Skip to main content
SpringerLink
Log in

The effect of caffeine on cerebral metabolism during alpha-chloralose anesthesia differs from isoflurane anesthesia in the rat brain

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Rationale

Caffeine is a widely studied psychostimulant, even though its exact effect on brain activity remains to be elucidated. Positron emission tomography (PET) allows studying mechanisms underlying cerebral metabolic responses to caffeine in caffeine-naïve rats. Rodent studies are typically performed under anesthesia. However, the anesthesia may affect neurotransmitter systems targeted by tested drugs.

Objectives

The scope of the present study was to address the impairing or enhancing effect of two common anesthetics, alpha-chloralose and isoflurane, on the kinetics of caffeine.

Methods

The first group of rats (n = 15) were anesthetized under 1.5% isoflurane anesthesia. The second group of rats (n = 15) were anesthetized under alpha-chloralose (80 mg/kg). These rats received an intravenous injection of saline (n = 5) or of 2.5 mg/kg (n = 5) or 40 mg/kg (n = 5) caffeine for both groups.

Results

With 2.5 mg/kg or 40 mg/kg caffeine, whole-brain cerebral metabolism was significantly reduced by 17.2% and 17% (both P < 0.01), respectively, under alpha-chloralose anesthesia. However, the lower dose of caffeine (2.5 mg/kg) had a limited effect on brain metabolism, whereas its higher dose (40 mg/kg) produced enhancements in brain metabolism in the striatum, hippocampus, and thalamus (all P < 0.05) under isoflurane anesthesia.

Conclusion

These findings demonstrate significant differences in brain responses to caffeine on the basic of the anesthesia regimen used, which highlights the importance of attention to the anesthetic used when interpreting findings from animal pharmacological studies because of possible interactions between the anesthetic and the drug under study.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  • Acquas E, Tanda G, Di Chiara G (2002) Differential effects of caffeine on dopamine and acetylcholine transmission in brain areas of drug-naive and caffeine-pretreated rats. Neuropsychopharmacology 27:182–193

    Article  CAS  PubMed  Google Scholar 

  • Antunes LM, Golledge HD, Roughan JV, Flecknell PA (2003a) Comparison of electroencephalogram activity and auditory evoked responses during isoflurane and halothane anaesthesia in the rat. Vet Anaesth Analg 30:15–23

    Article  CAS  PubMed  Google Scholar 

  • Antunes LM, Roughan JV, Flecknell PA (2003b) Effects of different propofol infusion rates on EEG activity and AEP responses in rats. J Vet Pharmacol Ther 26:369–376

    Article  CAS  PubMed  Google Scholar 

  • Antunes LM, Roughan JV, Flecknell PA (2003c) Excitatory effects of fentanyl upon the rat electroencephalogram and auditory-evoked potential responses during anaesthesia. Eur J Anaesthesiol 20:800–808

    Article  CAS  PubMed  Google Scholar 

  • Azdad K, Gall D, Woods AS, Ledent C, Ferre S, Schiffmann SN (2009) Dopamine D2 and adenosine A2A receptors regulate NMDA-mediated excitation in accumbens neurons through A2A-D2 receptor heteromerization. Neuropsychopharmacology 34:972–986

    Article  CAS  PubMed  Google Scholar 

  • Benveniste H, Fowler JS, Rooney WD, Scharf BA, Backus WW, Izrailtyan I, Knudsen GM, Hasselbalch SG, Volkow ND (2010) Cocaine is pharmacologically active in the nonhuman primate fetal brain. Proc Natl Acad Sci U S A 107:1582–1587

    Article  PubMed  PubMed Central  Google Scholar 

  • Berkowitz BA, Spector S (1971) The effect of caffeine and theophylline on the disposition of brain serotonin in the rat. Eur J Pharmacol 16:322–325

    Article  CAS  PubMed  Google Scholar 

  • Berkowitz BA, Tarver JH, Spector S (1970) Release of norepinephrine in the central nervous system by theophylline and caffeine. Eur J Pharmacol 10:64–71

    Article  CAS  PubMed  Google Scholar 

  • Buzsaki G, Kaila K, Raichle M (2007) Inhibition and brain work. Neuron 56:771–783

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cannella N, Cosa-Linan A, Roscher M, Takahashi TT, Vogler N, Wangler B, Spanagel R (2017) [18F]-Fluorodeoxyglucose-positron emission tomography in rats with prolonged cocaine self-administration suggests potential brain biomarkers for addictive behavior. Frontiers in psychiatry 8:218

    Article  PubMed  PubMed Central  Google Scholar 

  • Chung YH, Hsu PH, Huang CW, Hsieh WC, Huang FT, Chang WC, Chiu H, Hsu ST, Yen TC (2014) Evaluation of prognostic integrin alpha2beta1 PET tracer and concurrent targeting delivery using focused ultrasound for brain glioma detection. Mol Pharm 11:3904–3914

    Article  CAS  PubMed  Google Scholar 

  • Dager SR, Layton ME, Strauss W, Richards TL, Heide A, Friedman SD, Artru AA, Hayes CE, Posse S (1999) Human brain metabolic response to caffeine and the effects of tolerance. Am J Psychiatry 156:229–237

    CAS  PubMed  Google Scholar 

  • Dews PB, O'Brien CP, Bergman J (2002) Caffeine: behavioral effects of withdrawal and related issues. Food Chem Toxicol 40:1257–1261

    Article  CAS  PubMed  Google Scholar 

  • Dunwiddie TV, Masino SA (2001) The role and regulation of adenosine in the central nervous system. Annu Rev Neurosci 24:31–55

    Article  CAS  PubMed  Google Scholar 

  • Ferre S (2010) Role of the central ascending neurotransmitter systems in the psychostimulant effects of caffeine. J Alzheimer's Dis : JAD 20(Suppl 1):S35–S49

    Article  CAS  Google Scholar 

  • Fredholm BB, Battig K, Holmen J, Nehlig A, Zvartau EE (1999) Actions of caffeine in the brain with special reference to factors that contribute to its widespread use. Pharmacol Rev 51:83–133

    CAS  PubMed  Google Scholar 

  • Fukumitsu N, Ishii K, Kimura Y, Oda K, Sasaki T, Mori Y, Ishiwata K (2003) Imaging of adenosine A1 receptors in the human brain by positron emission tomography with [11C]MPDX. Ann Nucl Med 17:511–515

    Article  CAS  PubMed  Google Scholar 

  • Garrett KM, Gan J (1998) Enhancement of gamma-aminobutyric acidA receptor activity by alpha-chloralose. J Pharmacol Exp Ther 285:680–686

    CAS  PubMed  Google Scholar 

  • Griffeth VE, Perthen JE, Buxton RB (2011) Prospects for quantitative fMRI: investigating the effects of caffeine on baseline oxygen metabolism and the response to a visual stimulus in humans. NeuroImage 57:809–816

    Article  PubMed  PubMed Central  Google Scholar 

  • Hendrich KS, Kochanek PM, Melick JA, Schiding JK, Statler KD, Williams DS, Marion DW, Ho C (2001) Cerebral perfusion during anesthesia with fentanyl, isoflurane, or pentobarbital in normal rats studied by arterial spin-labeled MRI. Magn Reson Med 46:202–206

    Article  CAS  PubMed  Google Scholar 

  • Ishiwata K, Mishina M, Kimura Y, Oda K, Sasaki T, Ishii K (2005) First visualization of adenosine A(2A) receptors in the human brain by positron emission tomography with [11C]TMSX. Synapse 55:133–136

    Article  CAS  PubMed  Google Scholar 

  • Johansson B, Ahlberg S, van der Ploeg I, Brene S, Lindefors N, Persson H, Fredholm BB (1993) Effect of long term caffeine treatment on A1 and A2 adenosine receptor binding and on mRNA levels in rat brain. Naunyn Schmiedeberg's Arch Pharmacol 347:407–414

    Article  CAS  Google Scholar 

  • Keita H, Henzel-Rouelle D, Dupont H, Desmonts JM, Mantz J (1999) Halothane and isoflurane increase spontaneous but reduce the N-methyl-D-aspartate-evoked dopamine release in rat striatal slices: evidence for direct presynaptic effects. Anesthesiology 91:1788–1797

    Article  CAS  PubMed  Google Scholar 

  • Laurienti PJ, Field AS, Burdette JH, Maldjian JA, Yen YF, Moody DM (2002) Dietary caffeine consumption modulates fMRI measures. NeuroImage 17:751–757

    Article  PubMed  Google Scholar 

  • Lee HB, Blaufox MD (1985) Blood volume in the rat. J Nucl Med 26:72–76

    CAS  PubMed  Google Scholar 

  • Leoni RF, Paiva FF, Henning EC, Nascimento GC, Tannus A, de Araujo DB, Silva AC (2011) Magnetic resonance imaging quantification of regional cerebral blood flow and cerebrovascular reactivity to carbon dioxide in normotensive and hypertensive rats. NeuroImage 58:75–81

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lindauer U, Villringer A, Dirnagl U (1993) Characterization of CBF response to somatosensory stimulation: model and influence of anesthetics. Am J Phys 264:H1223–H1228

    CAS  Google Scholar 

  • Logothetis NK (2008) What we can do and what we cannot do with fMRI. Nature 453:869–878

    Article  CAS  PubMed  Google Scholar 

  • Low LA, Bauer LC, Klaunberg BA (2016) Comparing the effects of isoflurane and alpha chloralose upon mouse physiology. PLoS One 11:e0154936

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Makaryus R, Lee H, Yu M, Zhang S, Smith SD, Rebecchi M, Glass PS, Benveniste H (2011) The metabolomic profile during isoflurane anesthesia differs from propofol anesthesia in the live rodent brain. J Cerebral Blood Flow Metab 31:1432–1442

    Article  CAS  Google Scholar 

  • Masamoto K, Kim T, Fukuda M, Wang P, Kim SG (2007) Relationship between neural, vascular, and BOLD signals in isoflurane-anesthetized rat somatosensory cortex. Cereb Cortex 17:942–950

    Article  PubMed  Google Scholar 

  • Merola A, Germuska MA, Warnert EA, Richmond L, Helme D, Khot S, Murphy K, Rogers PJ, Hall JE, Wise RG (2017) Mapping the pharmacological modulation of brain oxygen metabolism: the effects of caffeine on absolute CMRO2 measured using dual calibrated fMRI. NeuroImage 155:331–343

    Article  CAS  PubMed  Google Scholar 

  • Nakao Y, Itoh Y, Kuang TY, Cook M, Jehle J, Sokoloff L (2001) Effects of anesthesia on functional activation of cerebral blood flow and metabolism. Proc Natl Acad Sci U S A 98:7593–7598

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nehlig A, Boyet S (2000) Dose-response study of caffeine effects on cerebral functional activity with a specific focus on dependence. Brain Res 858:71–77

    Article  CAS  PubMed  Google Scholar 

  • Nehlig A, Lucignani G, Kadekaro M, Porrino LJ, Sokoloff L (1984) Effects of acute administration of caffeine on local cerebral glucose utilization in the rat. Eur J Pharmacol 101:91–100

    Article  CAS  PubMed  Google Scholar 

  • Paasonen J, Salo RA, Shatillo A, Forsberg MM, Narvainen J, Huttunen JK, Grohn O (2016) Comparison of seven different anesthesia protocols for nicotine pharmacologic magnetic resonance imaging in rat. Eur Neuropsychopharmacol 26:518–531

    Article  CAS  PubMed  Google Scholar 

  • Paasonen J, Stenroos P, Salo RA, Kiviniemi V, Grohn O (2018) Functional connectivity under six anesthesia protocols and the awake condition in rat brain. NeuroImage 172:9–20

    Article  PubMed  Google Scholar 

  • Park CA, Kang CK, Son YD, Choi EJ, Kim SH, Oh ST, Kim YB, Park CW, Cho ZH (2014) The effects of caffeine ingestion on cortical areas: functional imaging study. Magn Reson Imaging 32:366–371

    Article  CAS  PubMed  Google Scholar 

  • Savic N, Sciancalepore M (1998) Intracellular calcium stores modulate miniature GABA-mediated synaptic currents in neonatal rat hippocampal neurons. Eur J Neurosci 10:3379–3386

    Article  CAS  PubMed  Google Scholar 

  • Shi D, Daly JW (1999) Chronic effects of xanthines on levels of central receptors in mice. Cell Mol Neurobiol 19:719–732

    Article  CAS  PubMed  Google Scholar 

  • Shih YY, Chen CC, Shyu BC, Lin ZJ, Chiang YC, Jaw FS, Chen YY, Chang C (2009) A new scenario for negative functional magnetic resonance imaging signals: endogenous neurotransmission. J Neurosci 29:3036–3044

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shih YY, Chiang YC, Chen JC, Huang CH, Chen YY, Liu RS, Chang C, Jaw FS (2008) Brain nociceptive imaging in rats using (18)f-fluorodeoxyglucose small-animal positron emission tomography. Neuroscience 155:1221–1226

    Article  CAS  PubMed  Google Scholar 

  • Solinas M, Ferre S, You ZB, Karcz-Kubicha M, Popoli P, Goldberg SR (2002) Caffeine induces dopamine and glutamate release in the shell of the nucleus accumbens. J Neurosci 22:6321–6324

    Article  CAS  PubMed  Google Scholar 

  • Solt K, Forman SA (2007) Correlating the clinical actions and molecular mechanisms of general anesthetics. Curr Opin Anaesthesiol 20:300–306

    Article  PubMed  Google Scholar 

  • Ueki M, Mies G, Hossmann KA (1992) Effect of alpha-chloralose, halothane, pentobarbital and nitrous oxide anesthesia on metabolic coupling in somatosensory cortex of rat. Acta Anaesthesiol Scand 36:318–322

    Article  CAS  PubMed  Google Scholar 

  • Uftring SJ, Wachtel SR, Chu D, McCandless C, Levin DN, de Wit H (2001) An fMRI study of the effect of amphetamine on brain activity. Neuropsychopharmacology 25:925–935

    Article  CAS  PubMed  Google Scholar 

  • Vidyasagar R, Greyling A, Draijer R, Corfield DR, Parkes LM (2013) The effect of black tea and caffeine on regional cerebral blood flow measured with arterial spin labeling. J Cereb Blood Flow Metab 33:963–968

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang Q, Fong R, Mason P, Fox AP, Xie Z (2014) Caffeine accelerates recovery from general anesthesia. J Neurophysiol 111:1331–1340

    Article  CAS  PubMed  Google Scholar 

  • Williams KA, Magnuson M, Majeed W, LaConte SM, Peltier SJ, Hu X, Keilholz SD (2010) Comparison of alpha-chloralose, medetomidine and isoflurane anesthesia for functional connectivity mapping in the rat. Magn Reson Imaging 28:995–1003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xu F, Liu P, Pekar JJ, Lu H (2015) Does acute caffeine ingestion alter brain metabolism in young adults? NeuroImage 110:39–47

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This work was funded by Ministry of Science Technology (MOST 105-2314-B-039-044-MY2).

Author information

Authors and Affiliations

  1. Department of Biomedical Imaging and Radiological Science, China Medical University, 91 Hsueh-Shih Road, Taichung, 40402, Taiwan

    Shin-Lei Peng, Chun-Yi Wu & Wu-Chung Shen

  2. Center for Advanced Molecular Imaging and Translation, Chang Gung Memorial Hospital, Taoyuan, Taiwan

    Han Chiu, Chiun-Wei Huang & Yi-Hsiu Chung

  3. Department of Medical Imaging and Radiological Sciences, Chung Shan Medical University, Taichung, Taiwan

    Cheng-Ting Shih

  4. Department of Radiology, China Medical University Hospital, Taichung, Taiwan

    Wu-Chung Shen

Authors
  1. Shin-Lei Peng
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Han Chiu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chun-Yi Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chiun-Wei Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yi-Hsiu Chung
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Cheng-Ting Shih
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Wu-Chung Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Shin-Lei Peng.

Ethics declarations

All animal experiments were approved by China Medical University Institutional Animal Care and Use Committee and were carried out in accordance with the approved guidelines.

Conflict of interest

The authors declare that there are no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Peng, SL., Chiu, H., Wu, CY. et al. The effect of caffeine on cerebral metabolism during alpha-chloralose anesthesia differs from isoflurane anesthesia in the rat brain. Psychopharmacology 236, 1749–1757 (2019). https://doi.org/10.1007/s00213-018-5157-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-018-5157-4

Keywords

Search

Navigation