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Alcohol exposure induces multiple neuroadaptive changes in the CNS that can have serious long-term consequences on CNS function including cognitive effects and attenuation of learning and memory. The cellular mechanisms underlying the CNS effects of alcohol have yet to be fully elucidated and are likely to depend on the pattern and dose of alcohol exposure. Using electrophysiological recordings from hippocampal slices obtained from control and chronic alcohol-treated rats, we have investigated the effects of a binge pattern of alcohol abuse on synaptic plasticity in the CNS. The alcohol-treated animals were exposed to ethanol vapor for 12-14 days using an intermittent exposure paradigm (14 h ethanol exposure/10 h ethanol withdrawal daily; blood alcohol levels approximately 180 mg/dl), a paradigm that models human binge alcohol use. Induction of long-term potentiation (LTP) in the CA1 region of the hippocampus by tetanic stimulation of Schaffer collaterals was completely blocked in slices from the chronic alcohol-treated animals. LTP remained blocked 1 day after withdrawal of animals from alcohol, indicating that the neuroadaptive changes produced by alcohol were not readily reversible. Partial recovery was observed after withdrawal from alcohol for 5 days. Other measures of synaptic plasticity including posttetanic potentiation and paired-pulse facilitation were also altered by the intermittent alcohol treatment paradigm. The results suggest that alterations in synaptic plasticity induced by chronic intermittent ethanol consumption play an important role in the effects of binge alcohol use on learning and memory function.

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Using electrophysiological and biochemical approaches, we investigated the effects of chronic, intermittent ethanol (CIE) treatment on activation of the mitogen activated protein kinase (MAPK), also known as extracellular signal regulated protein kinase 1 and 2. In hippocampal slices taken from control rats, brief high-frequency stimulation to Schaffer collateral fibers induced a large post-tetanic potentiation (PTP) in the CA1 region that decayed to stable long-term potentiation (LTP) of field extracellular postsynaptic potentials. Western blot analyses showed that phosphorylation of MAPK was increased during PTP and returned to baseline levels during LTP. In slices from the rats removed immediately from CIE treatment, PTP and MAPK activation during the PTP was significantly less than that observed in control slices and LTP was absent. In slices from rats subjected to 1 day withdrawal from CIE treatment, both the reduction in MAPK phosphorylation during PTP and the impairment of PTP and LTP were still evident. Recovery of PTP and partial recovery of LTP was observed in slices obtained from 5-day withdrawn rats. However, MAPK activation during PTP was still attenuated significantly. Interestingly, MAPK activation was enhanced significantly during LTP in 5-day withdrawn rats as well as the sensitivity to MAPK inhibitor PD 098059. In addition to these changes in HFS-induced MAPK activation, we also observed a significant reduction in the basal phosphorylation of MAPK in slices removed from rats immediately after CIE treatment. These results implicate the MAPK signal transduction pathway as a potential cellular target of ethanol. Alterations in MAPKs could play an important role in the alcohol-induced changes in synaptic plasticity associated with the effects of alcohol abuse on learning and memory processes.

The cytokine interleukin-6 (IL-6) is chronically expressed at elevated levels within the CNS in many neurological disorders and may contribute to the histopathological, pathophysiological, and cognitive deficits associated with such disorders. However, the effects of chronic IL-6 exposure on neuronal function in the CNS are largely unknown. Therefore using intracellular recording and calcium imaging techniques, we investigated the effects of chronic IL-6 exposure on the physiological properties of cerebellar Purkinje neurons in primary culture. Two weeks of exposure to 1,000 units/ml (U/ml) IL-6 resulted in altered electrophysiological properties of Purkinje neurons, including a significant reduction in action potential generation, an increase in input resistance, and an enhanced electrical response to the ionotropic glutamate receptor agonist, alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) compared with untreated neurons. Lower concentrations of IL-6 (100 and 500 U/ml) had no effects on these electrophysiological parameters. However, neurons exposed to 500 U/ml chronic IL-6 resulted in significantly elevated resting levels of intracellular calcium as well as an increase in the intracellular calcium signal of Purkinje neurons in response to AMPA, effects not observed in neurons exposed to 1,000 U/ml chronic IL-6. Morphometric analysis revealed a lack of gross structural changes following chronic IL-6 treatment, such as in the number, size, and extent of dendritic arborization of Purkinje neurons in culture. Using immunohistochemistry, we found that cultured Purkinje neurons express both the IL-6 receptor and its intracellular signaling subunit, gp130, indicating that IL-6 may act directly on Purkinje neurons to alter their physiological properties. The present data show that chronic exposure to elevated levels of IL-6, such as occurs in various neurological diseases, produces alterations in several important physiological properties of Purkinje neurons and that these changes occur in the absence of neuronal toxicity, damage, or death. The results support the hypothesis that chronic IL-6 exposure can disrupt normal CNS function and thereby contribute to the pathophysiology associated with many neurological diseases.