The past decade has brought many advances in our understanding of GABA A receptor-mediated ethanol action in the central nervous system. We now know that specific GABA A receptor subtypes are sensitive to ethanol at doses attained during social drinking while other subtypes respond to ethanol at doses attained by severe intoxication. Furthermore, ethanol increases GABAergic neurotransmission through indirect effects, including the elevation of endogenous GABAergic neuroactive steroids, presynaptic release of GABA, and dephosphorylation of GABA A receptors promoting increases in GABA sensitivity. Ethanol's effects on intracellular signaling also influence GABAergic transmission in multiple ways that vary across brain regions and cell types. The effects of chronic ethanol administration are influenced by adaptations in GABA A receptor function, expression, trafficking, and subcellular localization that contribute to ethanol tolerance, dependence, and withdrawal hyperexcitability. Adolescents exhibit altered sensitivity to ethanol actions, the tendency for higher drinking and longer lasting GABAergic adaptations to chronic ethanol administration. The elucidation of the mechanisms that underlie adaptations to ethanol exposure are leading to a better understanding of the regulation of inhibitory transmission and new targets for therapies to support recovery from ethanol withdrawal and alcoholism.

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It is suggested that ethanol exposure during the periadolescent period results in long-term neurobehavioral changes, which lessen a conditioned aversion to ethanol in adulthood. It is suggested that this age-related effect may underlie the increased susceptibility to alcohol-related problems which is negatively correlated with the age of onset for alcohol abuse.

Early postnatal exposure to ethanol (EtOH) that results in daily high-peak blood ethanol concentration (BEC) retarded the acquisition of single-patterned alteration (PA), a kind of memory-based discrimination learning, and was related to reduced brain weight, hippocampal cell number, and CA1 area in infant rats. These behavioral and neuroanatomical effects survived into young adulthood. On the PA discrimination, in both pups and young adults, postnatal exposure to high-peak EtOH condition, in relation to low-peak and control conditions, impaired the acquisition of PA at 60-s but not at 30-s intertrial intervals. These results provide further evidence of hippocampal involvement in intermediate-term memory and indicate that early postnatal EtOH is a behavioral and neuroanatomical teratogen, particularly when the BEC is relatively high.

Repeated ethanol withdrawal experience has been shown to result in exacerbated seizures associated with future withdrawal episodes. This sensitization of the withdrawal response has been postulated to represent a "kindling" phenomenon. The present study employed an established model of repeated ethanol withdrawals to examine the potential role of GABA(A), and NMDA and non-NMDA glutamate receptor systems in mediating enhanced seizure activity, as assessed by sensitivity to seizures induced by pentylenetetrazol (PTZ), NMDA, and kainic acid (KA) i.v. infusions, respectively. Adult C3H mice were chronically exposed to ethanol vapor in inhalation chambers. A multiple withdrawal (MW) group received four cycles of 16-h ethanol vapor exposure interrupted by 8-h periods of abstinence; a single withdrawal (SW) group was tested after a single 16-h bout of ethanol intoxication; and the third group was ethanol-naive, serving as controls (C). Results indicated that the MW group evidenced significantly lower PTZ and NMDA seizure thresholds compared to SW and C groups at 8 and 24 h post-withdrawal. In contrast, MW and SW groups exhibited reduced sensitivity (higher seizure threshold) to KA in comparison to controls, and this effect only emerged at 24 h post-withdrawal. Further, MW mice required significantly less additional PTZ or NMDA to induce more severe convulsions once initial signs of seizures were elicited. Conversely, latency and amount of KA required to transition from initial seizure signs to more severe end-stage convulsions was significantly greater for MW and SW groups compared to controls. Taken together, these results suggest that repeated ethanol withdrawal experience does not result in a global non-specific lowering of threshold to convulsive stimuli, but rather, selective changes in CNS mechanisms associated with neural excitability may underlie potentiated withdrawal responses. Thus, reduced GABA(A) receptor function and increased NMDA receptor activity may become exaggerated as a consequence of repeated withdrawal experience, while reduced sensitivity to KA induced seizures may represent a compensatory response to withdrawal-related CNS hyperexcitability.

Background Adolescent rats are less sensitive to the motor-impairing effects of ethanol than adults. However, the cellular and molecular mechanisms underlying this age dependent effect of ethanol have yet to be fully elucidated. Method Male rats of various ages were used to investigate ethanol-induced ataxia and its underlying cellular correlates. In addition, Purkinje neurons from adolescent and adult rats were recorded both in vivo and in vitro. Finally, PKCγ expression was determine in three brain regions in both adolescent and adult rats. Results The present multi-methodological investigation confirms that adolescents are less sensitive to the motor impairing effects of ethanol, and this differential effect is not due to differential blood ethanol levels. In addition, we identify a particular cellular correlate that may underlie the reduced motor impairment. Specifically, the in vivo firing rate of cerebellar Purkinje neurons recorded from adolescent rats are insensitive to an acute ethanol challenge, while the firing rate of adult cerebellar Purkinje neurons are significantly depressed. Finally, it is demonstrated that PKCγ expression in the cortex and cerebellum mirrors the age-dependent effect of ethanol: adolescents have significantly less PKCγ expression compared to adults. Conclusions Adolescents are less sensitive than adults to the motor-impairing effects of ethanol, and a similar effect is seen with in vivo electrophysiological recordings of cerebellar Purkinje neurons. While still under investigation, PKCγ expression mirrors the age effect of ethanol and may contribute to the age-dependent differences in the ataxic effects of ethanol.

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