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

Kuzmin A, Chefer V, Bazov I, Meis J, Ögren SO, Shippenberg T, Bakalkin G - Transl Psychiatry (2013)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroscience, Karolinska Institute, Stockholm, Sweden.

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.

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Effects of ethanol administration on rat performance in the WMT. Rats were treated daily for 6 days with water or ethanol followed by the WMT initiated in 2 days after the last water/ethanol administration. (a) Escape latencies (s); the upper and lower right panels show escape latencies (s) for the first and last daily trials. ANOVA: water, time effect F(4, 888)=10.3, P<0.01; ethanol, treatment × time: F(4, 888)=3.68, P<0.05. (b) Swim speed (cm s−1). ANOVA: ethanol, F(4, 888)=0.77, P=0.42. (c) Time in the platform associated quadrant (% to total time of swimming). ANOVA: water, time effect F(4, 888)=14.6, P<0.01; ethanol, treatment × time: F(4, 888)=2.66, P<0.05. The data for the retention trials (RT) are shown as bar graphs associated with and on the same scale as the acquisition curves. Data are shown as mean±s.e.m. n=42 and 27 rats treated with ethanol and water, respectively. *P<0.05; the Newman–Keuls test was used.
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fig1: Effects of ethanol administration on rat performance in the WMT. Rats were treated daily for 6 days with water or ethanol followed by the WMT initiated in 2 days after the last water/ethanol administration. (a) Escape latencies (s); the upper and lower right panels show escape latencies (s) for the first and last daily trials. ANOVA: water, time effect F(4, 888)=10.3, P<0.01; ethanol, treatment × time: F(4, 888)=3.68, P<0.05. (b) Swim speed (cm s−1). ANOVA: ethanol, F(4, 888)=0.77, P=0.42. (c) Time in the platform associated quadrant (% to total time of swimming). ANOVA: water, time effect F(4, 888)=14.6, P<0.01; ethanol, treatment × time: F(4, 888)=2.66, P<0.05. The data for the retention trials (RT) are shown as bar graphs associated with and on the same scale as the acquisition curves. Data are shown as mean±s.e.m. n=42 and 27 rats treated with ethanol and water, respectively. *P<0.05; the Newman–Keuls test was used.

Mentions: Spatial learning and memory analyzed on the WMT are hippocampally dependent and sensitive to ethanol treatment.8, 33, 44 Escape latencies (averaged for four daily trials) significantly decreased over the five blocks of training in water-treated group while this decline was affected by ethanol treatment (Figure 1a). The differences were significant on day 3 to day 5 of training. Effects of ethanol were not attributed to the decrease in swim speed because ethanol treatment did not change this parameter (Figure 1b). Analysis of the spatial distribution of swimming revealed that the increase in quadrant selectivity over the five blocks of training observed in the water-treated group was significantly reduced by ethanol treatment (Figure 1c). Latency to reach the position of the platform was increased, and percentage of time in the correct quadrant was reduced by ethanol treatment in the probe tests conducted 4 h after the final training block (Figures 1a and c). Between-trial analysis revealed that impairment of learning (latency to escape) in ethanol-treated rats was evident for the first but not for the last daily trials (Figure 1a; treatment × time interaction for the first trial (upper right panel), (F(4,112)=4.2, P<0.05); for the last trial (lower right panel), nonsignificant) suggesting that ethanol-induced cognitive impairment is related to the retrieval deficit. Experiment with the visible platform revealed no differences between ethanol- (n=6) and water- (n=6) treated rats (ANOVA: time × treatment interaction, P=0.7) in the latency to navigate to the platform. Thus, the ethanol treatment did not affect the sensory and motor systems (abilities to navigate using local and distal cues and swim) or the motivation to escape from water.


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

Kuzmin A, Chefer V, Bazov I, Meis J, Ögren SO, Shippenberg T, Bakalkin G - Transl Psychiatry (2013)

Effects of ethanol administration on rat performance in the WMT. Rats were treated daily for 6 days with water or ethanol followed by the WMT initiated in 2 days after the last water/ethanol administration. (a) Escape latencies (s); the upper and lower right panels show escape latencies (s) for the first and last daily trials. ANOVA: water, time effect F(4, 888)=10.3, P<0.01; ethanol, treatment × time: F(4, 888)=3.68, P<0.05. (b) Swim speed (cm s−1). ANOVA: ethanol, F(4, 888)=0.77, P=0.42. (c) Time in the platform associated quadrant (% to total time of swimming). ANOVA: water, time effect F(4, 888)=14.6, P<0.01; ethanol, treatment × time: F(4, 888)=2.66, P<0.05. The data for the retention trials (RT) are shown as bar graphs associated with and on the same scale as the acquisition curves. Data are shown as mean±s.e.m. n=42 and 27 rats treated with ethanol and water, respectively. *P<0.05; the Newman–Keuls test was used.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3818015&req=5

fig1: Effects of ethanol administration on rat performance in the WMT. Rats were treated daily for 6 days with water or ethanol followed by the WMT initiated in 2 days after the last water/ethanol administration. (a) Escape latencies (s); the upper and lower right panels show escape latencies (s) for the first and last daily trials. ANOVA: water, time effect F(4, 888)=10.3, P<0.01; ethanol, treatment × time: F(4, 888)=3.68, P<0.05. (b) Swim speed (cm s−1). ANOVA: ethanol, F(4, 888)=0.77, P=0.42. (c) Time in the platform associated quadrant (% to total time of swimming). ANOVA: water, time effect F(4, 888)=14.6, P<0.01; ethanol, treatment × time: F(4, 888)=2.66, P<0.05. The data for the retention trials (RT) are shown as bar graphs associated with and on the same scale as the acquisition curves. Data are shown as mean±s.e.m. n=42 and 27 rats treated with ethanol and water, respectively. *P<0.05; the Newman–Keuls test was used.
Mentions: Spatial learning and memory analyzed on the WMT are hippocampally dependent and sensitive to ethanol treatment.8, 33, 44 Escape latencies (averaged for four daily trials) significantly decreased over the five blocks of training in water-treated group while this decline was affected by ethanol treatment (Figure 1a). The differences were significant on day 3 to day 5 of training. Effects of ethanol were not attributed to the decrease in swim speed because ethanol treatment did not change this parameter (Figure 1b). Analysis of the spatial distribution of swimming revealed that the increase in quadrant selectivity over the five blocks of training observed in the water-treated group was significantly reduced by ethanol treatment (Figure 1c). Latency to reach the position of the platform was increased, and percentage of time in the correct quadrant was reduced by ethanol treatment in the probe tests conducted 4 h after the final training block (Figures 1a and c). Between-trial analysis revealed that impairment of learning (latency to escape) in ethanol-treated rats was evident for the first but not for the last daily trials (Figure 1a; treatment × time interaction for the first trial (upper right panel), (F(4,112)=4.2, P<0.05); for the last trial (lower right panel), nonsignificant) suggesting that ethanol-induced cognitive impairment is related to the retrieval deficit. Experiment with the visible platform revealed no differences between ethanol- (n=6) and water- (n=6) treated rats (ANOVA: time × treatment interaction, P=0.7) in the latency to navigate to the platform. Thus, the ethanol treatment did not affect the sensory and motor systems (abilities to navigate using local and distal cues and swim) or the motivation to escape from water.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroscience, Karolinska Institute, Stockholm, Sweden.

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.

Show MeSH
Related in: MedlinePlus