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This review summarizes new findings on the bidirectional interactions between alcohol and the clock genes, underlying the generation of circadian rhythmicity. At the behavioral level, both adult and perinatal ethanol treatments after the free-running period and light response of the circadian clock in rodents; genetic ethanol preference in alcohol-preferring rat lines is also associated with alterations in circadian pacemaker function. At the neuronal level, it has been shown that ethanol consumption alters the circadian expression patterns of period (per) genes in various brain regions, including the suprachiasmatic nucleus. Notably, circadian functions of beta-endorphin-containing neurons that participate in the control of alcohol reinforcement become disturbed after chronic alcohol intake. In turn, per2 gene activity regulates alcohol intake through its effects on the glutamatergic system through glutamate reuptake mechanisms and thereby may affect a variety of physiological processes that are governed by our internal clock. In summary, a new pathologic chain has been identified that contributes to the negative health consequences of chronic alcohol intake. Thus, chronic alcohol intake alters the expression of per genes, and as a consequence, a variety of neurochemical and neuroendocrine functions become disturbed. Further steps in this pathologic chain are alterations in physiological and immune functions that are under circadian control, and, as a final consequence, addictive behavior might be triggered or sustained by this cascade.

Background: Onset of alcohol use during adolescence has potentially long-lasting consequences, e.g., prospective alcohol dependence. To obtain new insight into the effects of early chronic ethanol consumption, we compared the drinking behavior of two adult male Wistar rat groups: one that initiated alcohol consumption during adolescence (adolescent group) and the other that initiated their drinking during adulthood (adult group) in a model of long-term alcohol self-administration. We investigated the magnitude of the effects of deprivation and stress on alcohol intake and the influence of these events on the alcohol drinking behavior across time. Methods: Heterogeneous Wistar rats aged 31 days (adolescents) and 71 days (adults) were given ad libitum access to water, as well as 5% and 20% ethanol solutions during an observation period of 30 wk. A deprivation phase of 14 days was instituted after eight wk of access to alcohol. After 16 and 26 wk of alcohol access, all animals were subjected for three consecutive days to forced swimming and electric foot shocks, respectively. Results: At the onset of drinking, adolescent animals consumed less alcohol and showed lower preference than adults. The deprivation phase was followed by increased intake of highly concentrated ethanol solution without appreciable differences between age groups. Repeated swim stress produced a slight increase in ethanol consumption in both animal groups; however, alcohol intake was not significantly different between groups, whereas the foot shock stress-induced increase in alcohol intake was significantly higher in the animal group that initiated alcohol consumption during adolescence. After swim stress, the drinking behavior of the adolescent group resembled that of the adult group. In particular, the adolescent group increased their preference for 20% ethanol solution for the remainder of the experiment. Conclusions: Age of voluntary alcohol drinking onset does not appear to be a strong predictor for prospective alcohol intake and relapse-like drinking behavior under the present experimental conditions. However, male Wistar rats that initiated alcohol consumption during adolescence seem to be more susceptible to acute stressor-specific effects in terms of alcohol consumption.

BACKGROUND: Exposure of the developing brain to ethanol disposes the fetus to fetal alcohol syndrome and causes a number of changes in several neurochemical systems. In particular, the glutamatergic system is affected by ethanol. Thus, increased sensitivity of glutamate receptors and enhanced transmembrane transport of glutamate were found in primary astrocyte cultures. However, in these in vitro studies, changes in the expression of glutamate transporters were not detected. To further characterize the influence of chronic ethanol exposure on the developing brain, we assessed the transcriptional and translational regulation of glutamate transporters in a less artificial in vitro system. METHODS: We exposed postnatal rat cortical organotypic slice cultures to ethanol (100 mM) for 4 and 8 days. Expression of the excitatory amino acid transporters EAAT1 and EAAT2 was analyzed in comparison to untreated controls with semiquantitative reverse transcriptase-polymerase chain reaction. In addition, changes in protein expression were detected by Western blotting. RESULTS: In ethanol-exposed cortical slices, we observed more prominent fiber outgrowth and significantly increased gene expression (EAAT1: +35%, p = 0.029; EAAT2: +251%, p = 0.015). These findings could be verified on the protein level, because Western blot analysis revealed significantly higher levels of EAAT1 (+76%; p = 0.008) and EAAT2 (+104%; p = 0.018) in ethanol-treated slices compared with controls. CONCLUSIONS: Our results are in concert with earlier studies describing the induction of glutamate transport by ethanol. Enhanced expression of EAAT1 and EAAT2 after ethanol exposure can be viewed as a maladaptive process that disposes the developing brain to fetal alcohol syndrome.