Fetal Alcohol Syndrome

Does Alcohol Withdrawal Play a Role?

Jennifer D. Thomas, Ph.D., and Edward P. Riley, Ph.D.

Alcohol use by a pregnant woman may interfere with the development of her fetus. Newborns whose mothers are intoxicated during delivery can experience withdrawal symptoms, such as tremors and even seizures. It is likely that withdrawal also can occur during fetal development. Thus, the possibility exists that withdrawal by the pregnant woman may exacerbate alcohol’s adverse effects on her fetus. One potential mechanism through which alcohol withdrawal might damage the fetus involves the receptor for the neurotransmitter glutamate (i.e., the N-methyl-D-aspartate [NMDA] receptor). This receptor plays a crucial role during neuronal development. Excessive activation of the NMDA receptor, which occurs during withdrawal, may lead to neuronal cell death. Animal studies suggest that these effects may contribute to behavioral deficits following prenatal exposure to alcohol. KEY WORDS: fetal alcohol syndrome; AOD withdrawal syndrome; symptom; gestation; fetus; neonate; mother; prenatal alcohol exposure; heavy AOD use; binge AOD use; congenital anomaly; fetal development; central nervous system; NMDA receptors; cytolysis; cell growth and differentiation; teratogenesis; brain damage; AOD abstinence; animal model; literature review

woman who drinks alcoholic Withdrawal Symptoms estimated to consume two or more beverages during pregnancy in Pregnant Women drinks per day (Abel 1990). A exposes not only herself but and Newborns One of the consequences of heavy also her fetus to alcohol. Alcohol read- alcohol use is the potential for experi- ily crosses the placenta; consequently, encing withdrawal symptoms during the blood alcohol levels (BAL’s) of the Pregnant Women periods of abstinence. Symptoms of fetus are similar to those of the mother. Likewise, if the woman suddenly Despite warning labels on alcoholic abstains from alcohol, both she and beverages and an increased awareness JENNIFER D. THOMAS, PH.D., is a her fetus may undergo withdrawal. among the general population of alco- research assistant professor and EDWARD This article briefly describes the with- hol’s deleterious effects on the devel- P. R ILEY, PH.D., is a professor and the drawal symptoms observed in pregnant oping fetus, the women who are the director of the Center for Behavioral women and newborns, discusses the heaviest alcohol abusers frequently do Teratology, Department of Psychology, birth defects associated with prenatal San Diego State University, San Diego, not change their drinking practices alcohol exposure, and explores the California. possibility that alcohol withdrawal during pregnancy. Such women are at (AW) may contribute to the adverse the greatest risk for giving birth to a This work was partially supported by effects of prenatal alcohol exposure child with alcohol-related problems. National Institute on Alcohol Abuse on fetal brain function and behavioral In the United States, approximately and Alcoholism grants AA–06902, development. 3.3 percent of pregnant women are AA–03249, and AA–11634.

Vol. 22, No. 1, 1998 47 mild to moderate withdrawal from sedatives or tranquilizers has been used subsequent behavioral alterations are alcohol may include tremors, sweating, only for infants with the most serious among the challenges that researchers stomach pain, anxiety, and sleep dis- symptoms (e.g., seizures and vomiting). currently face. turbances. Severe withdrawal symptoms The observations described here may include delirium tremors and violent leave little doubt that newborns can agitation (i.e., seizures). These effects undergo AW, and similar effects may Can Alcohol Withdrawal may begin within hours of the last drink occur in the fetus. The effects of Damage the Fetus or and may persist for several days. Various maternal or fetal withdrawal (and its Newborn? tranquilizers and sedatives, including treatment) on the developing fetus, alcohol itself, have been used to man- however, remain unknown. There is little doubt that alcohol age these symptoms (Thorp 1995). interferes with normal fetal development (i.e., is a teratogenic agent). Fetal alcohol Consequences of Prenatal exposure can adversely affect numer- Newborns Alcohol Exposure ous developmental processes, such as When a pregnant woman undergoes the multiplication (i.e., proliferation), AW, so does her fetus. To date, no studies Women who drink alcohol during migration, and survival of cells, as well have analyzed the symptoms and effects pregnancy place their fetuses at risk as the cells’ development into specific of withdrawal on fetuses in utero. for numerous developmental problems, cell types (i.e., differentiation). The However, researchers have studied ranging from prenatal mortality to mechanisms by which alcohol disrupts withdrawal in newborns whose mothers disruptions in physical and behavioral these processes have yet to be fully were intoxicated during delivery. For development. The most serious con- elucidated. Given alcohol’s ubiquitous example, Beattie (1986) reported the sequence of heavy maternal drinking distribution throughout all body regions, case of a newborn who had a BAL of is a cluster of characteristic anomalies however, it likely interferes with devel- more than 200 milligrams per deciliter termed fetal alcohol syndrome (FAS) opment through many direct and indi- (mg/dL) (i.e., over 0.2 percent1) and (Jones and Smith 1973). Symptoms rect actions (for a review, see West et exhibited signs of AW—including of FAS include prenatal and postnatal al. 1994). tremors, irritability, frequent mouth growth retardation, characteristic facial Like alcohol itself, withdrawal from movements, and vomiting—between abnormalities, and CNS anomalies. alcohol initiates a cascade of physio- 24 and 48 hours after delivery. The distinct facial characteristics of logical events that might also affect The onset of withdrawal symptoms children with FAS include such features the developing organism. Although in newborns may be delayed compared as a flat midface, thin upper lip, and there is no direct evidence that with- with adults, because alcohol metabolism small eye openings (i.e., palpebral drawal contributes to alcohol’s adverse in newborns is slower than in adults. fissures). CNS anomalies associated effects on development, the possibility Neonatal AW typically manifests itself with FAS include an abnormally small demands further investigation. as hyperexcitability of the central ner- head (i.e., microcephaly) and behavioral The clearest indications that with- vous system (CNS) and gastrointestinal problems, such as attention deficits, drawal from drugs can have long-term symptoms. CNS hyperexcitability hyperactivity, motor dysfunction, adverse effects on the developing fetus results in symptoms such as tremors, mental retardation, and learning and have come from animal studies exam- excessive muscle tension, irritability, social skills deficits. Although some ining the teratogenic effects of narcotics. increased respiratory rate, poor sleeping of the physical characteristics of FAS For example, a series of studies evalu- patterns, and increased sense of hearing become less pronounced as the child ating the effects of prenatal opiate (i.e., hyperacusis). These infants also matures into adulthood, many of the exposure have shown that withdrawal may exhibit spontaneous seizures behavioral problems persist. contributes considerably to the adverse accompanied by cessation of breathing Even if they do not meet all the effects of these agents, increasing (i.e., apnea) and arching of the back (i.e., criteria for a diagnosis of FAS, children mortality and morbidity in fetal and opisthotonos). Gastrointestinal symp- exposed to alcohol in utero may exhibit newborn rat pups (for a review, see toms may include abdominal distention a wide range of developmental prob- Sparber 1986). In those studies, pregnant and, in a few cases, vomiting (Robe et lems, particularly behavioral disorders. rats (and their fetuses) were exposed al. 1981; see also Coles et al. 1984). These developmental problems often throughout gestation to high doses of Newborns undergoing AW are best are referred to as fetal alcohol effects a long-acting opiate (i.e., 1-alpha- treated by being placed in a calm envi- or alcohol-related birth defects. The acetylmethadol [LAAM]). Of the rat ronment with decreased sensory stim- identification of the factors that place pups, 50 percent died within 24 hours ulation. Pharmacological treatment with a fetus at risk for the harmful effects of birth, a time during which the pups of prenatal alcohol exposure and the were undergoing withdrawal. This 1In most States, the legal BAL for driving ranges elucidation of the mechanisms by which mortality rate decreased to 30 percent from 0.08 to 0.1 percent. alcohol causes CNS dysfunction and when the rats were injected with

48 Alcohol Health & Research World The Role of Alcohol Withdrawal in FAS

opiates to alleviate withdrawal. Con- with more chronic alcohol consumption. example, acute AW is associated with versely, injection of naloxone, an In animals, for example, a lower dose changes in many of the hormones agent that increases withdrawal severity, of alcohol consumed in a bingelike related to stress. The possibility exists increased the pups’ mortality rate to manner that produces a high peak that the stress to the mother and/or more than 90 percent. Moreover, when BAL causes more severe microencephaly, the fetus associated with a withdrawal pregnant rats receiving LAAM were neuronal cell loss, and behavioral episode could damage the fetus. injected with naloxone, thereby pre- deficits in the offspring than does a Episodes of stress during the prenatal cipitating withdrawal in both the higher daily dose that is administered period can reduce birth weight, disrupt mother and the fetus, prenatal mor- throughout the day and produces a brain development, decrease immune tality increased and body weight and continuous but lower BAL (Goodlett function, and induce behavioral alter- length decreased in the offspring, ations (e.g., hyperactivity and cognitive compared with offspring of mothers deficits). These consequences of prena- receiving only LAAM. These observa- tal stress all are commonly observed tions suggest that opiate withdrawal following alcohol exposure during caused problems independent from Alcohol gestation (Abel and Hannigan 1995). narcotic exposure itself and that the withdrawal may In addition to this indirect pathway, severity of these adverse effects was AW may directly affect the fetal CNS. related to the severity of withdrawal. directly affect the The following sections explore this These studies also indicate that fetal central possibility. Because only few published withdrawal can contribute to behav- studies have examined the contribution ioral alterations associated with early nervous system. of withdrawal to alcohol’s effects on the narcotic exposure. For example, rats fetus, this hypothesis remains speculative. that have been prenatally exposed to opiates generally are more sensitive to aversive stimuli, such as heat, com- and West 1992). Similarly, maternal Alcohol Withdrawal pared with normal rats. The studies in binge drinking in humans produces and the NMDA Receptor LAAM-treated rats demonstrated that more severe disruptions in brain elec- when postnatal withdrawal was atten- trical wave patterns (i.e., the electroen- Recently, researchers have been increas- uated by injection of opiates during cephalogram [EEG]) in the offspring ingly interested in the direct interaction the withdrawal period, the heightened than does continuous drinking (Ioffe of alcohol with proteins in the mem- sensitivity to aversive stimuli was and Chernick 1988). Maternal binge branes of nerve cells (i.e., neurons) that mitigated (Sparber 1986). drinking also predicts cognitive vari- contribute to the symptoms associated Just as opiate withdrawal exacerbates ables (e.g., IQ, attention, vigilance, with AW. Some of these proteins form the effects of opiate exposure, with- and academic achievement) in prena- receptors, molecules that interact with drawal from alcohol might contribute tally exposed children and adolescents the chemicals released by neurons for to alcohol’s teratogenicity. To date, to a greater extent than does frequency neuronal communication (i.e., neuro- only a few studies have examined this of drinking (e.g., Streissguth et al. 1990). transmitters). Activation of these recep- possibility. For example, Trofimov and Binge drinking produces a cyclical tors can either excite the cell, making it colleagues (1996) found that alcohol- pattern of high BAL’s followed by more likely to transmit information to treated rats exhibited more severe withdrawal. Accordingly, these results other neurons, or inhibit the cell, cognitive deficits if the alcohol expo- have been used primarily to illustrate making it less likely to transmit infor- sure was stopped abruptly than if the the importance of peak BAL’s as a risk mation. One receptor in particular alcohol levels were tapered off slowly. factor for alcohol’s effects on the fetus. has received much attention in the analy- Because withdrawal would have been However, withdrawal—particularly sis of alcohol’s effects on the brain. more severe following the abrupt repeated episodes of withdrawal— This receptor, which interacts with removal of alcohol than following its possibly contributes to the increased the neurotransmitter glutamate—an gradual reduction, these observations severity of alcohol’s effects on children amino acid that excites certain neurons suggest that the cognitive deficits were whose mothers were binge drinkers during normal neurotransmission— at least in part affected by withdrawal. during pregnancy. can also be specifically activated by In addition, both animal and Researchers are only beginning to N-methyl-D-aspartate (NMDA) and human studies suggest that maternal address the question of how with- is therefore referred to as the NMDA consumption of a large amount of drawal from alcohol could damage receptor. (For more information on alcohol in a short period of time (i.e., the fetus or newborn. Several mecha- the role of neurotransmitters and binge drinking) produces more severe nisms that are related either to maternal their receptors, including the NMDA brain damage and behavioral alterations or fetal withdrawal could conceivably receptor, in AW, see the article by in the developing organism compared play a role in these processes. For Littleton, pp. 13–24.)

Vol. 22, No. 1, 1998 49 In adult rats, acute alcohol treatment example, Davidson and colleagues • Affects the pattern of dendrite inhibits NMDA receptors, thereby (1995) have demonstrated that hip- branching producing an overall inhibitory effect. pocampal cells, which are rich in With continued alcohol exposure, how- NMDA receptors, are more sensitive • Influences the formation of synap- ever, the CNS attempts to offset this to NMDA-induced damage in sub- tic connections that allow neurons inhibitory effect by increasing the jects undergoing withdrawal than in to communicate with each other. number and/or activity of NMDA control subjects. Studies using isolated receptors. This process is called nero- neurons from the cerebellum3 and the Through these functions, NMDA adaptation. During abstinence, as cortex also have demonstrated that receptors play a critical role in the alcohol is eliminated from the body, NMDA’s excitotoxic effects on these ability of neurons to alter their structure alcohol’s inhibitory action decreases. cells are enhanced during alcohol or function (i.e., neuronal plasticity), As a result, the cells with elevated withdrawal (for a review, see Hoffman a process that is essential for brain NMDA receptor levels are much more and Tabakoff 1994). Finally, slices of development. excited than under normal conditions, brain tissue from the hippocampus that During periods of neurite outgrowth a phenomenon called rebound excitabil- are intermittently exposed to alcohol and synapse formation, the number ity. This hyperexcitability may con- are more sensitive to NMDA-induced of NMDA receptors on many neurons tribute to the symptoms associated excitotoxicity compared with slices increases for a short period of time. For example, in the rat hippocampus, with AW, such as tremors, agitation, continuously exposed to alcohol (Becker and seizures. This hypothesis is sup- NMDA receptor levels between 6 and 1996). The most severe excitotoxic 14 days after birth are at 150 to 200 ported by findings that agents which effects were observed in slices that had block activation of NMDA receptors percent of the adult level (Tremblay et undergone the greatest number of al. 1988; for a review, see also Hattori reduce withdrawal symptoms, whereas “withdrawal” episodes, a phenomenon agents that activate these receptors and Wasterlain 1990). A similar transient called kindling (for more information increase in NMDA receptor levels exacerbate withdrawal symptoms. on kindling, see the article by Becker, During normal neurotransmission, occurs in the hippocampal formation pp. 25–33). activation of the NMDA receptor excites of the human fetus between 23 and 27 the neuron. If this receptor becomes weeks of gestation, and the density of overactivated, however, a cascade of The NMDA Receptor in Fetal NMDA receptors in human newborns intracellular events may occur, resulting Development and Alcohol is higher than in adults (Retz et al. 1996). ultimately in cell death. This process Withdrawal The increase in NMDA receptor is called excitotoxicity. Excitotoxicity levels also enhances the neurons’ may result from several different types Mechanisms similar to those described vulnerability to glutamate’s excitotoxic of insult, including lack of oxygen (i.e., in the previous section may play a action. For example, the susceptibility hypoxia), interrupted blood supply role in alcohol’s effects on the fetus, of rat pups to NMDA receptor-medi- (i.e., ischemia), low blood sugar levels particularly because the developing ated excitotoxicity rises dramatically (i.e., hypoglycemia), and epilepsy. organism is more vulnerable to NMDA after birth, peaking at postnatal days Excitotoxicity also may occur in several receptor-related excitotoxicity com- 6 and 7. At the same time, the animals chronic neurodegenerative diseases, such pared with the adult. This vulnerability become more vulnerable to alcohol- as Alzheimer’s disease and Huntington’s appears to result from the role that related disruptions in the development disease (for a review, see Choi 1992). NMDA receptor activation plays of behaviors that require the functional NMDA receptor-mediated excito- during neuronal development (for a integrity of the hippocampus, which toxicity also may occur during AW, review, see McDonald and Johnston is rich in NMDA receptors. Moreover, possibly leading to cell loss in various 1990). Both NMDA and glutamate on postnatal day 6, rats become more brain regions, including the cortex, promote neuronal growth and regulate vulnerable to alcohol-induced weight hippocampus, and striatum2 (Lovinger the formation of connections among reductions of the forebrain, which also 1993). This hypothesis is supported neurons (i.e., neuronal circuits). For is rich in NMDA receptors. Thus, the by the observation that withdrawal example, NMDA receptor activation 2The cortex, the outer layer of neurons covering symptoms during abstinence occur at has the following effects: the brain, contains areas for processing sensory the same time at which glutamate levels information and controlling motor functions, in the brain rise and their interaction • Promotes survival of the neuron speech, and higher cognitive functions. The with the NMDA receptor increases. whose receptors are activated hippocampus is a brain region thought to play a role in learning and memory. The striatum is a Experiments both on isolated neurons brain region below the cortex that is thought to and on intact brains have demonstrated • Stimulates the outgrowth of den- be involved in motor function and some cogni- that during this period, the neurons drites, the branchlike extensions of tive functions. are more vulnerable to glutamate- or neurons where signals from other 3The cerebellum is a brain region involved in NMDA-induced excitotoxicity. For neurons are received motor control.

50 Alcohol Health & Research World The Role of Alcohol Withdrawal in FAS

vulnerabilities to alcohol and NMDA- alcohol-induced cell death (see also only one of two locations. The investiga- related insults coincide during develop- Reynolds and Brien 1995). These tor then reversed the location where the ment, suggesting that NMDA receptor- findings indicate cell death could be escape was afforded and recorded how associated mechanisms may contribute prevented by activating the NMDA often the animals went to the wrong to alcohol’s effects on the fetus. receptor during alcohol treatment. location before they found the new During fetal development, NMDA Thomas and colleagues (1997) escape location. The animals’ perfor- receptor activity must be tightly con- investigated the relationship between mance on this task was shown to be trolled to maintain a balance between the NMDA receptor, AW, and the impaired by early alcohol exposure as the receptor’s neuronal growth-pro- severity of alcohol-related behavioral well as by damage to the hippocam- moting effects and its excitotoxic deficits. In their study, rat pups were pus and cortex, two areas that are effects. Accordingly, both underacti- exposed to a high level of alcohol on vulnerable to excitotoxic cell death. vation and overactivation of this postnatal day 6, a period of brain As expected, performance on this receptor could be damaging to the development that is equivalent to a task was impaired in animals that had developing organism. Thus, alcohol portion of the human’s third trimester been exposed to alcohol compared exposure could disrupt neuronal of pregnancy. During the withdrawal with control animals. However, those development by directly inhibiting phase, the animals were injected animals that had been exposed to NMDA receptors, whereas AW could either with saline or MK-801, a sub- alcohol and treated with MK-801 interfere with development by over- stance that blocks the NMDA receptor during withdrawal performed signifi- activating NMDA receptors. For and mitigates excitotoxic cell death cantly better than did animals that example, in studies using cultured (see figure 1). Approximately 5 weeks cells, Pantazis and colleagues (1995) later, the animals were tested on a had been treated with saline during have demonstrated that the addition spatial reversal learning task. For this withdrawal (see figure 2). Admin- of NMDA to cerebellar cells in the test, the animals first learned that they istration of MK-801 alone had no presence of alcohol protected against could escape from a water maze in effect on any behavioral measure. These findings indicate that the sever- ity of alcohol-related behavioral def- icits can be significantly reduced by MK-801 blocking NMDA receptors during withdrawal, thereby reducing the sever- CH3 ity of the withdrawal. These data support the contention Na+ that excitotoxicity may occur during ++ NH Gly NMDA GLU Ca episodes of withdrawal in the devel- oping organism and may contribute to alcohol’s detrimental effects on the fetus. However, more direct evidence of the effects of alcohol exposure and withdrawal on NMDA receptors and glutamate release during development is needed. For example, the study Mg by Thomas and colleagues (1997) examined only the effects of acute ++ + alcohol administration and may not Ca K reflect events occurring during more prolonged exposure, which may be required to initiate withdrawal in Figure 1 The NMDA receptor complex. Activation (i.e., excitation) occurs when humans. Some studies have indicated, either glutamate (Glu) or N-methyl-D-aspartate (NMDA) and glycine (Gly) however, that withdrawal may be bind to the receptor molecule. A channel within the receptor complex enables molecules to cross the cell membrane. Magnesium (Mg) blocks related to total alcohol exposure and this channel. When Mg is removed from the channel and the receptor that even one-time alcohol exposure is activated, calcium (Ca++) and sodium (Na+) ions enter the cell and can induce a regular withdrawal potassium ions (K+) leave. MK-801 prevents the flow of ions across the response if the alcohol dose is high membrane by binding to a site within the ion channel, thereby blocking enough (Goldstein 1986). Obviously, NMDA receptor function and protecting the cell against excess activation more studies involving various models (i.e., excitotoxicity). of alcohol exposure are necessary to resolve these issues.

Vol. 22, No. 1, 1998 51 Conclusions complex in the dynamic context of treatment strategies to reduce the development, because the neurotrans- long-term consequences of prenatal Prenatal alcohol exposure can have mitters that react with these receptors alcohol exposure. ■ devastating effects on the growth and also play important roles in neural development of the fetus. Although development. For example, NMDA alcohol can disrupt development receptor activation can result in both References through many mechanisms, both neuronal growth-promoting and direct and indirect, little research has ABEL, E.L. Fetal Alcohol Syndrome. Oradell, NJ: excitotoxic effects, and its activity Medical Economics, 1990. addressed the issue of whether with- therefore must be finely balanced. drawal contributes to alcohol’s Consequently, both inhibition of the ABEL, E.L., AND HANNIGAN, J.H. Maternal risk deleterious effects. Researchers are NMDA receptor after alcohol expo- factors in fetal alcohol syndrome: Provocative and permissive influences. Neurotoxicology and Teratology now beginning to understand the sure and activation of the receptor 17:445–462, 1995. role of neurotransmitter receptors in during withdrawal could interfere excitotoxic brain damage and in the with neuronal development. Future BEATTIE, J.O. Transplacental alcohol intoxica- development of withdrawal symp- research on the direct and indirect tion. Alcohol and Alcoholism 21:163–166, 1986. toms. The consequences of alcohol’s effects of withdrawal on the fetus and BECKER, H.C. The alcohol withdrawal “kindling” actions at these receptors are highly newborn may result in more effective phenomenon: Clinical and experimental findings. Alcoholism: Clinical and Experimental Research 20:121A–124A, 1996.

CHOI, D.W. Excitotoxic cell death. Journal of 8 Neurobiology 23:1261–1276, 1992.

7 COLES, C.D.; SMITH, I.E.; FERNHOFF, P.M.; AND FALEK, A. Neonatal ethanol withdrawal: Characteristics in clinically normal, nondysmorphic neonates. 6 The Journal of Pediatrics 15:445–451, 1984.

5 DAVIDSON, M.; SHANLEY, B.; AND WILCE, P. Increased NMDA-induced excitability during ethanol withdrawal: A behavioural and histologi- 4 cal study. Brain Research 674:91–96, 1995.

GOLDSTEIN, D.B. The alcohol withdrawal syn- 3 drome: A view from the laboratory. In: Galanter, M., ed. Recent Developments in Alcoholism: Volume

Mean Number of Errors Mean Number of Errors 2 4. Combined Alcohol and Drug Abuse Problems. New York: Plenum Press, 1986. pp. 231–240.

1 GOODLETT, C.R., AND WEST, J.R. Fetal alcohol effects: Rat model of alcohol exposure during the 0 brain growth spurt. In: Zagon, I.S., and Slotkin, T., (incorrect attempts to escape the water tank within trials) EtOH EtOH + MK-801 GC SC eds. Maternal Substance Abuse and the Developing Only MK-801 Only Nervous System. San Diego, CA: Academic Press, 1992. pp. 45–75.

Figure 2 Administration of MK-801 during neonatal withdrawal reduced alcohol’s HATTORI, H., AND WASTERLAIN, C.G. Excitatory teratogenic effects on learning behavior. Researchers administered MK- amino acids in the developing brain: Ontogeny, 801 to neonatal animals after treating them with alcohol to see if it would plasticity, and excitotoxicity. Pediatric Neurology affect the rats’ ability to perform a learning task (i.e., to find the escape route 6:219–228, 1990. out of a water tank) later in life. During withdrawal from alcohol, some of HOFFMAN, P.L., AND TABAKOFF, B. The role of the animals were given MK-801 (EtOH + MK-801). For comparison, other the NMDA receptor in ethanol withdrawal. In: animals were given only alcohol and no MK-801 (EtOH Only), were given Jannson, B.; Jornvall, H.; Rydberg, U.; Terenius, only MK-801 but no alcohol (MK-801 Only), or were not treated with anything L.; and Valle, B.E., eds. Toward a Molecular Basis at all (GC and SC). Of the five groups, the EtOH Only group committed the of Alcohol Use and Abuse. Boston: Birkhauser greatest number of errors, showing difficulty in switching from the incorrect Verlag, 1994. pp. 61–70. to the correct location within the maze. Alcohol-exposed rats treated with IOFFE, S., AND CHERNICK, V. Development of the MK-801 during the withdrawal period (EtOH + MK-801) did not do as well EEG between 30 and 40 weeks gestation in normal as the control rats but did much better than the EtOH Only group. MK- and alcohol-exposed infants. Developmental 801Ðtreatment alone did not significantly affect performance. Medicine and Child Neurology 30:797–807, 1988. SOURCE: The results presented here have been simplified for presentation purposes. For details JONES, K.L., AND SMITH, D.W. Recognition of on the methodology used in this experiment, see Thomas et al. 1997. the fetal alcohol syndrome in early infancy. Lancet 2:999–1001, 1973.

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LOVINGER, D.M. Excitotoxicity and alcohol- L-glutamate in the fetal hippocampus. Canadian THORP, J.M. Management of drug dependency, related brain damage. Alcoholism: Clinical and Journal of Physiology and Pharmacology 73:1209– overdose, and withdrawal in the obstetric patient. Experimental Research 17:19–27, 1993. 1223, 1995. Obstetrics and Gynecology Clinics of North America 22:131–142, 1995. MCDONALD, J.W., AND JOHNSTON, M.V. ROBE, L.B.; GROMISCH, D.S.; AND IOSUB, S. Physiological and pathophysiological roles of Symptoms of neonatal ethanol withdrawal. In: TREMBLAY, E.; ROISIN, M.P.; REPRESA, A.; excitatory amino acids during central nervous Galanter M., ed. Currents in Alcoholism: Volume CHARRIAUT-MARLANGUE, C.; AND BEN-ARI, Y. system development. Brain Research Reviews VIII. Recent Advances in Research and Treatment. Transient increased density of NMDA binding 15:41–70, 1990. New York: Grune & Stratton, 1981. pp. 485–493. sites in the developing rat hippocampus. Brain Research 461:393–396, 1988. PANTAZIS, N.J.; DOHRMAN, D.P.; LUO, J.; SPARBER, S.B. Developmental effects of narcotics. THOMAS, J.D.; GOODLETT, C.R.; AND WEST, J.R. Neurotoxicology 7:335–348, 1986. TROFIMOV, S.S.; OSTROVSKAYA, R.U.; SMOL’NIKOVA, NMDA prevents alcohol-induced neuronal cell STREISSGUTH, A.P.; BARR, H.M.; AND SAMPSON, N.M.; NEMOVA, E.P.; AND VORONINA, T.A. The death of cerebellar granule cells in culture. role of perinatal alcoholization and its withdrawal Alcoholism: Clinical and Experimental Research P.D. Moderate prenatal alcohol exposure: Effects 1 in the development of remote cognitive disorders 19:846–853, 1995. on child IQ and learning problems at age 7 /2 years. Alcoholism: Clinical and Experimental in rats. Eksperimentalnaia I Klinicheskata Farmakologia RETZ, W.; KORNHUBER, J.; AND RIEDERER, P. Research 14:662–669, 1990. 59:44–46, 1996. Neurotransmission and the ontogeny of human WEST, J.R.; CHEN, W.A.; AND PANTAZIS, N.J. brain. Journal of Neural Transmission 103:403– THOMAS, J.D.; WEINERT, S.; SHARIF, S.; AND RILEY, Fetal alcohol syndrome: The vulnerability of 419, 1996. E.P. MK-801 administration during ethanol withdrawal in neonatal rat pups attenuates ethanol- the developing brain and possible mechanisms REYNOLDS, J.D., AND BRIEN, J.F. Ethanol neu- induced behavioral deficits. Alcoholism: Clinical of damage. Metabolic Brain Disease 9:291–322, robehavioural teratogenesis and the role of and Experimental Research 21:1218–1225, 1997. 1994.

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