Advertisement

Psychopharmacology

, Volume 186, Issue 2, pp 159–167 | Cite as

Metabolic correlates of toluene abuse: decline and recovery of function in adolescent animals

  • Wynne K. SchifferEmail author
  • Dianne E. Lee
  • David L. Alexoff
  • Rich Ferrieri
  • Jonathan D. Brodie
  • Stephen L. Dewey
Original Investigation

Abstract

Rationale

Children and adolescents will readily abuse household products that contain solvents such as toluene. It is likely that reinforcing exposures to toluene alter brain glucose metabolism.

Objective

Using an animal model of drug reinforcement, we sought to identify a metabolic signature of toluene abuse in the adolescent rodent brain. Small animal PET (microPET), in combination with the glucose analog radiotracer, 18FDG, were used to evaluate the metabolic consequences of inhaled toluene.

Methods

The exposure protocol paralleled our previously established method for assessing the conditioned reinforcing effects of toluene (5,000 ppm) using the conditioned place preference (CPP) paradigm. Animals were scanned at baseline and 2 h after the last exposure. Follow-up 18FDG scans occurred 1 day, 3 weeks, and 2 months later. Results: After six pairings, 38% of the animals preferred the toluene paired chamber and 25% were averse. The immediate metabolic effect in toluene-exposed animals was a 20% decline in whole brain 18FDG uptake. Twenty-four hours following the last exposure, the whole brain decline was 40%, and 2 months later, the decline was 30% of pretoluene levels. A region-by-region analysis demonstrated significant additional decreases in the pons, cerebellum, striatum, midbrain, temporal cortex, and hippocampus. Two months after toluene cessation, regions of complete metabolic recovery were the thalamus and cerebellum; however, the temporal cortex did not recover.

Conclusions

Brain uptake of 18FDG appears to be a useful tool for examining the metabolic impact of toluene abuse, which include a profound decline followed by region-specific recovery after cessation.

Keywords

Abuse Brain imaging PET Deoxyglucose Animal model Inhalant abuse 

Notes

Acknowledgements

Supported by National Institutes of Health grants DA15082, DA16025, DA15041, and T32-DA07316 and performed under Brookhaven Science Associates contract No. DE-AC02-98CH10886 with the US Department of Energy. We greatly appreciate the efforts of Madina Gerasimov, Colleen Shea, Lisa Muench, Youwen Xu and Drs. Mike Schueller, Paul Vaska and David Schlyer, and technical assistance from James Anselmini, Steve Howell and Barry Laffler in the BNL Chemistry Department. We are thankful for the helpful discussions with Drs. Joanna S. Fowler and Helene Benveniste.

References

  1. Ameno K, Kiriu T, Fuke C, Ameno S, Shinohara T, Ijiri I (1992) Regional brain distribution of toluene in rats and in a human autopsy. Arch Toxicol 66:153–156PubMedCrossRefGoogle Scholar
  2. Balster RL (1998) Neural basis of inhalant abuse. Drug Alcohol Depend 51:207–214PubMedCrossRefGoogle Scholar
  3. Biegon A, Fry PA, Paden CM, Alexandrovich A, Tsenter J, Shohami E (2004) Dynamic changes in N-methyl-d-aspartate receptors after closed head injury in mice: implications for treatment of neurological and cognitive deficits. Proc Natl Acad Sci USA 101:5117–5122PubMedCrossRefGoogle Scholar
  4. Cairney S, Maruff P, Burns CB, Currie J, Currie BJ (2005) Neurological and cognitive recovery following abstinence from petrol sniffing. Neuropsychopharmacology 30:1019–1027PubMedCrossRefGoogle Scholar
  5. Cruz SL, Mirshahi T, Thomas B, Balster RL, Woodward JJ (1998) Effects of the abused solvent toluene on recombinant N-methyl-d-aspartate and non-N-methyl-d-aspartate receptors expressed in Xenopus oocytes. J Pharmacol Exp Ther 286:334–340PubMedGoogle Scholar
  6. Duncan GE, Moy SS, Knapp DJ, Mueller RA, Breese GR (1998) Metabolic mapping of the rat brain after subanesthetic doses of ketamine: potential relevance to schizophrenia. Brain Res 787:181–190PubMedCrossRefGoogle Scholar
  7. Fern R, Davis P, Waxman SG, Ransom BR (1998) Axon conduction and survival in CNS white matter during energy deprivation: a developmental study. J Neurophysiol 79:95–105PubMedGoogle Scholar
  8. Filley CM, Kleinschmidt-DeMasters BK (2001) Toxic leukoencephalopathy. N Engl J Med 345:425–432PubMedCrossRefGoogle Scholar
  9. Filley CM, Heaton RK, Rosenberg NL (1990) White matter dementia in chronic toluene abuse. Neurology 40:532–534PubMedGoogle Scholar
  10. Filley CM, Halliday W, Kleinschmidt-DeMasters BK (2004) The effects of toluene on the central nervous system. J Neuropathol Exp Neurol 63:1–12PubMedGoogle Scholar
  11. Fornazzari L, Pollanen MS, Myers V, Wolf A (2003) Solvent abuse-related toluene leukoencephalopathy. J Clin Forensic Med 10:93–95PubMedCrossRefGoogle Scholar
  12. Gerasimov MR, Ferrieri RA, Schiffer WK, Logan J, Gatley SJ, Gifford AN, Alexoff DA, Marsteller DA, Shea C, Garza V, Carter P, King P, Ashby CR Jr, Vitkun S, Dewey SL (2002a) Study of brain uptake and biodistribution of [11C]toluene in non-human primates and mice. Life Sci 70:2811–2828PubMedCrossRefGoogle Scholar
  13. Gerasimov MR, Schiffer WK, Marstellar D, Ferrieri R, Alexoff D, Dewey SL (2002b) Toluene inhalation produces regionally specific changes in extracellular dopamine. Drug Alcohol Depend 65:243–251PubMedCrossRefGoogle Scholar
  14. Gerasimov MR, Collier L, Ferrieri A, Alexoff D, Lee D, Gifford AN, Balster RL (2003) Toluene inhalation produces a conditioned place preference in rats. Eur J Pharmacol 477:45–52PubMedCrossRefGoogle Scholar
  15. Glowa JR (1981) Some effects of sub-acute exposure to toluene on schedule-controlled behavior. Neurobehav Toxicol Teratol 3:463–465PubMedGoogle Scholar
  16. Glowa JR, DeWeese J, Natale ME, Holland JJ, Dews PB (1986) Behavioral toxicology of volatile organic solvents. I. Methods: acute effects of toluene. J Environ Pathol Toxicol Oncol 6:153–168PubMedGoogle Scholar
  17. Gospe SM Jr, Calaban MJ (1988) Central nervous system distribution of inhaled toluene. Fundam Appl Toxicol 11:540–545PubMedCrossRefGoogle Scholar
  18. Hassoun W, Le Cavorsin M, Ginovart N, Zimmer L, Gualda V, Bonnefoi F, Leviel V (2003) PET study of the [11C]raclopride binding in the striatum of the awake cat: effects of anaesthetics and role of cerebral blood flow. Eur J Nucl Med Mol Imaging 30:141–148PubMedCrossRefGoogle Scholar
  19. Himnan DJ (1984) Tolerance and reverse tolerance to toluene inhalation: effects on open-field behavior. Pharmacol Biochem Behav 21:625–631PubMedGoogle Scholar
  20. Hormes JT, Filley CM, Rosenberg NL (1986) Neurologic sequelae of chronic solvent vapor abuse. Neurology 36:698–702PubMedGoogle Scholar
  21. Ikeuchi Y, Hirai H (1994) Toluene inhibits synaptic transmission without causing gross morphological disturbances. Brain Res 664:266–270PubMedCrossRefGoogle Scholar
  22. Lee DE, Schiffer WK, Dewey SL (2004) Gamma-vinyl GABA (vigabatrin) blocks the expression of toluene-induced conditioned place preference (CPP). Synapse 54:183–185PubMedCrossRefGoogle Scholar
  23. Matsumura A, Mizokawa S, Tanaka M, Wada Y, Nozaki S, Nakamura F, Shiomi S, Ochi H, Watanabe Y (2003) Assessment of microPET performance in analyzing the rat brain under different types of anesthesia: comparison between quantitative data obtained with microPET and ex vivo autoradiography. Neuroimage 20:2040–2050PubMedCrossRefGoogle Scholar
  24. Miyamoto Y, Yamada K, Nagai T, Mori H, Mishina M, Furukawa H, Noda Y, Nabeshima T (2004) Behavioural adaptations to addictive drugs in mice lacking the NMDA receptor epsilon1 subunit. Eur J Neurosci 19:151–158PubMedCrossRefGoogle Scholar
  25. Moser VC, Balster RL (1981) The effects of acute and repeated toluene exposure on operant behavior in mice. Neurobehav Toxicol Teratol 3:471–475PubMedGoogle Scholar
  26. Paxinos G, Watson C (1986) The rat brain in stereotaxic coordinates. Academic, New YorkGoogle Scholar
  27. Ransom BR, Waxman SG, Davis PK (1990) Anoxic injury of CNS white matter: protective effect of ketamine. Neurology 40:1399–1403PubMedGoogle Scholar
  28. Riegel AC, French ED (1999a) Acute toluene induces biphasic changes in rat spontaneous locomotor activity which are blocked by remoxipride. Pharmacol Biochem Behav 62:399–402PubMedCrossRefGoogle Scholar
  29. Riegel AC, French ED (1999b) The susceptibility of rat non-dopamine ventral tegmental neurones to inhibition during toluene exposure. Pharmacol Toxicol 85:44–46PubMedCrossRefGoogle Scholar
  30. Riegel AC, Ali SF, French ED (2003) Toluene-induced locomotor activity is blocked by 6-hydroxydopamine lesions of the nucleus accumbens and the mGluR2/3 agonist LY379268. Neuropsychopharmacology 28:1440–1447PubMedCrossRefGoogle Scholar
  31. Rosenberg NL, Kleinschmidt-DeMasters BK, Davis KA, Dreisbach JN, Hormes JT, Filley CM (1988a) Toluene abuse causes diffuse central nervous system white matter changes. Ann Neurol 23:611–614PubMedCrossRefGoogle Scholar
  32. Rosenberg NL, Spitz MC, Filley CM, Davis KA, Schaumburg HH (1988b) Central nervous system effects of chronic toluene abuse-clinical, brainstem evoked response and magnetic resonance imaging studies. Neurotoxicol Teratol 10:489–495PubMedCrossRefGoogle Scholar
  33. Schiffer WK, Mirrione MM, Biegon A, Alexoff DL, Patel V, Dewey SL (2005) Serial microPET measures of the metabolic reaction to a microdialysis probe implant. J Neurosci Methods (in press)Google Scholar
  34. Schutz CG, Chilcoat HD, Anthony JC (1994) The association between sniffing inhalants and injecting drugs. Compr Psychiatry 35:99–105PubMedCrossRefGoogle Scholar
  35. Schweinhardt P, Fransson P, Olson L, Spenger C, Andersson JL (2003) A template for spatial normalisation of MR images of the rat brain. J Neurosci Methods 129:105–113PubMedCrossRefGoogle Scholar
  36. Shapiro HM, Greenberg JH, Reivich M, Ashmead G, Sokoloff L (1978) Local cerebral glucose uptake in awake and halothane-anesthetized primates. Anesthesiology 48:97–103PubMedCrossRefGoogle Scholar
  37. 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
  38. Spencer PS, Schaumburg HH (1985) Organic solvent neurotoxicity. Facts and research needs. Scand J Work Environ Health 11(Suppl 1):53–60PubMedGoogle Scholar
  39. Sullivan MJ, Rarey KE, Conolly RB (1988) Ototoxicity of toluene in rats. Neurotoxicol Teratol 10:525–530PubMedCrossRefGoogle Scholar
  40. Toyama H, Ichise M, Liow JS, Vines DC, Seneca NM, Modell KJ, Seidel J, Green MV, Innis RB (2004) Evaluation of anesthesia effects on [18F]FDG uptake in mouse brain and heart using small animal PET. Nucl Med Biol 31:251–256PubMedCrossRefGoogle Scholar
  41. Wada H, Hosokawa T, Saito K (1986) Effects of single exposure to toluene on shock avoidance and time estimation in rats. Neurobehav Toxicol Teratol 8:727–730PubMedGoogle Scholar
  42. Yamanouchi N, Okada S, Kodama K, Hirai S, Sekine H, Murakami A, Komatsu N, Sakamoto T, Sato T (1995) White matter changes caused by chronic solvent abuse. AJNR Am J Neuroradiol 16:1643–1649PubMedGoogle Scholar
  43. Yamanouchi N, Okada S, Kodama K, Sakamoto T, Sekine H, Hirai S, Murakami A, Komatsu N, Sato T (1997) Effects of MRI abnormalities on WAIS-R performance in solvent abusers. Acta Neurol Scand 96:34–39PubMedGoogle Scholar
  44. You L, Muralidhara S, Dallas CE (1995) Comparisons of the regional brain distributions of inhaled 1,1,1-trichloroethane in mice and rats. Toxicologist 15:193–199Google Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Wynne K. Schiffer
    • 1
    • 2
    Email author
  • Dianne E. Lee
    • 1
  • David L. Alexoff
    • 1
  • Rich Ferrieri
    • 1
  • Jonathan D. Brodie
    • 2
  • Stephen L. Dewey
    • 1
    • 2
  1. 1.Chemistry Department, Bldg #555Brookhaven National LaboratoryUptonUSA
  2. 2.Department of PsychiatryNYU School of MedicineNew YorkUSA

Personalised recommendations