasselbalch SG, Paulson OB, Lassen NA (1998) Activation-induced resetting of cerebral oxygen and glucose uptake in the rat. J Cereb Blood Flow Metab 18:742–748CrossRefPubMedGoogle Scholar
  29. Mandeville JB, Jenkins BG, Kosofsky BE, Moskowitz MA, Rosen BR, Marota JJ (2001) Regional sensitivity and coupling of BOLD and CBV changes during stimulation of rat brain. Magn Reson Med 45:443–447CrossRefPubMedGoogle Scholar
  30. Mandeville JB, Marota JJ, Ayata C, Moskowitz MA, Weisskoff RM, Rosen BR (1999) MRI measurement of the temporal evolution of relative CMRO(2) during rat forepaw stimulation. Magn Reson Med 42:944–951CrossRefPubMedGoogle Scholar
  31. Marota JJ, Mandeville JB, Weisskoff RM, Moskowitz MA, Rosen BR, Kosofsky BE (2000) Cocaine activation discriminates dopaminergic projections by temporal response: an fMRI study in Rat. Neurolmage 11:13–23CrossRefGoogle Scholar
  32. Nestler EJ (2002) From neurobiology to treatment: progress against addiction. Nat Neurosci 5(Suppl):1076–1079CrossRefPubMedGoogle Scholar
  33. Nestler EJ, Hyman SE, Malenka RC (2001) Molecular neuropharmacology: a foundation for clinical neuroscience. McGraw-Hill, New YorkGoogle Scholar
  34. O’Brien CP (2003) Research advances in the understanding and treatment of addiction. Am J Addict 12(Suppl 2):S36–47PubMedCrossRefGoogle Scholar
  35. Ogawa S, Menon RS, Tank DW, Kim SG, Merkle H, Ellermann JM, Ugurbil K (1993) Functional brain mapping by blood oxygenation level-dependent contrast magnetic resonance imaging. A comparison of signal characteristics with a biophysical model. Biophys J 64:803–812PubMedCrossRefGoogle Scholar
  36. Paxinos G, Watson C (1998) The rat brain in stereotaxic coordinates: fourth edition. Academic, New YorkGoogle Scholar
  37. Pitts DK, Udom CE, Marwah J (1987) Cardiovascular effects of cocaine in anesthetized and conscious rats. Life Sci 40:1099–1111CrossRefPubMedGoogle Scholar
  38. Porrino LJ, Domer FR, Crane AM, Sokoloff L (1988) Selective alterations in cerebral metabolism within the mesocorticolimbic dopaminergic system produced by acute cocaine administration in rats. Neuropsychopharmacology 1:109–118CrossRefPubMedGoogle Scholar
  39. Sicard K, Shen Q, Brevard ME, Sullivan R, Ferris CF, King JA, Duong TQ (2003) Regional cerebral blood flow and BOLD responses in conscious and anesthetized rats under basal and hypercapnic conditions: implications for functional MRI studies. J Cereb Blood Flow Metab 23:472–481CrossRefPubMedGoogle Scholar
  40. Silva AC, Lee SP, Yang G, Iadecola C, Kim SG (1999) Simultaneous blood oxygenation level-dependent and cerebral blood flow functional magnetic resonance imaging during forepaw stimulation in the rat. J Cereb Blood Flow Metab 19:871–879CrossRefPubMedGoogle Scholar
  41. Sokoloff L, Reivich M, Kennedy C, Des Rosiers MH, Patlak CS, Pettigrew KD, Sakurada O, Shinohara M (1977) The [14C]deoxyglucose method for the measurement of local cerebral glucose utilization: theory, procedure, and normal values in the conscious and anesthetized albino rat. J Neurochem 28:897–916PubMedCrossRefGoogle Scholar
  42. Stein EA (2001) fMRI: a new tool for the in vivo localization of drug actions in the brain. J Anal Toxicol 25:419–424PubMedGoogle Scholar
  43. Stein EA, Fuller SA (1992) Selective effects of cocaine on regional cerebral blood flow in the rat. J Pharmacol Exp Ther 262:327–334PubMedGoogle Scholar
  44. Thulborn KR, Waterton JC, Matthews PM, Radda GK (1982) Oxygenation dependence of the transverse relaxation time of water protons in whole blood at high field. Biochim Biophys Acta 714:265–270PubMedGoogle Scholar
  45. Ueki M, Linn F, Hossmann KA (1988) Functional activation of cerebral blood flow and metabolism before and after global ischemia of rat brain. J Cereb Blood Flow Metab 8:486–494PubMedGoogle Scholar
  46. Uludag K, Dubowitz DJ, Yoder EJ, Restom K, Liu TT, Buxton RB (2004) Coupling of cerebral blood flow and oxygen consumption during physiological activation and deactivation measured with fMRI. Neuromage 23:148–155CrossRefGoogle Scholar
  47. Worsley KJ, Friston KJ (1995) Analysis of fMRI time-series revisited—again. Neurolmage 2:173–181CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Karl F. Schmidt
    • 1
  • Marcelo Febo
    • 1
  • Qiang Shen
    • 3
  • Feng Luo
    • 1
  • Kenneth M. Sicard
    • 1
  • Craig F. Ferris
    • 1
  • Elliot A. Stein
    • 2
  • Timothy Q. Duong
    • 3
    Email author
  1. 1.Center for Comparative NeuroimagingUniversity of MassachusettsWorcesterUSA
  2. 2.Neuroimaging Research Branch, National Institute on Drug AbuseNational Institutes of HealthBaltimoreUSA
  3. 3.Yerkes Imaging CenterEmory UniversityAtlantaUSA

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