Neurobiology of Alcohol and Inhalant Abuse

National Institute On Drug Abuse

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Abstract

In many societies, alcohol consumption is characterized by bouts of moderate drinking that may damage the brain and impair cognition. Abstract thinking, cognitive flexibility and inhibition of competing responses are impaired after binge alcohol consumption and binge drinking has been proposed as a risk factor for the development of dementia. Recent studies in experimental animals suggest that alcohol-induced deficits in cognition may be a critical factor underlying the habitual drug seeking and taking that characterizes addiction. Most studies examining ethanol-evoked alterations in learning and memory in experimental animals have typically administered high doses of ethanol intragastrically over a period of days or via a liquid diet for periods of weeks or months. Although clear deficits in learning and memory are observed, the doses employed typically produce blood ethanol concentrations equivalent to those observed in human heavy drinkers. Importantly, however, blood ethanol concentrations of binge drinkers are often significantly lower. Fundamental questions exist as to whether repeated exposure of rats to a moderate dose of ethanol that produces blood ethanol concentrations similar to those produced in humans following binge ethanol intoxication leads to cognitive impairment and increased ethanol consumption. To address this issue, male Wistar rats received ethanol or an equivalent volume of water once daily by gavage for 6 days. The dose of ethanol and treatment regimen employed produces blood ethanol concentrations (150-190 mg/dl) analogous to those observed in humans following repeated bouts of moderate dose ethanol consumption. Alterations in spatial learning and memory were analyzed using the Barnes maze. Since clinical studies have shown that cognitive performance improves during the course of abstinence, performance was analyzed at two time points: 3-6 days and 11-14 days after the cessation of ethanol exposure. The influence of the ethanol treatment regimen on the acquisition of operant ethanol self-administration and deprivation-evoked ethanol consumption was also assessed. Ethanol treated rats exhibited somatic signs of withdrawal five, but not twenty-four hrs, following treatment cessation. Spatial learning and memory, as assessed in the Barnes maze, were markedly impaired 3-6 days following the cessation of ethanol treatment. Consistent with recovery of cognitive function in human subjects following protracted abstinence, error rate and escape latency returned to control values at later time points. Reversal learning, however, was impaired throughout the two week observation period. Operant oral self-administration studies that commenced 48 hrs after the cessation of the ethanol treatment regimen revealed no difference between groups in ethanol consumption or the rate of acquisition of self-administration. In contrast, however, to controls, ethanol pre-exposed rats exhibited a significant increase in ethanol consumption following periods of ethanol deprivation. These data demonstrate that bouts of moderate dose ethanol administration are sufficient to promote cognitive inflexibility and increase deprivation-evoked ethanol consumption. It is suggested that impairment of spatial learning, memory and reversal learning in rats, which are thought to result from functional aberrations in hippocampal/cortical neurotransmission, may model, respectively, transient and long-lasting cognitive impairment in human binge alcohol drinkers. Finally, these data provide suggestive evidence that repeated, moderate dose ethanol exposure may lead to cognitive deficits and an enhanced propensity to develop alcohol dependence in humans. Kappa opioid receptors (KOPr) and dynorphin, the endogenous KOPr ligand, are enriched in the hippocampus and serve an important function in regulating hippocampal neuronal activity. Our collaborators (NIH and Karolinska Institute Collaborative Program In Postgraduate Education)have obtained evidence that tissue levels of dynorphin, as well as the expression of prodynorphin, the gene encoding dynorphin, are elevated in the hippocampus of human alcoholics. In contrast, other opioid peptides systems are unaltered. KOPr is located on glutamatergic neurons in the hippocampus and modulates glutamate release. Both glutamate and dynorphin have been implicated in the modulation of long-term depression (LTD), a form of synaptic plasticity which is important for learning. Importantly, however, excess glutamate is toxic to neurons and can impair learning and memory. Given the role of the dynorphin/KOPr pathway in synaptic plasticity we have examined whether up-regulation of this opioid system contributes to deficits in cognition produced by alcohol and/or alcohol-evoked alterations in hippocampal neurochemistry. For these studies we employed the 6 day ethanol treatment regimen described above, Animals then received a selective and long-acting, KOPr antagonist following the cessation of treatment. Hippocampal-dependent memory deficits were assessed. Microdialysis was used to quantify glutamate and GABA dynamics in the hippocampus of ethanol treated and control animals. Results of these studies have revealed that systemic adminsitration of KOPr antagonists following repeated, binge alcohol administration prevents memory deficits produced by ethanol. Similar effects are observed in response to the selective blockade of KOPr in the CA3 region indicating that blockade of KOPr in this region is sufficient to prevent the neurotoxic effects of alcohol. Using conventional and quantitative microdialysis (see Chefer et al., 2007 for review), we have found that alcohol-evoked deficits in hippocampal dependent memory are associated with increases in basal and depolarization-evoked glutamate release in the CA3 region of the hippocampus and that these neurochemical changes are prevented by administration of a selective KOPr antagonist. In contrast, to glutamate dynamics, GABA dynamics were unchanged. Blood alcohol concentrations are unaffected by KOPr antagonists suggesting that a pharmacodynamic mechanism underlies the protective effects of KOPr antagonist treatment. Ethanol activate several kinase cascades that have been implicated in cell death. We used Western blotting to determine whether these cascades are altered in ethanol treated animals relative to controls. No alteration in either p38 MAP kinase or ERK kinases were observed suggesting that activation of these cascades does not contribute to ethanol evoked cognitive deficits. Together, these data suggest an important role of the DYN/KOPr system in alcohol-evoked hippocampal neurotoxicity.