LONG-TERM EFFECTS OF NEONATAL EXPOSURE TO ISOBUTYLMETHYLXANTHINE .1. RETARDATION OF LEARNING WITH ANTAGONISM BY MIANSERIN

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.