Advertisement

Are metabolites of l-deprenyl (selegiline) useful or harmful? Indications from preclinical research

  • S. Yasar
  • J. P. Goldberg
  • S. R. Goldberg
Part of the Journal of Neural Transmission book series (NEURAL SUPPL, volume 48)

Summary

A frequent topic of controversy has been whether metabolism of l-deprenyl (selegiline) to active metabolites is a detriment to clinical use. This paper reviews possible roles of the metabolites of l-deprenyl in producing unwanted adverse side effects or in augmenting or mediating its clinically useful actions. Levels of l-amphctamine and l-methamphetamine likely to be reached, even with excessive intake of l-deprenyl, would be unlikely to produce neurotoxicity and there is no preclinical or clinical evidence of abuse liability of l-deprenyl. In contrast, there is evidence that l-amphetamine and l-methamphetamine have some qualitatively different actions than their disomer counterparts on EEG and cognitive functioning which might result in beneficial clinical effects and complement beneficial clinical actions of l-deprenyl itself.

Keywords

Discriminative Stimulus Theta Rhythm Discriminative Stimulus Effect Abuse Liability Psychomotor Stimulant 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Bartus RT (1990) Drugs to treat age-related neurodegenerative problems. J Aging Geriatr Sci 38: 680–695Google Scholar
  2. Berry MD, Juorio AV, Paterson IA (1994) Possible mechanisms of action of (−)deprenyl and other MAO-B inhibitors in some neurologic and psychiatric disorders. Prog Neurobiol 44: 141–161PubMedCrossRefGoogle Scholar
  3. Buu NT, Angers M (1987) Effects of different monoamine oxidase inhibitors on the metabolism of L-DOPA in the rat brain. Biochem Pharmacol 36: 1731–1735CrossRefGoogle Scholar
  4. Chiarello RJ, Cole JO (1987) The use of psychostimulants in general psychiatry. Arch Gen Psychiatry 44: 286–295PubMedCrossRefGoogle Scholar
  5. Cody JT, Schwarzhoff R (1993) Interpretation of methamphetamine and amphetamine enantiomer data. J Anal Toxicol 17: 321–326PubMedGoogle Scholar
  6. Colpaert FC, Niemegeers CJE, Janssen PAJ (1980) Evidence that a preferred substrate for type B monoamine oxidase mediates stimulus properties of MAO inhibitors: a possible role for β-phenylethylamine in the cocaine clue. Pharmacol Biochem Behav 13: 513–517PubMedCrossRefGoogle Scholar
  7. Corsi-Cabrera R, Ramos J, Guevara MA, Arce C, Gutierrez S (1993) Gender differences in the EEG during cognitive activity. Int J Neurosci 72: 257–264PubMedCrossRefGoogle Scholar
  8. Engberg G, Elebring T, Nissbrandt H (1991) Deprenyl (selegiline), a selective MAO-B inhibitor with active metabolites; effects on locomotor activity, dopaminergic neurotransmission and firing rate of nigral dopamine neurons. J Pharmacol Exp Ther 259: 841–847PubMedGoogle Scholar
  9. Fang J, YU PH (1994) Effect of L-deprenyl, its structural analogues and some monoamine oxidase inhibitors on dopamine uptake. Neuropharmacology 33: 763–768PubMedCrossRefGoogle Scholar
  10. Fozard JR, Zreika M, Robin M, Palfreyman MG (1985) The functional consequences of inhibition of monoamine oxidase type B: comparison of the pharmacological properties of L-deprenyl and MDL 72145. Naunyn Schmiedebergs Arch Pharmacol 334: 186–193CrossRefGoogle Scholar
  11. Gelowitz DL, Richardson JS, Wishart TB, Yu PH, Lai C-T (1993) Chronic L-deprenyl or l-amphetamine: equal cognitive enhancement, unequal MAO inhibition. Pharmacol Biochem Behav 47: 41–45CrossRefGoogle Scholar
  12. Goldberg SR, Stolerman IP (eds) (1986) Behavioral analysis of drug dependence. Academic Press, LondonGoogle Scholar
  13. Goldberg SR, Yasar S, Bergman J (1994) Introduction: examination of clinical and preclinical pharmacologic data relating to abuse liability of l-deprenyl (selegiline). Clin Pharmacol Ther 56: 721–724PubMedCrossRefGoogle Scholar
  14. Halliday R, Callaway E, Naylar H, Gratzinger P, Prael R (1986) The effects of stimulant drugs on information processing in elderly adults. J Gerontol 41: 748–757PubMedGoogle Scholar
  15. Heikkila RE, Orlansky H, Mytilineou C, Cohen G (1975) Amphetamine: evaluation of d-and l-isomers as releasing agents and uptake inhibitors for 3H-dopamine and 3Hnorepinephrine in slices of rat neostriatum and cerebral cortex. J Pharmacol Exp Ther 194: 47–56PubMedGoogle Scholar
  16. Katz JL (1982) Rate-dependent effects of d-and l-amphetamine on schedule-controlled responding in pigeons and squirrel monkeys. Neuropharmacology 21: 235–242PubMedCrossRefGoogle Scholar
  17. Knoll J, Ecseri Z, Kelemen K, Nievel J, Knoll B (1965) Phenylisopropylmethylpropinylamine (E-250), a new psychic energizer. Arch Int Pharmacodyn 155: 154–164PubMedGoogle Scholar
  18. Koelega HS (1993) Stimulant drugs and vigilance performance: a review. Psychopharmacology 111: 1–16PubMedCrossRefGoogle Scholar
  19. Kuczenski R, Segal DS, Cho AK, Melega W (1995) Hippocampus norepinephrine, caudate dopamine and serotonin, and behavioral responses to the stereoisomers of amphetamine and methamphetamine. J Neurosci 15: 1308–1317PubMedGoogle Scholar
  20. Lamb RJ, Griffiths RR (1990) Self-administration in baboons and the discriminative stimulus effects in rats of bupropion, nomifensine, diclofensine and imipramine. Psychopharmacology 102: 183–190PubMedCrossRefGoogle Scholar
  21. Lynch G, Kessler M, Arai A, Larson J (1990) The nature and causes of hippocampal long-term potentiation. In: Storm-Mathisen J, Zimmer J, Ottersen OP (eds) Progress in brain research, vol 83. Elsevier Science, New York, pp 233–248Google Scholar
  22. Marelt GJ, Vosmer G, Seiden LS (1990) Dopamine uptake inhibitors block long-term neurotoxic effects of methamphetamine upon dopaminergic neurons. Brain Res 513: 274–279CrossRefGoogle Scholar
  23. Masand P, Murray GB, Pickett P (1991) Psychostimulants in post-stroke depression. J Neuropsychiatr Clin Neurosci 3: 23–27Google Scholar
  24. Milgram NW, Ivy GO, Head E, Murphy MP, Wu PH, Ruehl WW, Yu PH, Durden DA, Davis BA, Paterson IA, Boulton AA (1993) The effect of L-deprenyl on behavior, cognitive function and biogenic amines in the dog. Neurochem Res 18: 1211–1219PubMedCrossRefGoogle Scholar
  25. Miller R (1991) Cortico-hippocampal interplay and the representation of contexts in the brain. Springer, Berlin Heidelberg New York Tokyo (Studies of Brain Function, vol 7)Google Scholar
  26. Moser PC (1990) Generalization of L-deprenyl, but not MDL-72974, to the D-amphetamine stimulus in rats. Psychopharmacology 101: S40Google Scholar
  27. Nickel B, Schultze G, Szelenyi I (1990) Effect of enantiomers of deprenyl (selegeline) and amphetamine on physical abuse liability and cortical electrical activity in rats. Neuropharmacology 29: 983–992PubMedCrossRefGoogle Scholar
  28. Philips SR (1981) Amphetamine, p-hydroxyamphetamine and β-phenylethylamine in mouse brain and urine after (−)-and (+)-deprenyl administration. Pharm Pharmacol 33: 739–741Google Scholar
  29. Porsolt RD, Pawelec C, Jalfre M (1984) Discrimination of amphetamine cue: effects of A, B and mixed type inhibitors of monoamine oxidase. Neuropharmacology 23: 569–573PubMedCrossRefGoogle Scholar
  30. Ramos E, Corsi-Cabrera M, Guevara MA, Arce C (1993) EEG activity during cognitive performance in women. Int J Neurosci 69: 189–195CrossRefGoogle Scholar
  31. Reynolds GP, Elsworth JD, Blau K, Sandler M, Lees AJ, Stern GM (1978) Deprenyl is metabolized to methamphetamine and amphetamine in man. Br J Clin Pharmacol 6: 542–544PubMedGoogle Scholar
  32. Risner ME, Jones BE (1977) Characteristics of β-phenylethylamine self-administration by dog. Pharmacol Biochem Behav 6: 689–696PubMedCrossRefGoogle Scholar
  33. Schechter MD (1978) Stimulus properties of d-amphetamine as compared to l-amphetamine. Eur J Pharmacol 47: 461–464PubMedCrossRefGoogle Scholar
  34. Shannon HE, De Georgio CM (1982) Self-administration of endogenous trace amines β-phenylethylamine, N-methyl phenylethylamine and phenylethanolamine in dogs. J Pharmacol Exp Ther 222: 52–60PubMedGoogle Scholar
  35. Sprague JE, Nichols DE (1995) The monoamine oxidase-B inhibitor L-deprenyl protects against 3,4-methylenedioxymethamphetamine-induced lipid peroxidation and long-term serotonergic deficits. J Pharmacol Exp Ther 273: 667–673PubMedGoogle Scholar
  36. Spyraki C, Fibiger HC (1981) Intravenous self-administration of nomifensine in rat: implications for abuse potential in humans. Science 212: 11671–1168CrossRefGoogle Scholar
  37. Tatton WG (1993) “Trophic-like” reduction of nerve cell death by deprenyl without monoamine oxidase inhibition. Neurology Forum 4: 3–10Google Scholar
  38. Taylor KM, Snyder SH (1970) Amphetamine: differentation by d and l isomers of behavior involving brain norepinephrine or dopamine. Science 168: 1487–1489PubMedCrossRefGoogle Scholar
  39. Terrace HS (1966) Stimulus control. In: Honig WK (ed) Operant behavior: areas of research and application. Prentice-Hall, Englewoods Cliffs NJ, pp 271–344Google Scholar
  40. Timár J, Knoll B (1986) The effect of repeated administration of (−)-deprenyl on the phenylethylamine-induced stereotypy in rats. Arch Int Pharmacodyn 279: 50–60PubMedGoogle Scholar
  41. Warneke L (1990) Psychostimulants in psychiatry. Can J Psychiatry 35: 3–10PubMedGoogle Scholar
  42. Woods SW, Tesar GE, Murray GB, Cassem NH (1986) Psychostimulant treatment of depressive disorders secondary to medical illness. J Clin Psychiatry 47: 12–15PubMedGoogle Scholar
  43. Winger GD, Palmer RK, Woods JH (1989) Drug-reinforced responding: rapid determination of dose-response functions. Drug Alcohol Depend 24: 135–142PubMedCrossRefGoogle Scholar
  44. Winger GD, Yasar S, Negus SS, Goldberg SR (1994) Intravenous self-administration studies with l-deprcnyl (selegiline) in monkeys. Clin Pharmacol Ther 56: 774–780PubMedCrossRefGoogle Scholar
  45. Wragg RE, Jeste DV (1989) Overview of depression and psychosis in Alzheimer’s disease. Am J Psychiatry 146: 577–587PubMedGoogle Scholar
  46. Yasar S, Bergman J (1994) Amphetamine-like effect of l-deprenyl (selegiline) in drug discrimination studies. Clin Pharmacol Ther 56: 768–773PubMedCrossRefGoogle Scholar
  47. Yasar S, Schindler CW, Thorndike EB, Szelenyi I, Goldberg SR (1993a) Evaluation of the stereoisomers of deprenyl for amphetamine-like discriminative stimulus effects in rats. J Pharmacol Exp Ther 265: 1–6PubMedGoogle Scholar
  48. Yasar S, Winger G, Nickel B, Schulze G, Goldberg SR (1993b) Preclinical evalation of l-deprenyl: lack of amphetamine-like abuse potential. In: Szelenyi I (ed) Inhibitors of monoamine oxidase B. Birkhäuser, Basel, pp 215–233Google Scholar
  49. Yasar S, Schindler CW, Thorndike EB, Goldberg SR (1994) Evaluation of deprenyl for cocaine-like discriminative stimlus effects in rats. Eur J Pharmacol 259: 243–250PubMedCrossRefGoogle Scholar
  50. Yokel RA, Pickens R (1973) Self-administration of optical isomers of amphetamine and methylamphetamine by rats. J Pharmacol Exp Ther 187: 27–33PubMedGoogle Scholar

Copyright information

© Springer-Verlag/Wien 1996

Authors and Affiliations

  • S. Yasar
    • 1
    • 2
  • J. P. Goldberg
    • 3
  • S. R. Goldberg
    • 2
  1. 1.Department of Anesthesiology and Critical Care MedicineJohns Hopkins University Medical SchoolBaltimore, MDUSA
  2. 2.Behavioral Pharmacology and Genetics Section, Preclinical Pharmacology Laboratory, Division of Intramural Research, National Institute on Drug AbuseNational Institutes of HealthBaltimore, MDUSA
  3. 3.Vista Hill HospitalChula Vista, CAUSA

Personalised recommendations