The effects of barbiturates on the behavior of rat offspring as measured in learning and reasoning situations.

Abstract

This study arose from the suspicion that decreased intellectual capacity can result from the administration of certain drugs during labor and parturition.In a recent paper Mengert states, "The principal cause of anoxia during and immediately following labor is the analgesic and anesthetic drug administered to produce relief of pain during labor" (7, p. 663). Cole, Kimball, and Daniels have (1) found that sedatives and anesthetics increase the incidence of asphyxia in the newborn, and the incidence is proportional to the amounts administered. Schreiber (8, 9) has shown that fetal anoxia can result in areas of necrosis frequently leading to so-called "devastation areas" that may mentally handicap the child throughout life.Even though there can be no direct inference from animal to human being, it is of interest to determine whether or not any deleterious effect can be produced by analgesics given just prior to parturition in animals. In this study an attempt has been made to approximate human conditions in so far as the time and duration of the drug administration was concerned. However, even though a varying dosage was given, the objective was to induce behavioral differences if possible. The amounts of drug, as a consequence, were often extremely high and in one instance exceeded the minimum lethal dose. EXPERIMENT I MethodThe apparatus used is extensively described in an article by Hanawalt (3). It consisted of two types of mazes and a reasoning problem adapted by Shepard (10) from the apparatus developed by Maier (5).The reasoning problem was constructed of the same materials and in the same manner as the mazes. Three main alleys radiated from a central starting point and led to three separate food boxes. In each of the paths there was a gate. Blocks could be placed in any of the pathways, closing them off at the starting point. In order to fulfill the criteria of reasoning (6), small groups of animals were allowed five J-hr. exploratory periods daily. During this time all paths were open from beginning to end and food was not introduced into the situation. At the conclusion of the fifth period, the initial stage of the testing began. Path 1 was closed and food was placed at B3. The gate in front of the food box was lowered and the rat dropped into the alley in front of it. After a bite of food the animal was taken out. This procedure was repeated three times in all. The gate was then raised and the animal placed at A. When the food had been reached, the rat was returned to the starting point. A trial consisted of two such runs, both of which had to be correctly performed to constitute a perfect trial. An error consisted of progress past the gate in a false pathway. One trial a

Neuronal deficits in mice following phenobarbital exposure during various periods in fetal development

“…These changes included devia tion from normal in learning-related behaviors in mice and rats [Armitage, 1952;Murai, 1966;Middaugh et al, 1975], and an increased functional (CNS) tolerance to barbiturates and ethanol in mice [ Yanai and Tabakoff, in press; Yanai, in press]. In humans, prenatal exposure to barbiturates resulted in behavioral signs which mostly reflected withdrawal [Desmond et al, 1972], Neuromorphologically, there is evi dence of gross changes, principally, brain weight reduction which occurred in rats fol lowing neonatal exposure to phénobarbital [Schain and Watanabe, 1975;Schain, 1977, 1978].…”

Behavioral Teratogenesis: An Extension to the Teratogenesis of Functions

“…Thus, in the 60s, it was shown that factors as different as X-rays [31] and antithyroid hormone [32], administered to pregnant rats, lead to behavioral disorders in their offspring. At the same time, we showed in our own team that while antinervous tissue antibodies administered at the be ginning of pregnancy led to gross malforma tions in the CNS [33], these substances, ad ministered at the end of pregnancy, only re sulted in a decrease in learning capacities in the adult progeny [34], Subsequently, other works showed that substances such as phéno barbital [28,35], chlorpromazine [36], me probamate [37] and halothane [38] or toxic agents such as cannabinol [39] and methylmercury [40], administered to pregnant rats or mice, led to the same effects. Some of these studies made the essentially functional char acter of the abnormalities understandable: in deed, they showed that phénobarbital de creased DNA and protein levels [41], that halothane [38] and methylmcrcury [42] led to microstructural changes in synapses and, caused by the latter, modifications in a regula tor of macromolecule synthesis, ornithine de carboxylase [43].…”

“…For 40 years, experimental data have re vealed the existence of long-term teratogenic effects: purely functional abnormalities, ap pearing in adult progeny, could follow some maternal environment variations [28]. In fact, the studies concerned behavioral disorders.…”

“…First, the amount of treatment admin istered to pregnant females: for example high doses of vitamin A lead to malformations [4] while low doses can lead to behavioral disor ders [44][45][46]. The type of substance is also important since phénobarbital, which does not cause malformations in mammals, only leads to a fall in learning capacities in progeny born from treated mothers [28,35], Finally, the period of development affected by terato genic factors also plays a role. Very different agents such as nervous tissue antibodies [33] or X-rays [2] cause malformations at the be ginning of gestation, that is to say during orga nogenesis, and functional disorders at the end [31,34], However, some works suggest that the neuroblast cell multiplication period in the primitive forebrain is similarly sensitive [8,10], and other functional disorders might also follow some environmental changes in very young embryos [68][69][70].…”

Effect of prenatal maternal administration of d-amphetamine on rat offspring activity and passive avoidance learning

“…Investigators have demonstrated the effects of drugs (Armitage, 1952;Hamilton, 1945 ;Hamilton & Hamed, 1944; Thompson, *This report is based on a dissertation submitted to Temple University in partial fulfillment of the requirements for the PhD degree. The author wishes to express gratitude to Hughbert C.…”