Advertisement

Psychopharmacology

, Volume 103, Issue 3, pp 398–406 | Cite as

Long-term effects of neonatal exposure to isobutylmethylxanthine

II. Attenuation of acute morphine withdrawal in mature rats
  • Bethany S. Neal
  • Rita B. Messing
  • Sheldon B. Sparber
Original Investigations

Abstract

An acute model of morphine withdrawal was used to determine if neonatal exposure to 3-isobutyl-1-methylxanthine (IBMX) would cause alterations in the expression of withdrawal in the adult rat. IBMX induces a quasi-morphine withdrawal syndrome (QMWS), which is almost identical to true morphine withdrawal both behaviorally and neurochemically. Transient IBMX treatment during infancy (on days 7–10 of life) caused an attenuated suppression of fixed ratio (FR) responding during acute morphine withdrawal in adulthood; however, there appeared to be no attenuation of withdrawal-induced hypothermia. The attenuated behavioral response was not due to an altered ability to express withdrawal, as these rats did not react differently to various doses of IBMX plus naloxone (i.e., varying severities of quasi-morphine withdrawal) in adulthood. Coad-ministration of the serotonin (5-HT) antagonist mianserin with IBMX in the neonate prevented the effects of IBMX. Both the mianserin-treated and the IBMX plus mianserin-treated groups had increased levels of [3H]naloxone binding in brainstem, while IBMX treatment alone apparently had no significant effect. None of the neonatal drug treatments affected [3H]naloxone binding in frontal cortex. Thus, the long-term effects of IBMX on the opioid withdrawal response cannot be explained by changes in the number of opioid binding sites (labelled with [3H]naloxone) within the brain. The results indicate that exposure to a methylxanthine, and thus quasi-morphine withdrawal, during development results in long-lasting alterations of a system which is involved in opioid withdrawal. Because coadministration of mianserin prevented the effects of IBMX, 5-HT and 5-HT2 receptors are implicated in these effects.

Key words

Isobutylmethylxanthine Development Mianserin Serotonin Morphine withdrawal 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Auguy-Valette P, Cros J, Gouarderes C, Gout R, Pontonnier G (1978) Morphine analgesia and cerebral opiate receptors: a developmental study. Br J Pharmacol 63:303–308Google Scholar
  2. Bickel WK, Stitzer ML, Liebson IA, Bigelow GE (1988) Acute physical dependence in man: Effects of naloxone after brief morphine exposure. J Pharmacol Exp Ther 244:126–132Google Scholar
  3. Caruso TP, Larson DL, Portoghese PS, Takemori AE (1980) Pharmacological studies with an alkylating narcotic agonist, chloroxymorphamine, and antagonist, chlornaltrexamine. J Pharmacol Exp Ther 213:539–544Google Scholar
  4. Clendeninn NJ, Petraitis M, Simon EJ (1976) Ontological development of opiate receptors in rodent brain. Brain Res 118:157–160Google Scholar
  5. Cohen CA, Messing RB, Sparber SB (1987) Selective learning impairment of delayed reinforcement autoshaped behavior caused by low doses of trimethyltin. Psychopharmacology 93:301–307Google Scholar
  6. Collier HOJ, Francis DL, Henderson G, Schneider C (1974) Quasi morphine-abstinence syndrome. Nature 249:471–473Google Scholar
  7. Collier HOJ, Cuthbert NJ, Francis DL (1981) Character and meaning of quasi-morphine withdrawal phenomena elicited by methylxanthines. Fed Proc 40:1513–1518Google Scholar
  8. Coyle JT, Pert CB (1976) Ontogenetic development of opiate receptors in rat brain. Neuropharmacology 14:555–560Google Scholar
  9. Dwoskin LP, Neal BS, Sparber SB (1983) Yohimbine exacerbates and clonidine attenuates acute morphine withdrawal in rats. Eur J Pharmacol 90:269–273Google Scholar
  10. Ferster CB, Skinner BF (1957) Schedules of reinforcement Appleton-Century-Crofst, New York, pp 39–132Google Scholar
  11. Finnegan LP (1983) Clinical perinatal and developmental effects of methadone. In: Cooper JR, Altman F, Brown BS, Czechowicz D (eds) Research on the treatment of narcotic addiction: state of the art. Treatment Research Monograph Series, National Institute on Drug Abuse, Rockville, MD, pp 392–443Google Scholar
  12. Francis DL, Roy AC, Collier HOJ (1975) Morphine abstinence and quasi-abstinence effects after phosphodiesterase inhibitors and naloxone. Life Sci 16:1901–1906Google Scholar
  13. Galloway MP, Roth RH (1983) Clonidine prevents methylxanthine stimulation of norepinephrine metabolism in rat brain. J Neurocherm 40:246–251Google Scholar
  14. Gellert VF, Sparber SB (1977) A comparison of the effect of naloxone upon body weight loss and suppression of fixed-ratio operant behavior in morphine-dependent rats. J Pharmacol Exp Ther 201:44–54Google Scholar
  15. Grant SJ, Redmond DE (1982a) Clonidine suppresses methylxanthine induced quasi-morphine withdrawal syndrome. Pharmacol Biochem Behav 17:655–658Google Scholar
  16. Grant SJ, Redmond DE (1982b) Methylxanthine activation of noradrenergic unit activity and reversal by clonidine. Eur J Pharmacol 85:105–109Google Scholar
  17. Hutchings DE, Fifer WP (1986) Neurobehavioral effects in human and animal offspring following prenatal exposure to methadone. In: Riley EP, Vorhees CV (eds) Handbook of behavioral teratology. Plenum Press, New York, pp 141–160Google Scholar
  18. Kinsley CH, Mann PE, Bridges RS (1988) Prenatal stress alters morphine- and stress-induced analgesia in male and female rats. Pharmacol Biochem Beh 30:123–128Google Scholar
  19. Kirby ML (1983) Changes in [3H]naloxone binding in spinal cord of rats treated prenatally with morphine. Neuropharmacology 22:303–308Google Scholar
  20. Kirby ML, Aronstam RS (1983) Levorphanol-sensitive [3H]-labeled naloxone binding in developing brainstem following prenatal morphine exposure. Neurosci Lett 35:191–195Google Scholar
  21. Kleven MS, Sparber SB (1987) Attenuation of isobutylmethylxanthine-induced suppression of operant behavior by pretreatment of rats with clonidine. Pharmacol Biochem Behav 28:235–241Google Scholar
  22. Kleven MS, Sparber SB (1989a) Modification of the behavioral effects of 3-isobutyl-1-methylxanthine by serotonin agonists and antagonists: evidence for a role of serotonin in the expression of opiate withdrawal. Psychopharmacology 98:231–235Google Scholar
  23. Kleven MS, Sparber SB (1989b) Morphine blocks and naloxone enhances the suppression of operant behavior by low doses of 3-isobutyl-1-methylxanthine. J Pharmacol Exp Ther 248:273–277Google Scholar
  24. Kosersky DS, Harris RA, Harris LS (1974) Naloxone-precipitated jumping activity in mice following the acute administration of morphine. Eur J Pharmacol 26:12–124Google Scholar
  25. Lewis ME, Pert A, Pert CB, Herkenham M (1983) Opiate receptor localization in rat cerebral cortex. J Comp Neurol 216:339–358Google Scholar
  26. Lichtblau L, Messing RB, Sparber SB (1984) Neonatal opiate withdrawal alters the reactivity of adult rats to the hot-plate. Life Sci 34:1725–1730Google Scholar
  27. Lowry DH, Rosebough NJ, Farr AL, Randall RJ (1951) Protein measurement with Folin phenol reagent. J Biol Chem 193:265–275Google Scholar
  28. Meyer DR, Sparber SB (1977) Evidence of possible opiate dependence during the behavioral depressant action of a single dose of morphine. Life Sci 21:1087–1094Google Scholar
  29. Neal BS, Sparber SB (1986a) Mianserin attenuates naloxone-precipatated withdrawal in rats acutely or chronically dependent upon morphine. J Pharmacol Exp Ther 236:157–165Google Scholar
  30. Neal BS, Sparber SB (1986b) Ketanserin and pirenperone attenuate acute morphine withdrawal in rats. Eur J Pharmacol 132:299–304Google Scholar
  31. Neal BS, Sparber SB (1991) Long-term effects of neonatal exposure to isobutylmethylxanthine: I. Retardation of learning with antagonism by mianserin. Psychopharmacology 103:388–397Google Scholar
  32. Nielsen JA, Sparber SB (1985) Indomethacin facilitates acute tolerance to and dependence upon morphine as measured by changes in fixed-ratio behavior and rectal temperature in rats. Pharmacol Biochem Behav 22:921–931Google Scholar
  33. O'Callaghan JP, Holtzmann SG (1976) Prenatal administration of morphine to the rat. Tolerance to the analgesic effect in the offspring. J. Pharmacol Exp Ther 197:533–544Google Scholar
  34. Pert CB, Snyder SH (1973) Opiate receptor demonstration in nervous system. Science 179:1011–1014Google Scholar
  35. Seyle H (1971) Protection by estradiol against cocaine, coniine, ethylmorphine, LSD, and strychnine. Horm Behav 2:337–341Google Scholar
  36. Sparber SB (1986) Developmental effects of narcotics. Neurotoxicology 7:335–348Google Scholar
  37. Sparber SB, Lichtblau L (1983) Postnatal abstinence or acute toxicity can account for morbidity in developmental studies with opiates. Life Sci 33:1135–1140Google Scholar
  38. Sparber SB, Meyer D (1978) Clonidine antagonizes naloxone-induced suppression of conditioned behavior and body weight loss in morphine-dependent rats. Pharmacol Biochem Behav 9:319–325Google Scholar
  39. Sparber SB, Gellert VF, Lichtblau L, Eisenberg R (1978) The use of operant behavior methods to study aggression and effects of acute and chronic morphine administration in rats. In: Adler MW, Manara L, Samanin R (eds) Factors affecting the action of narcotics. Raven Press, New York, pp 63–91Google Scholar
  40. Sparber SB, Lichtblau L, Kuwahara MD (1986) Experimental separation of direct and indirect effects of drugs on neurobehavioral development. In: Krasnegor NA, Gray DB, and Thompson T (eds) Developmental behavioral pharmacology, vol. 5. Lawrence Erlbaum, Hillsdale, New Jersey, pp 225–263Google Scholar
  41. Steele WJ, Johannesson T (1975) Effects of prenatally-administered morphine on brain development and resultant tolerance to the analgesic effect of morphine in offspring of morphine treated rats. Acta Pharmacol Toxicol 36:243–256Google Scholar
  42. Wang C, Pasulka P, Perry B, Pizzi WJ, Schnoll SH (1986) Effect of perinatal exposure to methadone on brain opioid and alpha2-adrenergic receptors. Neurobehav Toxicol Teratol 8:399–402Google Scholar
  43. Winer BJ (1971) Statistical principles in experimental design. McGraw-Hill, New YorkGoogle Scholar
  44. Zhang AZ, Pasternak GW (1981) Ontogeny of opioid pharmacology and receptors: High and low affinity site differences. Eur J Pharmacol 73:29–40Google Scholar

Copyright information

© Springer-Verlag 1991

Authors and Affiliations

  • Bethany S. Neal
    • 1
  • Rita B. Messing
    • 1
  • Sheldon B. Sparber
    • 1
  1. 1.Departments of Pharmacology and Psychiatry, Program in NeuroscienceUniversity of MinnesotaMinneapolisUSA

Personalised recommendations