Mechanisms involved in the neurotoxic, cognitive, and neurobehavioral effects of alcohol consumption during adolescence
Introduction
Alcohol is one of the first drugs of choice among young people and adolescents, and heavy binge-drinking is becoming increasingly frequent in high school students in different countries. The proportion of high school students consuming alcohol in the United States and the rate of heavy drinking in the last 10 years are very high (Donovan, 2004). Reports from the European School Survey Project on Alcohol and Other Drugs (Hibell et al., 2007; Kuntsche et al., 2004) carried out in 35 European countries, indicate that young people today drink more and with a clearer focus on drunkenness than earlier generations. In south Europe or Mediterranean countries, such as Italy or Spain, there has also been a substantial rise in concern about youth drinking in recent years. One clear trend is a shift to binge-drinking as a natural habit, which is associated with drunkenness, especially among teenagers, in all the “wine cultures” with moderate alcohol consumption (Lopez-Frias et al., 2001, Peretti-Watel et al., 2006, Tur et al., 2003).
A substantial body of evidence in human and experimental animals has demonstrated the vulnerability of the central nervous system to the effects of ethanol and that exposure to ethanol during brain ontogeny can cause irreversible abnormalities in the brain structure and functions (Guerri et al., 2009). Recent studies with magnetic resonance imaging (MRI) have clearly shown that the brain continues to develop throughout adolescence and into adulthood and that the brain undergoes important structural and functional changes in synaptic plasticity and neural connectivity during the juvenile and adolescence periods (Giedd, 2004, Giedd, 2008). These changes concomitantly occur with modifications in certain neurotransmitter systems and hormone secretion, which markedly influence the refinement of certain brain areas and neural circuits. In addition, dynamic processes allow the brain to specialize and sharpen its functions for the specific demands of its environment. By considering the enormous plastic changes occurring in the teenage/adolescent brain maturation stages and the vulnerability of the developing brain to the damaging effects of ethanol, one might expect that alcohol consumption in the juvenile and adolescence stages would have a significant impact on the adult brain functions (Paus et al., 2008).
Recent studies have shown the harmful consequences of alcohol abuse during adolescence. These studies demonstrate that adolescent drinking can induce brain structure abnormalities, deficits in memory, and poor academic performance (Brown and Tapert, 2004, Lopez-Frias et al., 2001, Medina et al., 2008, Nagel et al., 2005, Zeigler et al., 2005). The neurotoxic effects of ethanol have also been confirmed in experimental animals, providing further evidence of the vulnerability of the juvenile brain to the effects of ethanol and the long-term cognitive consequences (e.g., learning and memory processes) of binge-drinking during adolescence (Crews et al., 2000, Pascual et al., 2007).
At the behavioral level, adolescence is characterized by increased sensation-seeking, risk-taking behaviors, low levels of harm avoidance, impulsivity, and anxiety (Blakemore, 2008). These features are associated with changes in the secretion of gonadal steroids and stress-related hormones (Ceccarelli et al., 2007, Witt, 2007), which might explain the initiation pattern of alcohol and drug consumption. Likewise, the relatively late development of the prefrontal cortex (PFC) circuits involved in judgment and inhibitory control may underlie the propensity of adolescents to impulsivity and to ignore the negative consequences of their behavior, both of which could increase the risk of substance abuse.
This article will briefly review the dynamic processes involved in brain maturation during adolescence and will discuss the potential mechanisms by which ethanol impacts brain development and leads to brain impairments and long-term cognitive and behavioral dysfunctions. Specifically, the mechanisms involved in ethanol-induced alterations in the brain structure and cognitive deficits, as well as the neurobiological and neurochemical processes by which early alcohol intake predisposes to the later alcohol abuse, will be addressed.
Section snippets
Structural and functional maturational changes of the brain during adolescence
The human brain undergoes changes in terms of its morphology, volume, composition, and function during brain development and maturation (Dekaban, 1978, Giedd et al., 1999). Important alterations in brain weight occur during fetal and neonatal development but changes in brain structure and functions in childhood and adolescence are more subtle than those in the first 4 years of life (Paus et al., 2001). These changes in functional maturation of the neural pathways connecting individual brain
Human studies
Clinical and experimental studies demonstrate that alcohol affects adolescent and adult brain functions and behaviors differently and that adolescents are more vulnerable to the deleterious effects that alcohol has on brain functions and behavior. Indeed, by using MEDLINE search for the neurological and cognitive effects of underage drinking (Zeigler et al., 2005) and self-administered questionnaire in conjunction with school performance (Lopez-Frias et al., 2001), these studies have reported
Neurochemical mechanisms involved in the vulnerability of adolescents to alcohol abuse and dependence
Another important long-lasting consequence of alcohol use during adolescence is the greater risk of developing alcohol dependence in adulthood. Indeed in both prospective and retrospective human studies, an early onset of alcohol use typically emerges as a reliable predictor of a later problematic use and dependence on alcohol and other drugs (DeWit et al., 2000, Grant and Dawson, 1997, Hawkins et al., 1997, Labouvie et al., 1997). For instance, survey data indicate that the rate of lifetime
Potential role of epigenetic modifications in the long-term effects of early alcohol consumption
Changes in the gene expression in the brain reward regions are thought to contribute to the pathogenesis and persistence of drug addiction. Recent studies suggest that drugs of abuse and related environmental stimuli, such as drug-associated cues or stress, converge on the genome to alter specific gene programs. Specifically, the epigenetic mechanisms that alter the chromatin structure in specific gene promoters can lead to potent and often long-lasting changes in the gene expression, which
Conclusions
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Adolescence is a critical stage of development in which the brain undergoes neuromaturation and reorganization characterized by changes in neurotransmission, plasticity, and synaptic remodeling. The results of human and animal research suggest that alcohol exposure during adolescence adversely affects brain development and maturation, causing brain damage, structural alterations, and cognitive deficits.
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Neurochemical immaturity and the heightened neuroplasticity in the limbic brain regions might
Acknowledgments
The authors thank M. March for helping in the manuscript. This work has been supported by General Direction of Drug-Dependence (GV), the Spanish Ministry of Health (PNSD, G46923421), the Carlos III Institute, the RTA Network (G03/005), Fundación de Investigación Médica Mutua Madrileña, and the Spanish Ministry of Science and Innovation (SAF 2006-02178).
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