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The Effects of Alcohol on Physiological Processes and Biological Development

Adolescence is a period of rapid growth and physical change; a central question is whether consuming alcohol during this stage can disrupt development in ways that have long-term consequences. In general, the existing evidence suggests that adolescents rarely exhibit the more severe chronic disorders associated with alcohol dependence such as liver cirrhosis, hepatitis, gastritis, and pancreatitis. Adolescents who drink heavily, however, may experience some adverse effects on the liver, bone, growth, and endocrine development. Evidence also is mounting, at least in animal models, that early alcohol use may have detrimental effects on the developing brain, perhaps leading to problems with cognition later in life. This article summarizes the physiological effects of alcohol on adolescents, including a look at the long-term behavioral and physiological consequences of early drinking. Key words: underage drinking; binge drinking; AODU (alcohol and other drug use); adolescence; growth and development; puberty; physiological AODE (alcohol and other drug effects); psychological AODE; chronic AODE; brain; liver; bone; reproductive system; sexual maturation; long-term AOD (alcohol and other drug) use; animal studies

OVERVIEW

The damage that long-term heavy alcohol consumption can do to the health of adults is well documented. Some research suggests that, even over the shorter time frame of adolescence, drinking alcohol can harm the liver, bones, endocrine system, and brain, and interfere with growth. Adolescence is a period of rapid growth and physical change; a central question is whether consuming alcohol during this stage can disrupt development in ways that have long-term consequences.

Liver disease is a common consequence of heavy drinking. More severe alcohol-related liver disease typically reflects years of heavy alcohol use. However, elevated liver enzymes that are markers of harm have been found in adolescents with alcohol use disorders and in overweight adolescents who consume more modest amounts of alcohol.

During puberty, accelerating cascades of growth factors and sex hormones set off sexual maturation, growth in stature and muscle mass, and bone development. Studies in humans have found that alcohol can lower the levels of growth and sex hormones in both adolescent boys and girls. In animals, alcohol has been found to disrupt the interaction between the brain, the pituitary gland (which regulates secretion of sex hormones), and the ovaries, as well as systems within the ovaries that are involved in regulating sex hormones. In adolescent male animals, both short- and long-term alcohol administration suppresses testosterone; alcohol use also alters growth hormone levels, the effects of which differ with age.

Studies on alcohol and adolescent bone development are limited. In studies of male and female rats, chronic alcohol consumption (an alcohol diet) for the length of adolescence was found to stunt limb growth. One study found that feeding female rats alcohol in a way that mimics binge drinking resulted in either increases in bone length and density or in no change with more frequent bingeing. In human adolescent males but not females, studies have found that alcohol consumption decreases bone density.

The brain also is changing during adolescence. Adolescents tend to drink larger quantities on each drinking occasion than adults; this may in part be because adolescents are less sensitive to some of the unpleasant effects of intoxication. However, research suggests that adolescents may be more sensitive to some of alcohol’s harmful effects on brain function. Studies in rats found that alcohol impairs the ability of adolescent animals more than adult animals to learn a task that requires spatial memory. Research also suggests a mechanism for this effect; in adolescents more than adults, alcohol inhibits the process in which, with repeated experience, nerve impulses travel more easily across the gap between nerve cells (i.e., neurons) involved in the task being learned. The reasons for these differences in sensitivity to alcohol remain unclear.

Research also has found differences in the effects of bingelike drinking in adolescents compared with adults. Normally, as people age from adolescence to adulthood, they become more sensitive to alcohol’s effects on motor coordination. In one study, however, adolescent rats exposed to intermittent alcohol never developed this increased sensitivity. Other studies in both human subjects and animals suggest that the adolescent brain may be more vulnerable than the adult brain to chronic alcohol abuse.

Young people who reported beginning to drink at age 14 or younger also were four times more likely to report meeting the criteria for alcohol dependence at some point in their lives than were those who began drinking after age 21. Although it is possible that early alcohol use may be a marker for those who are at risk for alcohol disorders, an important question is whether early alcohol exposure may alter neurodevelopment in a way that increases risk of later abuse. Research in rats has found that prenatal or early postnatal exposure to alcohol results in a greater preference for the odor and consumption of alcohol later in life. Social experiences associated with youthful drinking also may influence drinking later in life. Additional research is needed to resolve the question of whether and how early alcohol exposure might contribute to drinking problems years down the road.

ALCOHOL’S EFFECTS ON THE LIVER, THE NEUROENDOCRINE SYSTEM, AND BONE

The medical consequences of chronic alcohol abuse and dependence have been well documented in adults. They include liver disease, lung disease, compromised immune function, endocrine disorders, and brain changes. Investigations of the health problems associated with adolescent alcohol abuse are sparse and rely mainly on self-report (see Clark et al. 2001; Aarons et al. 1999; Brown and Tapert 2004). In general, the existing evidence suggests that adolescents rarely exhibit the more severe chronic disorders associated with alcohol dependence, such as liver cirrhosis, hepatitis, gastritis, and pancreatitis. However, more research is needed to determine whether severe alcohol-induced organ damage is strictly a cumulative process that begins in adolescence and culminates in adulthood as a result of long-term chronic heavy drinking or whether serious alcohol-related health problems can emerge during the teenage years. The few studies available indicate that adolescents who drink heavily experience adverse effects on the liver, bones, growth, and endocrine development, as summarized below. The effects of chronic alcohol consumption on the adolescent brain are discussed in the section “Long-Term Behavioral and Physiological Conse quences of Early Drinking.”

Liver Effects

Elevated liver enzymes have been found in some adolescents who drink alcohol. Clark and colleagues (2001) found that adolescent alcohol use disorders were associated with higher gamma-glutamyl transpeptidase (GGT) and alanine amino transferase (ALT). Moreover, young drinkers who also are overweight or obese exhibit elevated levels of serum ALT with even modest amounts of alcohol intake (Strauss et al. 2000).

Growth and Endocrine Effects

In general, there has been a gradual decline in the onset of female puberty over the last century, at least when puberty is defined by age at menarche (Tanner 1989). Whether initiation of female puberty is continuing to decline and at what rate are the subjects of some debate (Lee et al. 2001; Herman-Giddens et al. 1997). Much less information exists on pubertal development in males because of the greater difficulty in assessing developmental milestones. However, a recent study comparing data from two national surveys, one conducted between 1988 and 1994 and the other between 1963 and 1970, found that American boys from the later generation had earlier onset of some pubertal stages as measured by standard Tanner staging (Herman-Giddens et al. 2001; Karpati et al. 2002). Perhaps not surprisingly, early puberty—especially among girls—is associated with early use of alcohol, tobacco, and other drugs (Wilson et al. 1994; Dick et al. 2000). In addition, alcohol use in early maturing adolescents has implications for normal growth and neuroendocrine development.

In both males and females, puberty is a period of activation of the hypothalamic-pituitary-gonadal (HPG) axis. Pulsatile secretion of gonadotrophin-releasing hormone (GnRH) from the hypothalamus stimulates pituitary secretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) pulses, followed by marked increases in gonadal sex steroid output (estrogen and testosterone), which in turn increases growth hormone (GH) and insulin-like growth factor-1 (IGF-1) production (see Mauras et al. 1996). Data from several studies suggest that both androgens and estrogens stimulate GH production, but that estrogen controls the feedback mechanism of GH production during puberty even in males (Mauras et al. 1996; Dees et al. 2001). The increase in these hormones not only promotes maturation of the gonads but also affects growth, muscle mass, and mineralization of the skeleton. Thus, alcohol consumed during rapid development (i.e., prior to or during puberty) has the potential to disrupt normal growth and endocrine development through its effects on the hypothalamus, the pituitary gland, and the various target organs such as the ovaries and testes.

Most human and animal research on alcohol and endocrine development has been conducted in females, but the limited data on both genders suggest that alcohol can have substantial effects on neuroendocrine function (see Dees et al. 2001; Emanuele et al. 1998; Emanuele et al. 2002a,b). Human studies have found that alcohol ingestion can lower estrogen levels in adolescent girls (Block et al. 1993) and lower both LH and testosterone levels in midpubertal boys (Diamond et al. 1986; Frias et al. 2000a). In both genders, acute alcohol intoxication produces a decrease in GH levels without significant change in either IGF-1 or insulin-like growth factor binding protein-3 (IGFBP3) (Frias et al. 2000b).

In female rats, alcohol has been shown to suppress the secretion of specific female reproductive hormones, thereby delaying the onset of puberty (see Dees et al. 2001 and Emanuele et al). Dees and colleagues (2000) found that immature female rhesus macaques exposed daily to alcohol (2 g/kg via nasogastric tube) exhibit lower levels of GH, FSH, LH, estradiol (E2), and IGF-1 (but not FSH or Leptin) compared with control subjects. Moreover, even though there was no effect on age of menarche in these animals, the interval between subsequent menstruations was lengthened, thereby interfering with the development of regular monthly cycles. Additional studies in rats have found that alcohol interferes with intraovarian systems, including IGF-1 and IGF-1 receptors; the nitric oxide (NO) system (Dees et al. 2001; Srivastava et al. 2001a), and the steroidogenic acute regulatory protein (StAR) (Srivastava et al. 2001b), all of which combine to decrease estradiol secretion. Thus, alcohol not only disrupts the interaction between the brain, pituitary gland, and ovaries, it also directly impairs the regulatory systems within the ovaries (see Dees et al. 2001 for review).

In male rats, both acute and chronic alcohol exposure during adolescence results in a reversible suppression of serum testosterone (Little et al. 1992; Cicero et al. 1990; Tentler et al. 1997; Emanuele et al. 1998, 1999a,b; Steiner et al. 1997). Evidence exists for involvement at the hypothalamic, pituitary, and gonadal levels, although the testes appear to be the prime target of alcohol’s actions (Emanuele et al. 1999a). Furthermore, GH levels are affected by acute and chronic alcohol exposure in male adolescent rats, whereas IGF-1, growth hormone releasing factor (GRF), and GRF mRNA content are variable, depending on the type of administration (Steiner et al. 1997; Tentler et al. 1997).

Thus, the data so far indicate that females who consume alcohol during early adolescence may be at risk for adverse effects on maturation of the reproductive system. Although in males the long-term effects of alcohol on reproductive function are unclear, the fact that GH as well as testosterone and/or estrogen levels are altered by alcohol in both genders may have serious implications for normal development because these hormones play a critical role in organ maturation during this stage of development.

Bone Density and Growth Effects

Only a handful of studies have examined the effects of adolescent drinking on bone development, with the most informative data thus far coming from animal research. Male rats chronically fed an alcohol liquid diet for 60 days encompassing the adolescent period (postnatal days 35 to 90) display limb length reduction and reduced metaphyseal and cortical bone growth in the limbs (Wezeman et al. 1999). These skeletal effects may be mediated through a reduction in osteoblast formation, which is associated with a decline in testosterone but not IGF-1. In addition, with abstinence, normal bone metabolism is not completely restored. Similarly, in female rats, Sampson and colleagues (Sampson et al. 1996; Sampson and Spears 1999) found that chronic alcohol consumption (4 weeks on an ethanol liquid diet) produces decreased limb length and reductions in cortical and cancellous bone, which are not fully reversed following cessation of drinking. Interestingly, female adolescent animals administered a binge model of drinking (i.e., 5 percent alcohol by gavage for either 2 or 5 consecutive days per week) show increased bone length, weight, and density, or no change, respectively (Sampson et al. 1999). Human studies indicate an inverse relationship between alcohol consumption and bone mineral density in adolescent males, but not females (Fehily et al. 1992; Neville et al. 2002; Elgan et al. 2002; Fujita et al. 1999). However, more studies are needed in humans and animals to get a clearer picture of alcohol’s effects on bone growth in adolescents, particularly with respect to dose and pattern of consumption.

A Snapshot of Findings on Alcohol’s Physiological Effects in Adolescent Humans & Animals
 

Findings

Study

On the Liver

In humans

Levels of enzymes that indicate liver damage are higher in adolescents with alcohol use disorders

Clark et al. 2001

And in obese adolescents who drink more moderate amounts.

Strauss et al. 2000

On the Endocrine System

In humans

Drinking alcohol can lower estrogen levels in adolescent girls.

Block et al. 1993

Drinking alcohol can lower luteinizing hormone and testosterone levels in adolescent boys.

Diamond et al. 1986; Frias et al. 2000a

In both sexes, acute intoxication reduces levels of growth hormones.

Frias et al. 2000b

In rats

In female rats, ingesting alcohol during adolescence is associated with adverse effects on maturation of the reproductive system.

Dees et al. 2001

Alcohol suppresses the secretion of certain female reproductive hormones, delaying the start of puberty.

Emanuelle et al. 2001, 2002

Alcohol not only disrupts the interaction between the brain, pituitary gland, and ovaries, but also impairs regulatory systems within the ovaries.

Dees et al. 2001

In male rats, alcohol consumption alters growth hormone and testosterone levels, which may have serious consequences for normal development.

Little et al. 1992; Cicero et al. 1990; Tentler et al. 1997; Emanuelle et al. 1998, 1999a, 1999b; Steiner et al. 1997

In rhesus macaques

In immature female monkeys, daily exposure to alcohol lowered levels of female hormones and affected the development of regular monthly cycles.

Dees et al. 2000

On Bone Density

In humans

Increased alcohol consumption is associated with lowered bone mineral density in adolescent males but not females.

Fehily et al. 1992; Neville et al. 2002; Elgan et al. 2002; Fujita et al. 1999

In rats

In adolescent female rats, chronic alcohol consumption produced shorter limb lengths and reductions in bone growth, neither of which was fully reversed with abstinence.

Sampson et al. 1996; Sampson and Spears 1999

In adolescent male rats, chronic alcohol ingestion was associated with shorter limb length and reduced bone growth, which are not fully reversed with abstinence.

Wezeman et al. 1999

On the Brain

In humans

A history of alcohol abuse or dependence in adolescents was associated with reduced hippocampal volumes

De Bellis et al. 2000

And with subtle white-matter microstructure abnormalities in the corpus callosum.

Tapert et al. 2003

In rats

Chronic intermittent exposure to high alcohol doses (i.e., bingeing) results in long-lasting changes in memory in adolescent rats

White et al. 2000

And to more damage to the frontal-anterior cortical regions of the brain than are produced in adult rats.

Crews et al. 2000

Prolonged alcohol exposure during adolescence produces:

  • Neurophysiological changes in the response to alcohol challenge and in the tolerance to alcohol’s sedative effects;
  • Enhanced expression of withdrawal behaviors; and
  • Long-lasting neurophysiological effects in the cortex and hippocampus.

Slawecki et al. 2001; Slawecki 2002; Slawecki and Roth 2004

LONG-TERM BEHAVIORAL AND PHYSIOLOGICAL CONSEQUENCES OF EARLY DRINKING

Although increased tolerance to alcohol’s sedative effects may enable greater intake in adolescents, repeated exposure to alcohol may produce increased sensitivity to alcohol’s harmful effects. Studies in rats show that ethanol-induced inhibition of synaptic potentials mediated by N-methyl-D-aspartate (NMDA) and long-term potentiation (LTP) is greater in adolescents than in adults (Swartzwelder et al. 1995a,b; see White and Swartzwelder 2005 for review). Initially, the developmental sensitivity of NMDA currents to alcohol was observed in the hippocampus, but more recently this effect was found outside the hippocampus in pyramidal cells in the posterior cingulate cortex (Li et al. 2002). Behaviorally, adolescent rats show greater impairment than adults in acquisition of a spatial memory task after acute ethanol exposure (Markwiese et al. 1998) in support of greater LTP sensitivity to alcohol in adolescents. Behavioral and neurobiological mechanisms for the ontogenetic differences in alcohol tolerance and sensitivity are unclear, as is the relationship between differential sensitivity to ethanol and onset of alcohol abuse and alcoholism.

Binge alcohol exposure (i.e., chronic intermittent exposure to high alcohol doses) in rats during adolescence produces long-lasting changes in memory function (White et al. 2000) and interferes with the normal development of sensitivity to alcohol-induced motor impairments (White et al. 2002). In addition, prolonged alcohol exposure during adolescence, but not adulthood, produces alterations in neurophysiological response to ethanol challenge, tolerance to the sedative effects of ethanol, enhanced expression of withdrawal-related behavior, and long-lasting neurophysiological changes in the cortex and hippocampus in rats (Slawecki et al. 2001; Slawecki 2002; Slawecki and Roth 2004). Further more, chronic ethanol treatment in rats may lead to increased NMDA-mediated neurotoxicity, which could be exacerbated by repeated withdrawals (Hunt 1993). Consistent with this hypothesis is the finding that severity of alcohol and drug withdrawal symptoms may be a powerful marker of neuropsychological impairments in detoxified older human adolescents and young adults (Brown et al. 2000; Tapert and Brown 1999; Tapert et al. 2002). Moreover, one recent study found reduced hippocampal volumes in human adolescents with a history of alcohol abuse/dependence disorder (De Bellis et al. 2000), and another preliminary investigation of alcohol-abusing teenagers observed subtle white-matter microstructure abnormalities in the corpus callosum (Tapert et al. 2003), which may be a precursor of more severe damage produced by long-term chronic drinking (Pfefferbaum and Sullivan 2002). Juvenile rats exposed to heavy bingelike episodes of ethanol have greater damage than adults in frontal-anterior cortical regions, including the olfactory frontal cortex, anterior perirhinal, and piriform cortex (Crews et al. 2000). Thus, the immature brain may be more susceptible to binge ethanol-induced neurotoxicity, although the mechanisms are unknown.

Because teenagers are likely to engage in binge drinking, it is important to study the effects of chronic binge patterns of ethanol exposure on brain structure, neurochemistry, and cognitive functioning. Care must be taken in extrapolating from the described animal studies to the binge-drinking adolescent. Because binge drinking does not usually entail withdrawal, it is important to distinguish between damage caused by the alcohol itself and that caused by repeated withdrawals. In addition, primate models may be a better choice for studying the long-term consequences of alcohol exposure because of primates’ prolonged adolescent period, which allows extensive manipulation of different types and lengths of exposure. These models, coupled with new neuroanatomical and neuroimaging techniques, offer a unique opportunity to study the brain changes associated with adolescent drinking and determine whether adolescent brains are able to recover more easily because of greater plasticity.

Early Exposure as a Predictor of Later Alcohol Abuse

Early exposure to alcohol—at or before age 14—is strongly associated with later alcohol abuse and dependence (Grant and Dawson 1998). Two possible explanations for this effect are obvious. First, early alcohol use may simply be a marker for later alcohol abuse rather than a causative factor. A good deal of evidence indicates that at least one behavioral factor, behavioral undercontrol, is measurable very early in life and is a consistently robust predictor of earlier alcohol use as well as of elevated risk for later alcohol use disorder (NIAAA 2000; Zucker and Wong 2005; Caspi et al. 1996).

Second, it is possible that alcohol exposure during adolescence actually may alter neurodevelopmental processes in such a way that the likelihood of later abuse is increased. For example, alcohol use could promote rewiring or alter normal maturation and pruning within the nervous system. Ample evidence exists that exposing rats to low or moderate doses of alcohol during the prenatal or early postnatal period yields a greater preference for ethanol’s odor and its consumption later in life (Abate et al. 2000; Honey and Galef 2003; see Molina et al. 1999 and Spear and Molina 2001 for reviews). The young rat’s response to alcohol also is mediated by social factors such as maternal interactions and/or nursing from an intoxicated dam (e.g., Hunt et al. 2001; Pepino et al. 2001, 2002; Spear and Molina 2001). Recent evidence shows that prior nursing experience from an ethanol-intoxicated dam heightens ethanol consumption in infant and adolescent rats (Ponce et al. 2004; Pepino et al. 2004). In contrast, relatively few reports using animal models to study the effects of adolescent alcohol exposure on later alcohol consumption exist, and the results are conflicting (see Spear and Varlinskaya 2005). Yet, as is the case with younger animals, social experiences associated with adolescent drinking may influence future drinking behaviors (Hunt et al. 2001; Varlinskaya and Spear 2002). More studies are needed, however, to explore whether a causal relationship between early chronic exposure to alcohol and later alcohol problems exists, as well as to discover the underlying mechanisms for this effect. Nonhuman primates, because of their extended adolescent period, offer a good opportunity to study the effects of early exposure to alcohol.

REFERENCES

Aarons, G.A.; Brown, S.A.; Coe, M.T.; et al. Adolescent alcohol and drug abuse and health. Journal of Adolescent Health 24:412–421, 1999. PMID: 10401969

Abate, P.; Pepino, M.Y.; Dominguez, H.D.; et al. Fetal associative learning mediated through maternal alcohol intoxication. Alcoholism: Clinical and Experimental Research 24:39–47, 2000. PMID: 10656191

Block, G.D.; Yamamoto, M.E.; Mallick, E.; and Styche, A. Effects on pubertal hormones by ethanol abuse in adolescents. Alcoholism: Clinical and Experimental Research 17:505, 1993.

Brown, S.A., and Tapert, S.F. Health consequences of adolescent alcohol involvement. In: NRC and IOM. Bonnie, R.J., and O’Connell, M.E., eds. Reducing Underage Drinking: A Collective Responsibility. Washington, DC: National Academies Press, 2004. pp. 383–401. Available online at: http://www.nap.edu/books/0309089352/html.

Brown, S.A.; Tapert, S.F.; Granholm, E.; and Dellis, D.C. Neurocognitive functioning of adolescents: Effects of protracted alcohol use. Alcoholism: Clinical and Experimental Research 24:164–171, 2000. PMID: 10698367

Caspi, A.; Moffitt, T.E.; Newman, D.L.; and Silva, E.P.A. Behavioral observations at age 3 years predict adult psychiatric disorders: Longitudinal evidence from a birth cohort. Archives of General Psychiatry 53:1033–1039, 1996. PMID: 8911226

Cicero, T.J.; Adams, M.L.; O’Connor, L.; et al. Influence of chronic alcohol administration on representative indices of puberty and sexual maturation in male rats and the development of their progeny. Journal of Pharmacology and Experimental Therapeutics 255:707–715, 1990. PMID: 2243349

Clark, D.B.; Lynch, K.G.; Donovan, J.E.; and Block, G.D. Health problems in adolescents with alcohol use disorders: Self-report, liver injury, and physical examination findings and correlates. Alcoholism: Clinical and Experimental Research 25:1350–1359, 2001. PMID: 11584156

Crews, F.T.; Braun, C.J.; Hoplight, B.; et al. Binge ethanol consumption causes differential brain damage in young adolescent rats compared with adult rats. Alcoholism: Clinical and Experimental Research 24:1712–1723, 2000. PMID: 11104119

De Bellis, M.D.; Clark, D.B.; Beers, S.R.; et al. Hippocampal volume in adolescent-onset alcohol use disorders. American Journal of Psychiatry 157:737–744, 2000. PMID: 10784466

Dees, W.L.; Dissen, G.A.; Hiney, J.K.; et al. Alcohol ingestion inhibits the increased secretion of puberty-related hormones in the developing female rhesus monkey. Endocrinology 141:1325–1331, 2000. PMID: 10746635

Dees, W.L.; Srivastava, V.K.; and Hiney, J.K. Alcohol and female puberty: The role of intraovarian systems. Alcohol Research & Health 25(4):271–275, 2001. PMID: 11910704

Diamond, F., Jr.; Ringenberg, L.; MacDonald, D.; et al. Effects of drug and alcohol abuse upon pituitary-testicular function in adolescent males. Journal of Adolescent Health Care 7:28–33, 1986. PMID: 2935515

Dick, D.M.; Rose, R.J.; Viken, R.J.; and Kaprio, J. Pubertal timing and substance use: Associations between and within families across late adolescence. Developmental Psychology 36:180–189, 2000. PMID: 10749075

Elgan, C.; Dykes, A.K.; and Samsioe, G. Bone mineral density and lifestyle among female students aged 16–24 years. Gynecological Endocrinology 16:91– 98, 2002. PMID: 12012629

Emanuele, M.A.; LaPaglia, N.; Steiner, J.; et al. Reversal of ethanol-induced testosterone suppression in peripubertal male rats by opiate blockade. Alcoholism: Clinical and Experimental Research 22:1199–1204, 1998. PMID: 9756033

Emanuele, M.A.; Wezeman, F.; and Emanuele, N.V. Alcohol’s effects on female reproductive function. Alcohol Research & Health 26(4):274–281, 2002a. PMID: 12875037

Emanuele, N.; Ren, J.; LaPaglia, N.; et al. EtOH disrupts female mammalian puberty: Age and opiate dependence. Endocrine 18:247–254, 2002b. PMID: 12450316

Emanuele, N.V.; LaPaglia, N.; Vogl, W.; et al. Impact and reversibility of chronic ethanol feeding on the reproductive axis in the peripubertal male rat. Endocrine 11:277–284, 1999a. PMID: 10786824

Emanuele, N.V.; Lapaglia, N.; Steiner, J.; et al. Reversal of chronic ethanol-induced testosterone suppression in peripubertal male rats by opiate blockade. Alcoholism: Clinical and Experimental Research 23:60–66, 1999b. PMID: 10029204

Fehily, A.M.; Coles, R.J.; Evans, W.D.; and Elwood, P.C. Factors affecting bone density in young adults. American Journal of Clinical Nutrition 56:579–586, 1992. PMID: 1503072

Frias, J.; Rodriguez, R.; Torres, J.M.; et al. Effects of acute alcohol intoxication on pituitary-gonadal axis hormones, pituitary-adrenal axis hormones, β-endorphin and prolactin in human adolescents of both sexes. Life Sciences 67:1081–1086, 2000a. PMID: 10954041

Frias, J.; Torres, J.M.; Rodriguez, R.; et al. Effects of acute alcohol intoxication on growth axis in human adolescents of both sexes. Life Sciences 67:2691–2697, 2000b. PMID: 11105985

Fujita, Y.; Katsumata, K.; Unno, A.; et al. Factors affecting peak bone density in Japanese women. Calcified Tissue International 64:107–111, 1999. PMID: 9914316

Grant, B.F., and Dawson, D.A. Age at onset of alcohol use and its association with DSM–IV alcohol abuse and dependence: Results from the National Longitudinal Alcohol Epidemiologic Survey. Journal of Substance Abuse 9:103–110, 1998. PMID: 9494942

Herman-Giddens, M.E.; Slora, E.J.; Wasserman, R.C.; et al. Secondary sexual characteristics and menses in young girls seen in office practice: A study from the Pediatric Research in Office Settings Network. Pediatrics 99:505–512, 1997. PMID: 9093289

Herman-Giddens, M.E.; Wang, L.; and Koch, G. Secondary sexual characteristics in boys: Estimates from the National Health and Nutrition Examination Survey III, 1988–1994. Archives of Pediatric & Adolescent Medicine 155:1022–1028, 2001. PMID: 11529804

Honey, P.L., and Galef, B.G., Jr. Ethanol consumption by rat dams during gestation, lactation and weaning increases ethanol consumption by their adolescent young. Developmental Psychobiology 42:252– 260, 2003. PMID: 12621651

Hunt, W.A. Are binge drinkers more at risk of developing brain damage? Alcohol 10:559–561, 1993. PMID: 8123218

Hunt, P.S.; Holloway, J.L.; and Scordalakes, E.M. Social interaction with an intoxicated sibling can result in increased intake of ethanol by periadolescent rats. Developmental Psychobiology 38:101–109, 2001. PMID: 11223802

Karpati, A.M.; Rubin, C.H.; Kieszak, S.M.; et al. Stature and pubertal stage assessment in American boys: The 1988–1994 Third National Health and Nutrition Examination Survey. Journal of Adolescent Health 30:205–212, 2002. PMID: 11869928

Lee, P.A.; Guo, S.S.; and Kulin, H.E. Age of puberty: Data from the United States of America. APMIS (Acta Pathologica, Microbiologica, et Immunologica Scandinavica) 109:81–88, 2001. PMID: 11398998

Li, Q.; Wilson, W.A.; and Swartzwelder, H.S. Differential effect of ethanol on NMDA EPSCs in pyramidal cells in the posterior cingulate cortex of juvenile and adult rats. Journal of Neurophysiology 87:705–711, 2002. PMID: 11826039

Little, P.J.; Adams, M.L.; and Cicero, T.J. Effects of alcohol on the hypothalamic-pituitary-gonadal axis in the developing male rat. Journal of Pharmacology and Experimental Therapeutics 263:1056–1061, 1992. PMID: 1469619

Markwiese, B.J.; Acheson, S.K.; Levin, E.D.; et al. Differential effects of ethanol on memory in adolescent and adult rats. Alcoholism: Clinical and Experimental Research 22:416–421, 1998. PMID: 9581648

Mauras, N.; Rogol, A.D.; Haymond, M.W.; and Veldhuis, J.D. Sex steroids, growth hormone, insulin-like growth factor-1: Neuroendocrine and metabolic regulation in puberty. Hormone Research 45:74–80, 1996. PMID: 8742123

Molina, J.C.; Dominguez, H.D.; Lopez, M.F.; et al. The role of fetal and infantile experience with alcohol in later recognition and acceptance patterns of the drug. In: Hannigan, J.; Goodlett, C.; Spear, L.; Spear, N., eds. Alcohol and Alcoholism: Brain and Development. Hillsdale, NJ: Erlbaum, 1999, pp. 199–227.

National Institute on Alcohol Abuse and Alcoholism (NIAAA). Alcohol involvement over the life course. In: Tenth Special Report to the U.S. Congress on Alcohol and Health: Highlights from Current Research. Bethesda, MD: Dept. of Health and Human Services, NIAAA, 2000. pp. 28–53. Available online at: http://pubs.niaaa.nih.gov/publications/10report/intro.pdf.

Neville, C.E.; Murray, L.J.; Boreham, C.A.G.; et al. Relationship between physical activity and bone mineral status in young adults: The Northern Ireland Young Hearts Project. Bone 30:792–798, 2002. PMID: 11996922

Pepino, M.Y.; Spear, N.E.; and Molina, J.C. Nursing experiences with an alcohol-intoxicated rat dam counteract appetitive conditioned responses toward alcohol. Alcoholism: Clinical and Experimental Research 25:18–24, 2001. PMID: 11198710

Pepino, M.Y.; Abate, P.; Spear, N.E.; and Molina, J.C. Disruption of maternal behavior by alcohol intoxication in the lactating rat: A behavioral and metabolic analysis. Alcoholism: Clinical and Experimental Research 26:1205–1214, 2002. PMID: 12198395

Pepino, M.Y.; Abate, P.; Spear, N.E.; and Molina, J.C. Heightened ethanol intake in infant and adolescent rats after nursing experiences with an ethanol-intoxicated dam. Alcoholism: Clinical and Experimental Research 28:895–905, 2004. PMID: 15201632

Pfefferbaum, A., and Sullivan, E.V. Micro structural but not macrostructural disruption of white matter in women with chronic alcoholism. Neuroimage 15:708–718, 2002. PMID: 11848714

Ponce, L.F.; Pautassi, R.M.; Spear, N.E.; and Molina, J.C. Nursing from an ethanol-intoxicated dam induces short- and long-term disruptions in motor performance and enhances later self-administration of the drug. Alcoholism: Clinical and Experimental Research 28:1039–1050, 2004. PMID: 15252290

Sampson, H.W., and Spears, H. Osteopenia due to chronic alcohol consumption by young actively growing rats is not completely reversible. Alcoholism: Clinical and Experimental Research 23: 324–327, 1999. PMID: 10069563

Sampson, H.W.; Perks, N.; Champney, T.H.; and Defee, B., 2nd. Alcohol consumption inhibits bone growth and development in young actively growing rats. Alcoholism: Clinical and Experimental Research 20:1375–1384, 1996. PMID: 8947313

Sampson, H.W.; Gallager, S.; Lange, J.; et al. Binge drinking and bone metabolism in a young actively growing rat model. Alcoholism: Clinical and Experimental Research 23:1228–1231, 1999. PMID: 10443990

Slawecki, C.J. Altered EEG responses to ethanol in adult rats exposed to ethanol during adolescence. Alcoholism: Clinical and Experimental Research 26:246–254, 2002. PMID: 11964565

Slawecki, C.J., and Roth, J. Comparison of the onset of hypoactivity and anxiety-like behavior during alcohol withdrawal in adolescent and adult rats. Alcoholism: Clinical and Experimental Research 28:598–607, 2004. PMID: 15100611

Slawecki, C.J.; Betancourt, M.; Cole, M.; and Ehlers, C.L. Periadolescent alcohol exposure has lasting effects on adult neurophysiological function in rats. Developmental Brain Research 128:63–72, 2001. PMID: 11356263

Spear, L.P., and Varlinskaya, E.I. Adolescence: Alcohol sensitivity, tolerance, and intake. In: Galanter, M., ed. Recent Developments in Alcoholism, Vol. 17: Alcohol Problems in Adolescents and Young Adults: Epidemiology, Neurobiology, Prevention, Treatment. New York: Springer, 2005. pp. 143–159. PMID: 15789864

Spear, N.E., and Molina, J.C. Consequences of early exposure to alcohol: How animal studies reveal later patterns of use and abuse in humans. In: Carroll, M.E., and Overmier, J.B., eds. Animal Research and Human Health: Advancing Human Welfare through Behavioral Science. Washington, DC: American Psychological Association, 2001. pp. 85–99.

Srivastava, V.K.; Hiney, J.K.; Dearth, R.K.; and Dees, W.L. Effects of alcohol on intraovarian insulin-like growth factor-1 and nitric oxide systems in prepubertal female rats. Recent Research Developments in Endocrinology 2(part 1):213–221, 2001a.

Srivastava, V.K.; Hiney, J.K.; Dearth, R.K.; and Dees, W.L. Acute effects of ethanol on steroidogenic acute regulatory protein (StAR) in the prepubertal rat ovary. Alcoholism: Clinical and Experimental Research 25:1500–1505, 2001b. PMID: 11696671

Steiner, J.C.; LaPaglia, N.; Hansen, M.; et al. Effect of chronic ethanol on reproductive and growth hormones in the peripubertal male rat. Journal of Endocrinology 154:363–370, 1997. PMID: 9291847

Strauss, R.S.; Barlow, S.E.; and Dietz, W.H. Prevalence of abnormal serum aminotransferase values in overweight and obese adolescents. Journal of Pediatrics 136:727–733, 2000. PMID: 10839867

Swartzwelder, H.S.; Wilson, W.A.; and Tayyeb, M.I. Age-dependent inhibition of long-term potentiation by ethanol in immature versus mature hippocampus. Alcoholism: Clinical and Experimental Research 19:1480–1485, 1995a. PMID: 8749814

Swartzwelder, H.S.; Wilson, W.A.; and Tayyeb, M.I. Differential sensitivity of NMDA receptor-mediated synaptic potentials to ethanol in immature versus mature hippocampus. Alcoholism: Clinical and Experimental Research 19:320–323, 1995b. PMID: 7625564

Tanner, J.M. Foetus into Man: Physical Growth From Conception to Maturity. Ware, Great Britain: Castlemead Publications, 1989.

Tapert, S.F., and Brown, S.A. Neuropsychological correlates of adolescent substance abuse: Four-year outcomes. Journal of the International Neuropsychological Society 5:481–493, 1999. PMID: 10561928

Tapert, S.F.; Granholm, E.; Leedy, N.G.; and Brown, S.A. Substance use and withdrawal: Neuropsychological functioning over 8 years in youth. Journal of the International Neuropsychological Society 8:873–883, 2002. PMID: 12405538

Tapert, S.F.; Theilmann, R.J.; Schweinsburg, A.D.; et al. Reduced fractional anisotropy in the splenium of adolescents with alcohol use disorder. Proceedings of the International Society for Magnetic Resonance in Medicine 11:8217, 2003.

Tentler, J.J.; LaPaglia, N.; Steiner, J.; et al. Ethanol, growth hormone and testosterone in peripubertal rats. Journal of Endocrinology 152:477–487, 1997. PMID: 9071969

Varlinskaya, E.I., and Spear, L.P. Acute effects of ethanol on social behavior of adolescent and adult rats: Role of familiarity of the test situation. Alcoholism: Clinical and Experimental Research 26:1502–1511, 2002. PMID: 12394283

Wezeman, F.H.; Emanuele, M.A.; Emanuele, N.V.; et al. Chronic alcohol consumption during male rat adolescence impairs skeletal development through effects on osteoblast gene expression, bone mineral density, and bone strength. Alcoholism: Clinical and Experimental Research 23:1534–1542, 1999. PMID: 10512321

White, A.M., and Swartzwelder, H.S. Age-related effects of alcohol on memory and memory-related brain function in adolescents and adults. In: Galanter, M., ed. Recent Developments in Alcoholism, Vol. 17: Alcohol Problems in Adolescents and Young Adults: Epidemiology, Neurobiology, Prevention, Treatment. New York: Springer, 2005. pp. 161–176. PMID: 15789865

White, A.M.; Ghia, A.J.; Levin, E.D.; and Swartzwelder, H.S. Binge pattern ethanol exposure in adolescent and adult rats: Differential impact on subsequent responsiveness to ethanol. Alcoholism: Clinical and Experimental Research 24:1251–1256, 2000. PMID: 10968665

White, A.M.; Truesdale, M.C.; Bae, J.G.; et al. Differential effects of ethanol on motor coordination in adolescent and adult rats. Pharmacology, Biochemistry, and Behavior 73:673–677, 2002. PMID: 12151043

Wilson, D.M.; Killen, J.D.; Hayward, C.; et al. Timing and rate of sexual maturation and the onset of cigarette and alcohol use among teenage girls. Archives of Pediatrics and Adolescent Medicine 148:789–795, 1994. PMID: 8044254

Zucker, R.A., and Wong, M.M. Prevention for children of alcoholics and other high risk groups. In: Galanter, M., ed. Recent Developments in Alcoholism, Vol. 17: Alcohol Problems in Adolescents and Young Adults: Epidemiology, Neurobiology, Prevention, Treatment. New York: Springer, 2005. pp. 299– 320. PMID: 15789872