Abstract
The dynorphin opioid peptides control glutamate neurotransmission in the hippocampus. Alcohol-induced dysregulation of this circuit may lead to impairments in spatial learning and memory. This study examines whether changes in the hippocampal dynorphin and glutamate systems are related, and contribute to impairment of spatial learning and memory in a rat model of cognitive deficit associated with alcohol binge drinking. Hippocampal dynorphins (radioimmunoassay) and glutamate (in vivo microdialysis) were analyzed in Wistar rats exposed to repeated moderate-dose ethanol bouts that impair spatial learning and memory in the Water Maze Task (WMT). The highly selective, long-acting κ-opioid receptor (KOR) antagonist nor-binaltorphimine (nor-BNI) was administered systemically or into the hippocampal CA3 region to test a role of dynorphins in alcohol-induced dysregulations in glutamate neurotransmission and behavior in the WMT. The ethanol treatment impaired learning and memory, upregulated dynorphins and increased glutamate overflow in the CA3 region. Administration of nor-BNI after cessation of ethanol exposure reversed ethanol-induced changes in glutamate neurotransmission in animals exposed to ethanol and normalized their performance in the WMT. The findings suggest that impairments of spatial learning and memory by binge-like ethanol exposure are mediated through the KOR activation by upregulated dynorphins resulting in elevation in glutamate levels. Selective KOR antagonists may correct alcohol-induced pathological processes, thus representing a novel pharmacotherapy for treating of ethanol-related cognitive deficits.
Highlights
IntroductionThe mechanisms of alcohol-induced cognitive impairments remain unknown but they may involve neurodegeneration and/or aberrant neurotransmission
We investigated whether dynorphin levels are altered in the rat model of cognitive deficits induced by binge-like ethanol exposure[26,27] and whether blockade of k-opioid receptor (KOR), a target for dynorphins, prevents alcohol-induced cognitive impairments
The present study found that dynorphins are upregulated in the hippocampus of rats exposed to ethanol that produced spatial memory impairment
Summary
The mechanisms of alcohol-induced cognitive impairments remain unknown but they may involve neurodegeneration and/or aberrant neurotransmission. Several studies indicate that cognitive effects of alcohol are mediated through the dysregulation of the glutamate system in the hippocampus and prefrontal cortex (PFC).[6,7,8] Glutamate neurotransmission in the hippocampus is tonically controlled by the dynorphin opioid peptides[17,18] that have been implicated in cognitive decline.[19,20,21,22,23,24] Administration of synthetic dynorphin into the dorsal hippocampus impairs spatial learning in rats.[19] Dynorphins contribute to age-related and stress-induced deficits in learning and memory.[20,21,22] In elderly humans, prodynorphin (PDYN) gene polymorphisms have a role in memory function.[23] In individuals with Alzheimer’s disease, dynorphins are elevated in the PFC and this increase correlates with neuropathological lesions.[24] In human alcohol-dependent subjects, dynorphins are upregulated in the hippocampus and PFC that may underlie, in part, cognitive impairments including the dysfunctions in cognitive control of addictive behavior and disrupted inhibitory control.[25]
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