Upregulated dynorphin opioid peptides mediate alcohol-induced learning and memory impairment

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.

Role of the Dynorphin/Kappa Opioid Receptor System in the Motivational Effects of Ethanol

“…The DYN/KOR system has also been linked to EtOH‐related cognitive impairment. One study conducted in Wistar rats found that 6 days of forced binge‐like EtOH administration resulted in cognitive deficits (i.e., increased escape latency) in a water maze task and elevated DYN levels in the hippocampus (Kuzmin et al., ). Treatment with nor‐BNI (either systemic or in the dorsal CA3 region of the hippocampus) restored escape behavior in the EtOH‐exposed rats whereas systemic nor‐BNI did not enhance performance in control subjects (Kuzmin et al., ).…”

“…One study conducted in Wistar rats found that 6 days of forced binge‐like EtOH administration resulted in cognitive deficits (i.e., increased escape latency) in a water maze task and elevated DYN levels in the hippocampus (Kuzmin et al., ). Treatment with nor‐BNI (either systemic or in the dorsal CA3 region of the hippocampus) restored escape behavior in the EtOH‐exposed rats whereas systemic nor‐BNI did not enhance performance in control subjects (Kuzmin et al., ). In accordance with these preclinical findings, a comparison of postmortem human brain tissue in alcoholic and control subjects revealed greater expression of prodynorphin and KOR mRNA in areas implicated in the cognitive control of addictive behavior—dorsolateral PFC, orbitofrontal cortex, and hippocampus (Bazov et al., ).…”

“…One day of intragastric binge‐like EtOH exposure (4.5 g/kg total) was sufficient to elevate prodynorphin mRNA expression in both the amygdala and prefrontal cortex of adult Sprague Dawley rats (D'Addario et al., ). Six days of intragastric EtOH exposure (4.3 g/kg/d) resulted in elevated DYN‐A and DYN‐B in the hippocampus of Wistar rats 3 or 7 days after the final exposure (Kuzmin et al., ). Acute injection (1 g/kg) or 1 month of voluntary EtOH consumption both resulted in elevated DYN mRNA and peptide levels in the paraventricular nucleus of the hypothalamus in rats (Chang et al., ).…”

Kappa opioid receptor signaling in the brain: Circuitry and implications for treatment

“…In addition, Dynorphin activates an inwardly rectifying potassium channel as well as voltage gated potassium channels (Wimpey & Chavkin 1991), including functioning to inhibit M current, a voltage-dependent potassium current, in CA1 neurons (Madamba et al 1999). Administration of the KOR antagonist norBNI directly into the HIPP reversed ethanol-induced changes in glutamate transmission (Kuzmin et al 2013). Bilkei-Gorzo et al showed that mice lacking dynorphin show increased partner recognition; in addition, when exposed to object or social recognition paradigms, mice showed increased Dynorphin-A immunoreactivity in the hippocampus, central amygdala, and basolateral amygdala (Bilkei-Gorzo et al 2014).…”

A functional polymorphism in the prodynorphin gene affects cognitive flexibility and brain activation during reversal learning

“…It may also inhibit the release of glutamate, GABA (Hjelmstad and Fields, 2001 , 2003 ), and serotonin (5-HT) (Pinnock, 1992 ; Tao and Auerbach, 2005 ). In terms of behavior, various studies across different species have demonstrated effects of dynorphins on memory, learning, and cognitive functions (Colombo et al, 1992 ; Yakovleva et al, 2007 ; Kölsch et al, 2009 ; Tejeda et al, 2012 ; Kuzmin et al, 2013 ; Bilkei-Gorzo et al, 2014 ). Dynorphins may also contribute to aberrant habit formation in humans, as shown by their link to drug consumption and addiction (Everitt et al, 2001 ; Hyman and Malenka, 2001 ; Shippenberg et al, 2007 ).…”