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On the identification and Measurement of Chemical Time Bombs: A Behavior Development Perspective Norman A. Krasnegor As a society, we in the United States take it as a given that our children have the right to develop normally. Moreover, our govern- ment takes a keen scientific and legislative interest in how to protect our population, both young and old, from the ill effects of chemicals, environmental pollutants, and contaminants of the food supply. The tragedies of thalidomide and diethylstilbestrol (DES) sensitized basic scientists, clinicians, and legislators to the dangers associated with the administration of drugs prenatally and to the health and well- being of the developing neonate (Krasnegor, 1986~. Further, evidence is accumulating that not all the damage suffered by the developing fetus exposed to toxicants during gestation results in physical or neurochemical anomalies. Rather, the effects upon the perinate, exposed to chemicals, may well be manifested in psychological or behavioral changes such as irritability, impaired learning ability, hyperactivity, or reduced capacity for information processing (Krasnegor, 1986~. It is therefore incumbent upon public health officials, clinicians, and scientists to discover those substances that may be harmful to the fetus and thereby affect an individual's behavioral development from birth. This chapter focuses upon an elucidation of new and proposed approaches for identifying substances (chemicals, drugs, etc.) that may put the developing human at risk for developmental disability. 191

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92 NORMAN A. KRASNEGOR METHODOLOGICAL CONSIDERATIONS Developmental behavior toxicology is a field of research devoted to the goals of discovering and elucidating abnormalities in develop- ment as a consequence of exposure to drugs or other chemicals (Thompson, 1986~. Researchers in this domain of science are faced with formidable methodological problems. In the course of their studies, they are constantly faced with the task of separating devel- opmental variables from toxicological and other environmental ones. The developing organism's rapidly shifting behavioral baseline poses special mensurational difficulties. For example, an organism may exhibit one set of behaviors early in development. These may subse- quently disappear from the repertoire only to reappear later in ontogeny. This state of affairs is commonly observed, particularly in the perinatal period of development. Without detailed knowledge of this phe- nomenon, one may erroneously conclude that a toxicant has produced the change. Another common problem concerns the issue of developmental delay. Large individual differences in when behaviors of interest ap- pear in an organism's repertoire are to be expected. Therefore, precise knowledge of the expected variability is essential to help differenti- ate between conclusions of a substance's toxic effects on behavior and its natural ontogenesis. Experimental paradigms that are appropriate for assessing the effects of a drug on mature organisms may not suffice for very young ones. Because the effects of a putative toxicant may result in damage to the formation of central nervous system (CNS) structures, which in turn may affect the development of behavioral processes later in life, researchers may be forced to adopt a longitudinal design. This tactic, although deemed appropriate for the problem under study, can significantly increase the cost of research and delay the publication of data. Another set of questions involves the choice of baselines that should be used to assess whether a substance has the potential for being behaviorally toxic. Should experimental paradigms be employed or should "naturalistic" behaviors be used? Is it better to study learning (classical or operant conditioning), conduct open field studies, or in- vestigate the social and emotional attachment of the neonate to its care giver? Answers to these queries are contingent to some extent on the questions being posed and the extant knowledge concerning the developmental trajectory of the behaviors in question. These tactical judgments are also based in part upon the availability of ex- perimental paradigms that can be employed with perinates and the behavioral mechanisms believed to be affected by the putative toxicant.

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IDENTIFICATION AND MEASUREMENT OF CHEMICAL TIME BOMBS ]93 A critical issue that confronts researchers in this field of inquiry is what subject should be employed to assess toxicity. Clearly, studies which employ prospective designs with substances that are suspected of having behaviorally toxic activity must employ animal models. A traditional choice for behavioral toxicity studies has been laboratory rats. The rationale for their use is based upon the enormous literature available on aspects of their behavior, physiology, and neurobiology. However, depending on the question, other organisms may be much better suited than rats. For example, caffeine use by pregnant women has been questioned as a potential behaviorally toxic agent. More specifically, its first metabolite, methylxanthine, has been the subject of recent studies designed to determine its potential for affecting behavioral development. The subject chosen for the study was the female rabbit and her offspring. The decision to use this animal was based upon the fact that rabbits metabolize caffeine much as does man (Denenberg, personal communication, 1988; Denenberg et al., 1986~. Further, the natural behaviors of the offspring and its interaction with its mother early in development have been well studied in this animal. Thus, rabbits became the logical choice for studying this important question concerning exposure of the fetus to methylxanthine during gestation. A number of other methodological issues are also unique to the study of behavioral toxicity in the developing organism. Dosing pa- rameters, including amount, route, and when during gestation, are all important considerations in undertaking studies of the developing organism. The planning for dose-effect relationships, Enough not unique to the study of young organisms, should be included in any comprehensive study of behavioral toxicity. Cross-fostering controls must be employed to obviate the effects that toxic substances may have on maternal behavior, which therefore affect normal mother- offspring interactions. Also of importance is the issue of when, after dosing (the developmental stage), the offspring should be tested. In summary, the methodological issues associated with the detection of behaviorally toxic substances are both numerous and complex. Meticulous attention must be paid to these methodological details because failure to do so could lead to erroneous conclusions about the behavioral toxicity of a chemical or drug that may be quite beneficial. APPROACHES TO DETECTING BEHAVIORALLY TOXIC SUBSTANCES Two approaches are generally employed to determine whether a substance of interest has behavioral toxicity. The first depends upon - - - r -- -

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194 NORMAN A. KRASNEGOR the availability of epidemiological data that can provide a statistical basis for evaluating the morbidity and mortality associated with a substance. Based upon such knowledge, one might design experi- mental studies, employing animal models, that can assess dose-response relationships between a substance and putative effects upon behavioral development. The second approach employs animal models to screen substances for behavioral toxicity. This tactic is the one most fre- quently used because regulatory procedures require testing prior to the release of a drug or chemical for use. Screening is a much more complex strategy because one is not sure what types of behavioral effects to expect or when during development they will be manifest. A typical approach to identifying substances that may impair normal behavioral development is to employ an animal model (e.g., laboratory rats). Pregnant females are administered the substance of interest. Dosing parameters, when dosing occurs, route of administration, how often, etc., are all variables that are predicated upon the best scientific information concerning when the substance is believed to undermine mechanisms that affect behavioral development. Typically, too, the knowledgeable behavioral toxicologist will cross-foster the offspring postnatally. He will raise the pups, who were exposed prenatally, until they attain the developmental stage of interest and then test them to ascertain whether the substance of interest produces effects upon behavior. Two categories of substance are of great interest to those who study developmental behavioral toxicology. These are drugs given to pregnant females for preexisting medical conditions or drugs associated with pregnancy and anesthetics associated with delivery. A short review of the literature associated with one class of drugs the barbiturates, given in association with quality medical care to pregnant human females, is provided below. Reyes et al. (1986) reported that pregnant rats given high doses of phenobarbital (10 times the therapeutic dose) had significant increase in pup mortality and decrease in birth weight of offspring. Voorhees (1985) and Middaugh (1986) both reported biochemical and behavioral anomalies in rat and mouse pups, respectively, after prenatal exposure to low levels of barbiturates. Changes in activity level, learning capacity, and seizure threshold in rodents were reported after early exposure to barbiturates (Chapman and Cutler, 1983; Diaz, 1978; Middaugh et al., 1981; Yanai et al., 1981~. In addition to these findings, researchers also report changes in sexual maturation and behavior after prenatal exposure to barbiturates. The presumed mechanism is alteration in brain loci responsible for sexual differentiation. For example, Clemens et al. (1979) found that

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IDENTIFICATION AND MEASUREMENT OF CHEMICAL TIME BOMBS ]95 the adult sexual behavior of male hamsters was altered compared with controls after prenatal exposure to barbiturates. Females, in the same study, showed no difference as adults after receiving the same dosing regimen. Prenatally administered barbiturates are capable of changing reproductive functions of male and female pups so exposed. Further, female offspring have lower birth weights at puberty, show lower fertility, and have delayed onset of puberty (Gupta et al., 1980~. Testosterone concentrations in plasma and brain of neonatal males exposed to barbiturates were lowered by prenatally administered barbiturates (Gupta et al., 1982~. This finding suggests that early testosterone deficits could be instrumental in altering masculine development and have a negative impact upon reproductive function in the adult. A POTENTIAL TIME BOMB? Barbiturates, as studied in rodents, have been shown to have the potential for being time bombs in that the behavioral deficits observed do not show up until late in development. Physicians have long prescribed barbiturates to their patients for anxiety, sedation, and seizure disorders. In the 1960s and 1970s, barbiturates were frequently prescribed to pregnant women. For example, among the subjects in the Collaborative Perinatal Project consisting of 50,000 pregnancies, some 25 percent of the women were prescribed barbiturates at some time during gestation (Heionen et al., 1977~. Based upon Medicaid data from Michigan, Rosa (personal communication, 1988) estimates that approximately 1.5 percent of women receive phenobarbital dur- ing the first trimester of their pregnancy. Prenatal exposure of the fetus to barbiturates is not the only time in early development when this class of drugs is given. Neonates are also prescribed the drug as a sedative or anticonvulsant. From an epidemiological perspective then, the number of children exposed, and therefore potentially at risk, is high. Although the prescription of barbiturates to pregnant women or newborns has been considered safe, recent studies employing animal models suggest that barbiturates may have the potential for neural or behavioral toxicity (Smith, 1977~. More recent literature reviews also support this conclusion (Coyle et al., 1980; Fishman and Yanai, 1983; Ornoy and Yanai, 1980; Reinisch and Sanders, 1982; Yanai, 1984~. Although there is a rich literature on animal studies concerning the putative behavioral toxicology of barbiturates, the research find- ings on humans are meager (van den Berg, personal communication, 1988~. A rigorous analysis of behavioral and biomedical data, by

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96 NORMAN A. KRASNEGOR using a case control matching design, is currently underway (Reinisch, personal communication, 1988). The investigators are employing a retrospective design, that is, studying a group of young adults (in their early 20s) whose mothers were prescribed barbiturates during pregnancy. The subjects comprise a cohort listed in a Danish birth registry. The study, which is still underway, will be, when completed, the most rigorously designed and comDrehen.sive one of heron ~v r ~ ~~ A ~ ~ posed prenatally to barbiturates. The data set includes records from school, the army, the criminal justice system, and parents. Psychological and behavioral test scores along with medical records concerning physical development are being amassed. The researchers will then be able to pose questions related to the findings from the animal literature to determine whether behavioral toxicity can be demonstrated in people who were exposed prenatally to barbiturates. The example provided by barbiturates is illustrative of the dilemma posed when the risk/benefit ratio is examined critically. The animal model data suggest the potential for behavioral toxicity, the behavioral epidemiology data are not yet complete, and the drug class is seen to be beneficial to both the mother and her offspring. Until there are some definitive findings on barbiturates, prescribing practice is unlikely to change. NEW METHODS FOR MEASURING BEHAVIORAL TOXICITY Although the usual approach to measuring behavioral toxicity is to dose prenatally and measure changes later in life, an alternative tactic is to measure behavior as early as possible after exposure. Carried to its extreme, this approach implies measurement of fetal behavior. During the early part of this century, there was considerable scien- tific interest in prenatal behavioral development. The questions of interest focused upon when during life learning can first be demon- strated. More specifically, scientists began to query whether learning could be shown to exist in the fetus. Learning for the purposes of the present discussion is defined as associative or Pavlovian conditioning. Workers during the 1930s attempted to classically condition the human fetus. Ray (1932), for example, paired a neutral stimulus (vibrotactile stimulus) with an unconditioned stimulus (WCS) that was known to produce movement in the fetus. The UCS, a loud noise, if made suddenly in the presence of a fetus is reliably followed by a startle movement. This latter response can be detected by plac- ing one's hand on the abdomen of a pregnant woman. The UCS was

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IDENTIFICATION AND MEASUREMENT OF CHEMICAL TIME BOMBS ]97 paired with the neutral stimulus (CS) for a number of trials deemed sufficient for the CS alone to elicit the startle response. This study did not confirm the capacity for classical conditioning in the fetus. A little over 15 years later, Spelt (1948) employed similar procedures and claimed success in demonstrating classical conditioning in the human fetus. He also concluded from the analysis of his data that the fetus has the capacity for extinction and retention of the classically conditioned response. It should be pointed out that more recently, other behavioral scientists have sharply criticized these findings on methodological grounds (Sameroff and Cavanaugh, 1979), thereby leaving open the question of whether classical conditioning of the fetus is possible. Significant progress on this topic had to await methodological innovations that emerged at the start of the current decade (Krasnegor et al., 1987~. The studies of interest employed fetal rats. The breakthrough was predicated upon methodological innovations that allowed researchers to directly observe and manipulate the fetus and thereby rigorously test questions of learning. Blass and Pedersen (1980) and Stickrod (1981) developed procedures for externalizing the uterus of pregnant female rats late in gestation and ways to inject substances into the amniotic fluid of the developing fetus. These new methodologies allowed the investigators to make their observations, the uterine horns to be reinserted, and the fetus to complete its development to term. At that time, fetuses could be delivered vaginally or taken by cesarean section and be cross-fostered to recently delivered mothers. At a workshop sponsored by the National Institute of Child Health and Human Development (NICHD), these and other techniques for viewing and manipulating the mammalian fetus were summarized (Kolata, 1984~. Attending that meeting was William Smotherman who, along with his coworkers, has carried out a number of studies on fetal behavior and fetal learning. In the first of a series of investigations on prenatal learning, Stickrod et al. (1982a) demonstrated that late in development, rat fetuses have the capacity for associative learning. On day 20 of gestation, the uterine horn of a female rat was externalized into a warm saline bath. Apple juice (CS) was injected into the amniotic fluid surrounding the exposed fetuses, and lithium chloride (WCS) was injected into their peritoneum. A single pairing of an aversive stimulus (LiCl) with a novel taste or odor (apple juice) causes adult rats so treated to avoid the taste or odor on subsequent presentations. The externalized uterus of the dam was reinserted into her perito- neum; she was sutured; and the fetuses, treated as described above, were delivered at term. When the pups were 2 weeks old and were allowed to suckle from an anesthetized dam, they were observed to

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98 NORMAN A. KRASNEGOR show preferential nipple attachment in accordance with their prena- tal experience. Those pups which had been exposed to the associative conditioning paradigm as fetuses attached less often to nipples that were painted with apple juice compared to control pups (Smotherman and Robinson, 1987~. In a follow-up study, Stickrod et al. (1982b) demonstrated that pups which had been conditioned prenatally showed greater delays in crossing a runway, where the air contained the odor of apple juice,.to gain access to their mother. In a variant of the procedure, these same authors demonstrated that prenatally condi- tioned pups preferred to stay at the low-concentration end of a box containing the odor of apple juice. These findings are quite important because they indicate both that conditioning took place before birth and that the learned response was retained postnatally. Smotherman and his coworkers continued their research on sev- eral fronts. They examined the influence of uterine position, a variable feature of the prenatal environment, upon conditioned taste aversion in adult rats (Babine and Smotherman, 1984; Smotherman, 1983~. They critically evaluated two existing techniques for the preparation of the female rat for fetal observation and demonstrated that the two procedures, chemomyelotomy and spinal transection, are not equivalent in their effects upon spontaneous fetal activity (Smotherman, 1984; Smotherman et al., 1984~. They also developed a new reversible anesthetic proce- dure for preparing the dam and observing the fetal rat in utero (Smotherman et al., 1986~. This method has the advantage of allow- ing the longitudinal study of behavior of the same subjects before and after birth. Further, Smotherman and Robinson (1986) made critical observations on age-related changes in fetal behavior during the last third of gestation. This work also documents fetal responsiveness to naturally occurring changes within the uterine environment. Similarly, it demonstrates the feasibility of observing fetuses after removal from the uterus and amniotic sac and the quantification of fetal behavior from day 16 to gestation. By combining the new observation techniques with the knowledge gained on the ontogenesis of movement patterns, Smotherman was able to study the capacity for conditioning to emerge during gestation. In a series of elegant experiments (Smotherman and Robinson, 1987) which included rigorous control procedures, the investigator and his colleagues demonstrated that rat fetuses exposed to a single-trial pairing of a neutral stimulus (mint) and an interperitoneal injection of LiCl on day 17 of gestation, are conditioned by day 19 of gestation. This was shown to be the case because the mint solution alone does not suppress endogenous movement patterns on day 17 or 19 of gestation, but when paired with the LiCl injection on day 17, it markedly sup-

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IDENTIFICATION AND MEASUREMENT OF CHEMICAL TIME BOMBS 799 presses movement by itself in 19-day-old fetuses who had received the conditioning trial. The work described above clearly and rigorously documents the capacity of the fetus for learning during gestation. It also demonstrates that the organization of fetal behavior patterns has an ontogenetic trajectory. Both of these conclusions indicate that a new window of opportunity exists for the behavioral toxicologist. Associative learning can be established prenatally and followed postnatally. Condition- ing, in terms of its acquisition and consolidation, can be studied dur- ing gestation. Thus, substances of interest can be studied for their effect both at the time of gestation when they have their putative action upon the developing brain and postnatally during neonatal development. Indeed, Smotherman and his colleagues (Smotherman and Robinson, 1987; Smotherman et al., 1986a, 1986b; also, Baron et al., 1986) have conducted studies of fetal behavior after chronic maternal exposure to ethanol. These studies are exemplars that point the way for demonstrating the power of the approach to identify both substances and mechanisms that may interfere with behavioral development. ADDITIONAL APPROACHES AND NEW DIRECTIONS Two questions with which developmentalists and behavioral toxi- cologists alike must constantly grapple revolve around the issues of prediction and validity. The prediction issue is brought out when studies of development are undertaken with children who are born at risk (e.g., intrauterine growth retardation, low birth weight). What researchers interested in such questions would like to know is whether behavior measured early in life (e.g., the neonatal or infancy phase of development) is predictive of behavioral development in childhood (e.g., at school entry). If reliable and valid measures could be estab- lished, children born at risk who would develop normally, from a behavioral perspective, could be accurately separated from those who may evidence behavioral deficits (Bornstein and Krasnegor, 1989~. Prediction of a different, albeit equally important, type is sought by behavioral toxicologists. They endeavor to predict whether a substance of interest has behavioral toxicity and whether early exposure will lead to behavioral deficits later in development. Further, they employ animal models which they believe validly relate to the human condition. Developmentalists and behavioral toxicologists also strive to pose questions that can elucidate the putative behavioral or neurobehavioral mechanisms which may subsume the observed deficits. Is it possible to address these multiple concerns and thereby ad-

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200 NORMAN A. KRASNEGOR Vance both fields of inquiry alluded to above? Research in the field of eyelid conditioning has much to recommend it conceptually and experimentally as a paradigm for asking questions of relevance to developmental behavioral toxicologists (Gormezano et al., 1983; Harvey and Gormezano, 1986; Solomon and Pendlebury, 1988~. There are three main factors that make the nictitating membrane response (NMR) an attractive one for addressing developmental questions in general and behavior toxicology ones in particular. Multiple Behaviors Can Be Studied There are at least 10 behavioral factors that can be studied utilizing the NMR/eye blink model system (Harvey and Gormezano, 1986~. These are (1) habituation and sensitization, (2) stimulus selection, (3) mediation associations, (4) motivation, (5) memory traces and short- or long-term memory, (6) simple and conditional discriminations, (7) transfer of training, (8) timing, (9) stimulus generalization, and (10) extinction and conditioned inhibition. Comparative Developmental Studies Can Be Undertaken Work on the NMR/eye blink has been carried out by using the rabbit as a model system. Research on humans has also been under- taken to study the conditioned eye blink. This has recently involved developmental studies that compared the acquisition of the classically conditioned eye blink across the age span ranging from childhood (8 years of age) to the eighth decade of life (Solomon et al., 1989~. Such work holds out the promise that specific comparative studies of the model system and the same response system in humans can be accomplished. Knowledge Concerning Neurocircuitry and Neurochemistry of the Response Is Accumulating Research to date has implicated two different brain circuits in this model system. These are found respectively in the cerebellum (McCormick and Thompson, 1984) and the hippocampus (Berger et al., 1986; Moore and Solomon, 1980~. The data collected by these investigators suggest that the cerebellum may be the CNS site of simple plasticity for simple delay conditioning. The hippocampus, on the other hand, has been implicated in trace conditioning (Solomon and Gottfried, 1981~; discrimination reversal (Berger and Orr, 1983~; and as a modulator of simple delay conditioning (Solomon et al., 1983~. Moreover, what is

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IDENTIFICATION AND MEASUREMENT OF CHEMICAL TIME BOMBS 20] known concerning the pharmacology of the conditioned response in rabbits suggests strongly that the cholinergic system is involved in mediating the response (Moore et al., 1976; Solomon et al., 1983~. These three factors provide a convincing argument that the condi- tioning model described may be a powerful tool for developmental behavior toxicology (see, for example, Yokel, 1983~. Additional research is needed to obtain developmental data for this model system. This should be conducted in neonatal humans and young rabbits to fill in the knowledge gap on the ontogeny of the response. The availability of such baseline data will provide developmentalists and behavioral toxicologists with the information needed to evaluate behavioral de- velopment and the effects of substances over an impressive age span. It will allow prospective questions to be asked from a developmental perspective. Most importantly, it will allow researchers to connect with a model system (the rabbit NMR/eye blink) which can help differentiate between CNS mechanisms that may be involved in impaired development. This can in turn provide clues to scientists who work with babies born at risk, or with those who were exposed to substances as fetuses, concerning the behavioral and neurobehavioral mechanisms that may have gone awry. Some progress toward the goal of collecting data in the neonatal human baby has already been made. (Although the work described below is not directly on eye blink conditioning, it is sufficiently related that inclusion is warranted.) Howard Hoffman and his colleagues have been studying the development and characteristics of the startle response for the past two decades. After analyzing this response by using animal models they discovered that the response could be modified. In experiments carried out in adult humans, Hoffman found that when an exteroceptive stimulus precedes one that elicits the glabella response by 100-200 ms, the resultant eye blink is reduced in ampli- tude (Hoffman and Ison, 1980~. If the same stimulus is presented simultaneously with the eliciting stimulus, the eye blink amplitude is enhanced compared to a control condition in which no stimulus is presented (Hoffman and Stilt, 1980; Hoffman et al., 1981~. Hoffman and his coworkers next turned their attention to a com- parison of adults and newborns to undertake a developmental analysis of these augmentation-inhibition results. They found that newborns (16-65 hours old) exhibited reflex augmentation to the simultaneous pairing of an exteroceptive stimulus and a gentle, calibrated tap between the eyes (Hoffman et al., 1985~. Although the comparative data are of interest, the most compelling information relates to the methodol- ogy. Eye blinks can be reliably measured on the first day of life, and systematic data on this response can be collected. This strongly suggests

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202 NORMAN A. KRASNEGOR that an approach can be worked out to collect eye blink conditioning data at this time in development and in older infants as well. In summary, new approaches for measuring simple learning dur- ing the perinatal period offer an opportunity to assess the potential for substances to affect behavioral development. Research on these new windows for observation can provide the field of behavioral toxicology with additional tools to effectively evaluate, early in an organism's development, whether and, potentially, how it may become impaired later in life. Investigations along these lines should be pur- sued and vigorously encouraged. ACKNOWLEDGMENT Thanks are due to Marsha Sotzsky for preparing this manuscript. REFERENCES Babine, A. M., and W. P. Smotherman. 1984. Uterine position and conditioned taste aversion. Behavioral Neuroscience 96:461~66. Barron S., E. P. Riley, and W. P. Smotherman. 1986. The effect of prenatal alcohol exposure on umbilical cord length in fetal rats. Alcoholism: Clinical and Experimental Research 10:493~95. Berger, T. W., and W. B. Orr. 1983. Hippocampectomy selectively disrupts discrimination reversal conditioning of the rabbit nictitating membrane response. Behavior Brain Research 8:49-68. Berger T. W., S. Berry, and R. Thompson. 1986. Role of the hippocampus in classical conditioning of aversive and appetitive behaviors. Pp. 203-240 in The Hippocampus, R. L. Isaacson and K. H. Pribram, eds. New York: Plenum. Blass E. M., and P. E. Pedersen. 1980. Surgical manipulation of the uterine environ- ment of rat fetuses. Physiology and Behavior 25:993-995. Bornstein, M. H., and N. A. Krasnegor. 1989. Stability and Continuity in Mental Development: Behavioral and Biological Perspectives. Hillsdale, N.J.: Lawrence Erlbaum Associates. Chapman, J. B., and M. G. Cutler. 1983. Behavioral effects of phenobarbitone. I. Effects in the offspring of laboratory mice. Psychopharmacology 29:155-160. Clemens L. G., T. V. Popham, and P. H. Ruppert. 1979. Neonatal treatment of hamsters with barbiturate alters adult sexual behavior. Developmental Psychobiology 12:115- 125. Coyle, I., A. Wagner, and G. Singer. 1980. Behavioral teratogenesis: A critical evalu- ation. In Advances in the Study of Birth Defects, Neural and Behavioral Teratol- ogy, T. V. N. Persaud, ed. Baltimore: University Park Press. Denenberg, V. H., E. B. Thomas, P. Kramer, and J. R. Raye. 1986. Sleep and wake behavioral state as a developmental assessment procedure. In Advances in Behavioral Pharmacology: Developmental Behavioral Pharmacology, N. A. Krasnegor, D. B. Gray, and T. Thompson, eds. Hillsdale, N. J.: Lawrence Erlbaum Associates. Diaz, J. 1978. Phenobarbital: Effects of long-term administration on behavior and brain of artifically reared rats. Science 199:90-91.

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