{"references": ["Abou-Khalil S., Abou-Khalil W.H. and Yunis A.A. (1980) Differential effects of chloramphenicol and its nitrosoanalogue on protein synthesis and oxidative phosphorylation in rat liver mitochondria. Biochem. Pharmacol. 29, 2605-2609.", "Barie P.S. (1998) Antibiotic-resistant Gram-Positive Cocci: Implications for surgical practice. World J. Surg 22, 118-126.", "Barrientos A. and Moraes T. (1999) Titrating the Effects of Mitochondrial Complex I Impairment in the Cell Physiology. J. Biol. Chem. 274, 16188-16197.", "Bories G.F. and Cravendi J.-P. (1994) Metabolism of chloramphenicol. A story of nearly 50 years. Drug Metabol. Rev. 26, 767-783.", "Cassarino D.S. and Bennet J.P. (1999) An evaluation of the role of mitochondria in neurodegenerative diseases: mitochondrial mutations and oxidative pathology, protective nuclear responses, and cell death in neurodegeneration. Brain Res. Rev. 29, 1-25.", "Cespuglio R., Houdouin F., Oulerich M., El Mansari M. and Jouvet M. (1992) Axonal and somato-dendritic modalities of serotonin release: their involvment in sleep preparation, triggering and maintenance. J. Sleep Res. 1, 150-156.", "Chance B., Cohen P., Jobsis F. and Schoener B. (1962) Intracellular oxidation-reduction states in vivo. Science 137, 499-508.", "Chazal G. and Ralston H.J. (1987) Serotonin-containing structures in the nucleus raphe dorsalis of the cat: an ultrastructural analysis of dendrites, presynaptic dentrites and axon terminals. J. Comp. Neurol. 259, 317.", "Davey G.P. and Clark J.B. (1996) Threshold effects and control of oxidative phosphorylation in nonsynaptic rat brain mitochondria. J. Neurochem. 66, 1617-1624.", "Davey G.P., Canevari L. and Clark J.B. (1997) Threshold effects in synaptosomal and nonsynaptic mitochondria from hippocampal CA1 and paramedian neocortex brain regions. J. Neurochem. 69, 2564-2570.", "Davey G.P., Peuchen S. and Clark J.B. (1998) Energy Thresholds in Brain Mitochondria. Potential involvement in neurodegeneration. J. Biol. Chem. 273, 12753-12757.", "Degli Esposti M. (1998) Inhibitors of NADH-ubiquinone reductase: an overview. Biochim. Biophys. Acta 1364, 222-235.", "Delpy D.T., Cope M., van der Zee P., Arridge S., Wray S. and Wray J. (1988) Estimation of optical pathlength through tissue from direct time of flight measurement. Phys. Med. Biol. 33, 1433-1442.", "Descarries L., Watkins K.C., Garcia S. and Beaudet A.J. (1982) The serotonin neurons in nucleus raphe dorsalis of adult rat: a light and electron microscope radioautographic study. Comp.Neurol. 207, 239-254.", "Dorph-Petersen, K.-A. (1999) Stereological estimation using vertical sections in a complex tissue. J. Microsc. 195, 79-86.", "Esposito L.A., Melov S., Panov A., Cottrell B.A. and Wallace D.C. (1999) Mitochondrial disease in mouse results in increased oxidative stress. Proc. Natl. Acad. Sci. USA 96, 4820-4825.", "Eto K., Tsubamoto Y., Teraushi Y., Sugiyama T., Kishimoto T., Takahashi N., Yamauchi N., Kubota N., Murayama S., Aizawa T., Akanuma Y., Aizawa S., Kasai H., Yazaki Y. and Kadowaki T. (1999) Role of NADH shuttle system in glucose-induced activation of mitochondrial metabolism and insulin secretion. Science 283, 981-985.", "Freeman K.B. and Haldar D. (1967) The inhibition of NADH oxidation in mammalian mitochondria by chloramphenicol. Biochem. Biophys. Res. Comm. 28, 8-12.", "Freeman K.B. and Haldar D. (1968) The inhibition of mammalian mitochondrial NADH oxidation by chloramphenicol and its isomers and analogues. Can. J. Biochem. 46, 1003-1008.", "Freeman K.B. and Haldar D. (1970) Effects of chloramphenicol and its isomers and analogues on the mitochondrial respiratory chain. Can. J. Biochem. 48, 469-485.", "Fride E., Ben-Or S. and Allweis C. (1989) Mitochondrial protein synthesis may be involved in long-term memory formation. Pharmacol Biochem. Behav. 32, 873-878.", "Glazko A.J. (1987) Early adventures in drug metabolism \u2013 Chloramphenicol. Ther. Drug Monit. 9, 320-330.", "Glinka Y., Tipton K.F. and Youdim M.B.H. (1998) Mechanism of inhibition of mitochondrial respiratory complex I by 6-hydroxydopamine and its prevention by desferrioxamine. Eur. J. Pharmacol. 351, 121-129.", "Hashimoto M., Takeda Y., Sato T., Kawahara H., Nagano O. and Hirakawa M. (2000) Dynamic changes of NADH fluorescence images and NADH content during spreading depression in the cerebral cortex of gerbils, Brain Res. 872, 294-300.", "Higgins D.S and Greenamyre J.T. (1996) [3H]Dihydrorotenone binding to NADH: ubiquinone reductase (complex I) of the electron transport chain: an autoradiographic study. J. Neurosci. 16, 3807-3816.", "Holt D., Harvey D. and Hurley R. (1993) Chloramphenicol toxicity. Adv. Drug. React. Rev.Toxicol. Rev. 12, 83-95.", "Jouvet M. (1994) Paradoxical sleep mechanisms. Sleep 17: S77-S83.", "Kanemitsu K, Shimada J. (1999) Neurotoxicity of antibacterial agents (tetracyclines, chloramphenicol, aminoglycosides, beta-lactams and others), Ryoikibetsu Shokogun Shirizu 27 (Pt 2), 545-551.", "Kroon A.M. and Arendzen A.J. (1972) Inhibition of mitochondrial biogenesis. FEBS Meeting, 28, 71-83.", "Kroon A.M. and de Jong L. (1979) The use of antibiotics to study mitochondrial protein synthesis. In: Methods in Enzymology, (Fleischer, S., Packer L., ed.). Academic Press, New York.", "Kumana C.R., Li K.Y. and Kou M. (1993) Do chloramphenicol blood dyscrasias occur in Hong Kong. Adv. Drug. React. Rev. Toxicol. Rev. 12, 97-106.", "Meulemans A., Vicard P., Mohler J., Vulpillat M. and Pocidalo J.J. (1986) Continuous sampling for determination of pharmacokinetics in rat cerebrospinal fluid. Antimicrob. Agents Chemother. 30, 888-891.", "Mottin S., Tran-Minh C., Laporte P., Cespuglio, R. and Jouvet M. (1993) Fiber optic time-resolved fluorescence sensor for in vitro serotonin determination, Applied Spectroscopy, 47, 590-597.", "Mottin S., Laporte P., Cespuglio, R. and Jouvet, M. (1997) Determination of NADH in the rat brain during sleep wake states with an optic fibre sensor and time resolved fluorescence procedures. Neuroscience 79, 683-693.", "Norrby S.R. (1996) Neurotoxicity of carbapenem antibacterials. Drug Saf. 15, 87-90.", "Norris A.H., Reilly J.P., Edelstein P.H., Brennan P.J., Schuster M.G. (1995) Chloramphenicol for the treatment of vancomycin-resistant enterococcal infections. Clin. Infect. Dis. 20, 1137-1142.", "Niel L., Lamarque D., Cou\u00e9 J.C., Soar\u00e8s J.L., Milleliri J.M., Boutin J.P., M\u00e9rouze F. and Rey J.L. (1997) Chronique d une \u00e9pid\u00e9mie annonc\u00e9e de m\u00e9ningite \u00e0 m\u00e9ningocoque (Goma, Za\u00efre). Bull. Soc. Path. Ex. 90, 299-302.", "Patterson G.H., Knobel S.M., Arkhammar P., Thastrup O. and Piston D.W. (2000) Separation of the glucose-stimulated cytoplasmic and mitochondrial NAD(P)H responses in pancreatic islet beta cells. Proc. Natl. Acad. Sci USA 97, 5203-5207.", "Payet M. (1997) Trafics sur ordonnance. Croissance 401, 14-18.", "Petitjean F., Buda C., Janin M., David M. and Jouvet M. (1979) Effets du chloramphenicol sur le sommeil du chat. psychopharmacology 66, 147-153.", "Prospero-Garcia O, Jimenez-Anguiano A. and Drucker-Colin R. (1993) Chloramphenicol prevents carbachol-induced REM sleep in cats. Neurosci. Lett. 154, 168-170.", "Ramilo O., Kinane B.T. and McCracken G.H. (1988) Chloramphenicol neurotoxicity. Ped. Infect. Dis. J. 7, 358-359.", "Rex A., Pfeifer L., Fink F. and Fink H. (1999) Cortical NADH during pharmacological manipulations of the respiratory chain and spreading depression in vivo. J. Neurosci. Res. 57, 359-370.", "Ross J.B.A., Subramanian S. and Brand L. (1982) Spectroscopic studies of the pyridine nucleotide coenzymes and their complexes with dehydrogenases. In: The Pyridine Nucleotide Coenzymes (Everse, J., Anderson, B., You, K-S., ed. ). Academic Press, New York.", "Rossignol R., Malgat M., Mazat J.-P., and Letellier T. (1999) Threshold Effect and Tissue Specificity. Implication for mitochondrial cytopathies. J. Biol. Chem., 274, 33426-33432.", "Rossignol R., Letellier T., Malgat M., Rocher C. and Mazat J.-P. (2000) Tissue variation in the control of oxidative phosphorylation: implication for mitochondrial diseases. Biochem. J. 347, 45\u201353.", "Sangiah S. and Burrows G.E. (1989) Hypotension produced by rapid intravenous administration of chloramphenicol in anaesthetised dogs. Res. Vet. Sci. 46, 62-67.", "Schuchmann S., Kovacsb R., Kanna O., Heinemanna U. and Buchheim K. (2001) Monitoring NAD(P)H autofluorescence to assess mitochondrial metabolic functions in rat hippocampal-entorhinal cortex slices. Brain Res. Protoc. 7, 267-276.", "Sick T.J. and Perez-Pinzon M.A. (1999) Optical methods for probing mitochondrial function in brain slices. Methods 18, 104-108.", "Snavely S.R. and Hodges G.R. (1984) The neurotoxicity of antibacterial agents. Ann. Intern. Med. 101, 92-104.", "Stoner C.D., Hodges T.K. and Hanson J.B. (1964) Chloramphenicol as an inhibitor of energy-linked processes in maize mitochondria. Nature 203, 258-261.", "Thomas R.J. (1994) Neurotoxicity of antibacterial therapy. South Med. J. 87, 869-874.", "Watanabe M., Koishi M., Fujiwara M., Takeshita T. and Cieslik W. (1994) Development of a new fluorescence decay measurement system using two-dimensional single-photon counting. J. Photochem. Photobiol. A:Chem 80, 429-432.", "Wong-Riley M.T.T. (1989) Cytochrome oxidase: an endogenous metabolic marker for neuronal activity, Trends Neurosci. 12, 94-101.", "Yaffe M.P. (1999) The machinery of mitochondrial inheritance and behavior. Science 283, 1493-1497.", "Yunis A.A. (1988) Chloramphenicol: relation of structure to activity and toxicity. Ann. Rev. Pharmacol. Toxicol.28, 83-100."]}

Owing to the lack of methods capable to monitor the energetic processes taking place within small brain regions (i.e. nucleus Raphe Dorsalis, nRD), the neurotoxicity of various categories of substances, including antibiotics and psycho-active drugs, still remains difficult to evaluate. Using an in vivo picosecond optical spectroscopy imaging method, we report that chloramphenicol (CAP), besides its well-known ability to inhibit the mitochondria protein synthesis, also influences the NADH/NAD+ redox processes of the respiratory chain. At a 200 mg/kg dose, CAP produces indeed a marked increase in the fluorescent signal of the nRD which, according to clear evidence, is likely to be related to the NADH concentration. This effect also implies an efficient inhibition of complex I of the respiratory chain by CAP. It refers to the mechanism through which the adverse effects of the antibiotic may take place. It could explain why paradoxical sleep, a state needing aerobic energy to occur, is suppressed after CAP administration. The present approach constitutes the first attempt to determine by fluorescence methods the effects of substances on deep brain structures of the freely moving animal. It points out that in vivo ultrafast optical methods are innovative and adequate tools for combined neurochemical and behavioural approaches.

License CC-BY-NC-ND. --------- French law about open access and open science: https://www.legifrance.gouv.fr/affichTexte.do?cidTexte=JORFTEXT000033202746&categorieLien=id ----------------------- LOI n° 2016-1321 du 7 octobre 2016 pour une République numérique - Article 30.