Abstract
Pregnant women regularly ingest the methylxanthines, caffeine and theophylline, during pregnancy and lactation. Also, theophylline is used to treat apnea in premature infants. In this study, rat pups were treated with 3-isobutyl-1-methylxanthine (IBMX), on days 7–10 of life. Transient IBMX treatment during infancy caused a retardation of acquisition of a delayed reinforced autoshaped lever touch response in adulthood. Treated rats required more trials to learn the task, but did not show altered exploratory activity in the operant chambers. Coadministration of the serotonin (5-HT) antagonist mianserin with IBMX was able to attenuate significantly the effects of IBMX in both males and females, even though mianserin treatment alone caused an apparent learning deficit in the males. The results indicate that 5-HT and 5-HT receptors are important during development for normal expression of a specific cognitive function later in life. Furthermore, a 5-HT system appears to play a role in the mechanism whereby perinatal methylxanthine exposure could lead to learning impairments or other undesirable behavioral consequences. The use of IBMX in developing rats may also offer a model for studying the long-term consequences of the expression of opioid withdrawal during the neonatal period, since this agent induces a quasi-morphine withdrawal syndrome (QMWS) in mature rats. It is of interest that mianserin can block or attenuate effects of both quasi- and true morphine withdrawal.
Similar content being viewed by others
References
Aghajanian GK (1978) Tolerance of locus coeruleus neurones to morphine and suppression of withdrawal response by clonidine. Nature 276:186–188
Aranda JV, Turmen T (1979) Methylxanthines in apnea of prematurity. Clin Perinatol 6:87–107
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
Butcher RE, Vorhees CV, Wooten V (1984) Behavioral and physical development of rats chronically exposed to caffeinated fluids. Fundam Appl Toxicol 4:1–13
Chasnoff IJ, Hatcher R, Burns WJ (1980) Early growth patterns of methadone-addicted infants. Am J Dis Child 134:1040–1051
Cohen CA, Messing RB, Sparber SB (1987) Selective learning impairment of delayed reinforcement autoshaped behavior caused by low doses of trimethyltin. Psychopharmacology 93:301–307
Collier HOJ, Francis DL, Henderson G, Schneider C (1974) Quasi morphine-abstinence syndrome. Nature 249:471–473
Collier HOJ, Cuthbert NJ, Francis DL (1981) Character and meaning of quasi-morphine withdrawal phenomena elicited by methylxanthines. Fed Proc 40:1513–1518
Colpaert FC, Niemegeers CJE, Janssen PAJ (1982) A drug discrimination analysis of lysergic acid diethylamide (LSD): in vivo agonist and antagonist effects of purported 5-hydroxytryptamine antagonists and of pirenperone, an LSD-antagonist. J Pharmacol Exp Ther 221:206–214
Concannon JT, Braughler JM, Schechter MD (1983) Pre- and postnatal effects of caffeine on brain biogenic amines, cyclic nucleotides and behavior in developing rats. J Pharmacol Exp Ther 226:673–679
Crawley JN, Laverty R, Roth RH (1979) Clonidine reversal of increased norepinephrine metabolite levels during morphine withdrawal. Eur J Pharmacol 57:247–250
DeCaballos ML, Benedi A, Urdin C, Del Rio J (1985) Prenatal exposure of rats to antidepressant drugs down-regulates beta-adrenoceptors and 5-HT2 receptors in cerebral cortex: lack of correlation between 5-HT2 receptors and serotonin-mediated behaviour. Neuropharmacology 24:947–952
Denenberg VH, Zeidner LP, Thoman EB, Kramer P, Rowe JC, Philipps AF, Raye JR (1982) Effects of theophylline on behavioral state development in the newborn rabbit. J Pharmacol Exp Ther 221:604–608
Desmond MM, Wilson GS (1975) Neonatal abstinence syndrome, recognition and diagnosis. Addict Dis 2:113–121
Enslen M, Milon H, Wurzner HP (1980) Brain catecholamines and sleep states in offspring of caffeine-treated rats. Experientia 36:1105–1106
Feuerstein TJ, Hertting G, Jackisch R (1985) Modulation of hippocampal serotonin (5-HT) release by endogenous adenosine. Eur J Pharmacol 107:233–242
Finnegan LP (1985) Effects of maternal opiate abuse on the newborn. Fed Proc 44:2314–2317
Furuhashi N, Sato S, Suzuki M, Hurta M, Tanaka M, Takahashi T (1985) Effects of caffeine ingestion during pregnancy. Gynecol Obstet Invest 19:187–191
Galloway MP, Roth RH (1983) Clonidine prevents methylxanthine stimulation of norepinephrine metabolism in rat brain. J Neurochem 40:246–251
Grant SJ, Redmond DE (1982) Methylxanthine activation of noradrenergic unit activity and reversal by clonidine. Eur J Pharmacol 85:105–109
Gregory E (1975) Comparison of postnatal CNS development between male and female rats. Brain Res 99:152–156
Grimm VE, Frieder B (1988) Prenatal caffeine causes long lasting behavioral and neurochemical changes. Int J Neurosci 41:15–28
Hardin CM (1973) Sex differences in serotonin synthesis from 5-hydroxytryptophan in neonatal rat brain. Brain Res 59:437–439
Hughes RN, Beveridge IJ (1986) Behavioral effects of prenatal exposure to caffeine in rats. Life Sci 38:861–868
Kaltenbach K, Finnegan LP (1986) Neonatal abstinence syndrome, pharmacotherapy and developmental outcome. Neurobehav Toxicol Teratol 8:353–355
Kleven MS, Sparber SB (1987) Attenuation of isobutylmethyl-xanthine-induced suppression of operant behavior by pretreatment of rats with clonidine. Pharmacol Biochem Behav 28:235–241
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 98:231–235
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 248:273–277
Kurpa J, Holmberg PC, Kuosma E, Saxen L (1983) Coffee consumption during pregnancy and selected congenital malformatation: a nationwide case-control study. Am J Public Health 73:1397–1399
Linn S, Schoenbaum SC, Monson RR, Rosner B, Stubblefield PG, Ryan KJ (1982) No association between coffee consumption and adverse outcomes of pregnancy. N Engl J Med 306:141–145
Liu DTY, Measday B, Melville HAH (1975) Premature labour-parameters for comparison employing methylxanthine therapy. Aus NZ J Obstet Gynecol 15:145–149
McGowan JD, Altman RE, Kanto WP Jr (1988) Neonatal withdrawal symptoms after chronic ingestion of caffeine. South Med J 81:1092–1094
Messing RB, Kleven MS, Sparber SB (1986) Delaying reinforcement in an autoshaping task generates adjunctive and superstitious behaviors. Behav Proc 13:327–338
Nakamoto T, Hartman AD, Miller HI, Temples TE, Quinby GE Jr (1986) Chronic caffeine intake by rat dams during gestation and lactation affects various parts of the neonatal brain. Biol Neonate 49:227–283
Neal BS, Sparber SB (1986a) Mianserin attenuates naloxone-precipitated withdrawal in rats acutely or chronically dependent upon morphine. J Pharmacol Exp Ther 236:157–160
Neal BS, Sparber SB (1986b) Ketanserin and pirenperone attenuate acute morphine withdrawal in rats. Eur J Pharmacol 132:299–304
Peters DV (1990) Maternal stress increases fetal brain and neonatal cerebral cortex 5-hydroxytryptamine synthesis in rats: a possible mechanism by which stress influences brain development. Pharmacol Biochem Beh 35:943–947
Rosecrans JA, Schechter MD (1972) Brain 5-hydroxytryptamine correlates of behavior in rats: strain and sex variability. Physiol Behav 8:503–510
Rowe MW, Meaney MJ (1989) Serotonin (5-HT) increases glucocorticoid, type II receptor binding capacity in cultured hippocampal cells. Soc Neurosci Abstr 15:717
Sanders-Bush E, Breeding M (1988) Putaive selective 5-HT2 antagonists block serotonin 5-HT1c receptors in the choroid plexus. J Phamacol Exp Ther 247:169–173
Skinner BF (1948) Superstition in the pigeon. J Exp Psychol 38:168–172
Soriero O, Ford DH (1971) Age and Sex: The effect on the composition of different regions of the neonatal rat brain. In: Ford DH (ed) Influence of hormones on the nervous system. Karger, Basel, pp 322–333
Sparber SB, Lichtblau L (1983) Postnatal abstinence or acute toxicity can account for morbidity in developmental studies with opiates. Life Sci 33:1135–1140
Sparber SB, Meyer D (1978) Clonidine antagonizes naloxone-induced suppression of conditioned behavior and body weight loss in morphine-dependent rats. Pharmacol Biochem Behav 9:319–325
Watkinson B, Fried PA (1985) Maternal caffeine use before, during and after pregnancy and effects upon offspring. Neurobehav Toxicol Teratol 7:9–17
West GL, Sobotka TJ, Brodie RE, Beier JM, O'Donnell MW Jr (1986) Postnatal neurobehavioral development in rats exposed in utero to caffeine. Neurobehav Toxicol Teratol 8:29–43
Wetherington CL (1982) Is adjunctive behavior a third class of behavior? Neurosci Biobehav Rev 6:329–350
Whitaker-Azmitia PM, Lauder JM, Shemmer A, Azmitia EC (1987) Postnatal changes in serotonin1 receptors following prenatal alterations in serotonin levels: further evidence for functional fetal serotonin1 receptors. Dev Brain Res 33:285–289
Wikland M, Lindblom B, Wiquist N (1984) Myometrial responses to prostaglandins during labor. Gynecol Obstet Invest 17:131–138
Winer BJ (1971) Statistical principles in experimental design. McGraw-Hill, New York, pp 191–195; 201–204; 378; 848–849
Yazdani M, Tran TH, Conley PM, Larent J Jr, Nakamoto T (1987) Effect of protein malnutrition and maternal caffeine intake on the growth of fetal rat brain. Biol Neonate 52:86–92
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Neal, B.S., Sparber, S.B. Long-term effects of neonatal exposure to isobutylmethylxanthine. Psychopharmacology 103, 388–397 (1991). https://doi.org/10.1007/BF02244295
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/BF02244295