Abstract
Aim:
The dorsal striatum has been proposed to contribute to the formation of drug-seeking behaviors, leading to excessive and compulsive drug usage, such as addiction. The current study aimed to investigate the involvement of extracellular signal-regulated kinase (ERK) pathway in the modification of striatal synaptic plasticity.
Methods:
Ethanol was administered to rats in drinking water at concentration of 6% (v/v) for 30 days. Rats were sacrificed on day 10, 20, or 30 during ethanol intake or on withdrawal day 1, 3, or 7 following 30-d ethanol intake. The striata were removed either for electrophysiological recording or for protein immuno-blot analysis. Extracellular recording technique was used to record population spikes (PS) induced by high-frequency stimulation (HFS) in the dorsolateral striatum (DLS).
Results:
Corticostriatal long-term depression (LTD) was determined to be dependent upon ERK signaling. Chronic ethanol intake (CEI) attenuated ERK phosphorylation and LTD induction, whereas withdrawal for one day (W1D) potentiated ERK phosphorylation and LTD induction. These results showed that the impact of chronic ethanol intake and withdrawal on corticostriatal synaptic plasticity was associated with ethanol's effect on ERK phosphorylation. In particular, pharmacological inhibition of ERK hyper-phosphorylation by U0126 prevented LTD induction in the DLS and attenuated ethanol withdrawal syndrome as well.
Conclusion:
In rat DLS, chronic ethanol intake and withdrawal altered LTD induction via ERK signaling pathway. Ethanol withdrawal syndrome is mediated, at least partly, by ERK hyper-phosphorylation in the DLS.
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Introduction
Addiction is increasingly viewed as a pathological process of learning, involving cell signaling and synaptic mechanisms similar to those implicated in neural models of learning and memory1, 2, 3, 4. Synaptic plasticity is required for neuroadaptations that result from a variety of environmental stimuli. Therefore, it is attractive to hypothesize that drug abuse causes long-term changes in behavior by altering synaptic function and plasticity in relevant brain circuits.
The involvement of the ventral striatum, or nucleus accumbens (NAc), in mediating drug reward and reinforcement is well established2, 4, 5, 6. Recently, it has also been proposed that the dorsal striatum (caudate nucleus and putamen) is likely to be involved in advanced stages of addiction when drug use progresses toward a compulsive, habitual pathology2, 5, 6. Previous work from our lab25. Nevertheless, it is not surprising that LTD was invariably recorded in our experiment, given the use of older rats (2-3 months) and the recording subregion of striatum (DLS).
Although it has been previously shown that ERK phosphorylation is required for both LTP9, 10 and LTD26, 11 in hippocampal CA1 as well as LTD in the cerebellum8 and LTP in other cortical areas12, we provide the first evidence that ERK activation is required for striatal LTD induction.
The ethanol-induced modulation of ERK activity in vitro has been controversial, with potentiation reported by some27, 28 and depression by others29, 30, 31. However, in vivo exposure data are more consistent, revealing an ethanol-induced decrease in ERK activation13, 14, 15, except in the report from Bachtell et al32. Our data are in agreement with previous reports in which chronic ethanol exposure in vivo decreased ERK phosphorylation. It should be noted that in CEI30 groups, the suppression of phospho-ERK levels was, while still significant, attenuated, which may reflect the adaptation or tolerance to long-term alcohol consumption. We also demonstrated an enhancement of ERK phosphorylation briefly after withdrawal14. This may be related to increased neural activity following disinhibition or hyperexcitability caused by ethanol withdrawal.
The mechanisms underlying the effects of chronic ethanol exposure on ERK phosphorylation are still under investigation. However, studies showing the activation of MAP kinase by Ca2+ via NMDA receptors or voltage-dependent Ca2+ channels have been very well documented33, 34, 35. Since ethanol inhibits both voltage-gated Ca2+ channels and NMDA receptor-associated Ca2+ influx36, 37, 38, it is possible that a decrease in the Ca2+ concentration in striatal neurons might decrease the phosphorylation of MAP kinase. Future studies will be required to identify the site and mechanism underlying the effects of ethanol on this pathway.
Anatomical studies have shown projections from the cortex to the medial striatum, including visual, auditory and limbic (ie, hippocampus, entorhinal and piriform cortices) afferents. In contrast, most cortical projections to the lateral striatum are of sensorimotor origin and, to a lesser degree, auditory and visual afferents39. Accordingly, recent studies suggest that the dorsomedial and dorsolateral striata have differential roles in different learning and memory paradigms. The dorsomedial striatum, in particular, has been shown to be critical for the learning of goal-directed actions. In contrast, the dorsolateral striatum appears to be involved in the formation of habits40, 41. By showing that chronic ethanol intake and withdrawal differentially altered synaptic plasticity in dorsolateral striatum through ERK signaling pathway, our findings suggest that chronic alcohol abuse could disrupt the habit-formation process, and this neural maladaptation may consequently lead to habitual drug-seeking behavior.
To summarize, our current studies have shown that induction of corticostriatal LTD in rat is differentially altered by chronic ethanol intake and withdrawal, which occurs through ERK signaling pathway. Understanding the biochemical mechanism underlying chronic ethanol treatment-induced changes in striatal synaptic plasticity may aid in the development of more effective therapeutic agents for alcohol abuse.
Author contribution
**ao-ru YUAN and **g LI designed the research; Sheng-zhong CUI, Shen-jun WANG, Rong ZHOU, and Gui-qin XIE performed the research; Sheng-zhong CUI, **ao-ru YUAN, and Ling CHEN analyzed the data and wrote the paper.
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Acknowledgements
This project was supported by the National Natural Science Foundation of China (No 30572173) and the Natural Science Foundation of the Education Committee of Jiangsu Province, China (No 06KJB180071).
We thank Dr Shang SHEN at University of Nevada, Las Vegas, for critical reading of the manuscript.
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Cui, Sz., Wang, Sj., Li, J. et al. Alteration of synaptic plasticity in rat dorsal striatum induced by chronic ethanol intake and withdrawal via ERK pathway. Acta Pharmacol Sin 32, 175–181 (2011). https://doi.org/10.1038/aps.2010.199
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DOI: https://doi.org/10.1038/aps.2010.199
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