Elsevier

Neuropharmacology

Volume 67, April 2013, Pages 144-154
Neuropharmacology

Distinct roles of methamphetamine in modulating spatial memory consolidation, retrieval, reconsolidation and the accompanying changes of ERK and CREB activation in hippocampus and prefrontal cortex

https://doi.org/10.1016/j.neuropharm.2012.10.020Get rights and content

Abstract

Drugs of abuse modulated learning and memory in humans yet the underlying mechanism remained unclear. The extracellular signal-regulated kinase (ERK) and the transcription factor cAMP response element-binding protein (CREB) were involved in neuroplastic changes associated with learning and memory. In the current study, we used a Morris water maze to examine the effect of methamphetamine (METH) on different processes of spatial memory in mice. We then investigated the status of ERK and CREB in the hippocampus and prefrontal cortex (PFC). We found that 1.0 mg/kg dose of METH facilitated spatial memory consolidation when it was injected immediately after the last learning trial. In contrast, the same dose of METH had no effect on spatial memory retrieval when it was injected 30 min before the test. Furthermore, 1.0 mg/kg dose of METH injected immediately after retrieval had no effect on spatial memory reconsolidation. Activation of both ERK and CREB in the hippocampus was found following memory consolidation but not after retrieval or reconsolidation in METH-treated mouse groups. In contrast, activation of both ERK and CREB in the PFC was found following memory retrieval but not other processes in METH-treated mouse groups. These results suggested that METH facilitated spatial memory consolidation but not retrieval or reconsolidation. Moreover, activation of the ERK and CREB signaling pathway in the hippocampus might be involved in METH-induced spatial memory changes.

Highlights

► METH facilitates spatial memory consolidation. ► METH has no effect on spatial memory retrieval or reconsolidation. ► Hippocampal ERK/CREB pathway may be involved in METH-induced memory changes.

Introduction

Psychostimulants was shown to enhance learning and memory (Carmack et al., 2010; Huang et al., 2009; Iñiguez et al., 2011; Kennedy et al., 2010), yet the underlying mechanism remained unclear. Previous studies focused on effects of amphetamine-type stimulates on different forms of memories (Blaiss and Janak, 2007; Kennedy et al., 2010; McGaugh, 2000; Simon and Setlow, 2006; Wiig et al., 2009), which suggested that amphetamine and methamphetamine (METH) could improve cognitive function in schizophrenia (Barch and Carter, 2005; Sahakian and Morein-Zamir, 2007), addictive (Berke and Hyman, 2000; Mahoney III et al., 2010) and healthy individuals (Barch and Carter, 2005; Greely et al., 2008; Sahakian and Morein-Zamir, 2007; Silber et al., 2006). Amphetamine was therefore illicitly used as cognitive enhancers in both university students (Greely et al., 2008; Sahakian and Morein-Zamir, 2007) and military pilots (Caldwell et al., 2003). Animal studies also found that acute low-dose amphetamine, METH or cocaine could facilitate memory performance (Kennedy et al., 2010; Wood et al., 2007), especially the consolidation of memory (Iñiguez et al., 2011; Wiig et al., 2009). Memory impairment was also detected in both humans and rodents which had been exposed to METH (Belcher et al., 2007; Kalechstein et al., 2003; Nordahl et al., 2003; Simon et al., 2000; Vorhees et al., 2009). Nevertheless, the effects of METH on specific memory processes and the molecular mechanism remained unclear.

Learning and memory was thought to include three processes which were attention/encoding, storage/consolidation and retrieval/recall (Clayton, 2000; Dudai, 2004; Horn, 2004). Briefly, pre-encoded events or information were then stabilized as a memory trace in the brain which was defined as the process of consolidation (Dudai, 2004), and this process was followed by retrieval of memory which referred to the subsequent re-accessing of an encoded and stored memory trace (Muzzio et al., 2009). The retrieval of a memory trace could then induce an additional labile phase named reconsolidation which referred to the stabilization of memory after retrieval (Tronson and Taylor, 2007). Consolidation, retrieval and reconsolidation were necessary and critical processes for memory storage or expression and could be distinguished by different behavioral models. Although previous studies demonstrated that METH could modulate learning and memory, the effects of METH on different memory processes remained unclear. Previous studies found that hippocampus and prefrontal cortex (PFC) were involved in the modulation of different processes of spatial learning and memory (Duva et al., 1997; Maviel et al., 2004; Nadel, 1991) and Morris water maze (MWM) was a commonly used behavioral paradigm for studying the neurobiology mechanism underlying distinct processes of spatial learning and memory (Iñiguez et al., 2011; Vorhees and Williams, 2006; Williams et al., 2003). Drugs were usually treated immediately after training (Dudai, 2004; Iñiguez et al., 2011) or memory test (Miller and Marshall, 2005) to study effects of drugs on memory consolidation and reconsolidation, or pretreated 30 min before memory test (Miller and Marshall, 2005) to study effects of drugs on memory retrieval.

The extracellular signal-regulated kinase (ERK) signal pathway was involved in neuroplasticity (Sweatt, 2001; Tronson and Taylor, 2007; Mazzucchelli and Brambilla, 2000) and spatial learning and memory (Xing et al., 2010). METH induced the phosphorylation of ERK in the striatum (Mizoguchi et al., 2004) and inhibition of ERK kinase MEK blocked the establishment of conditioned place preference induced by METH, cocaine and amphetamine (Gerdjikov et al., 2004; Miller and Marshall, 2005; Mizoguchi et al., 2004; Valjent et al., 2000). Once activated, ERK affected cellular function in multiple ways, including phosphorylation of membrane and cytosolic proteins and transcription and translational controls (Kelleher et al., 2004; Sweatt, 2001). CREB was one of the most prominent transcription factors capable of mediating a variety of neuronal functions (Sakamoto et al., 2011). Pharmacological studies indicated that inhibition of ERK was accompanied by attenuated CREB activation and contextual memory (Fricks-Gleason and Marshall, 2010; Miller and Marshall, 2005; Mizoguchi et al., 2004). Taken together, these results suggested that the ERK and CREB signal pathway might contribute to METH-induced memory alterations.

In the current study, we used the MWM to examine the roles of METH on spatial memory consolidation, retrieval and reconsolidation in mice. We also examined the status of ERK and CREB in the hippocampus and PFC in each behavioral context. Our results suggested that METH had distinct role in spatial memory processes and activation of the ERK and CREB signal pathway in the hippocampus might be involved in METH-induced spatial memory changes.

Section snippets

Animals

Male C57BL/6 mice were purchased from Beijing Vital River Laboratory Animal Technology Co. Ltd. 7–9 week-old mice (weighing about 20–25 g) were used in our experiment. Four animals per cage were housed in a regulated environment (23 ± 1 °C, 50 ± 5% humidity) with a 12:12 h light/dark cycle (lights on at 07:00) with food and water available ad libitum. Animals were allowed to habituate in the room for one week before experimental manipulations were undertaken. All experimental procedures were

Memory consolidation

In order to investigate effects of 1.0 mg/kg dose of METH on spatial memory consolidation, two groups of mice were injected with 1.0 mg/kg METH or saline immediately after four days of training and their memories were tested 24 h later. Two way repeated measures ANOVA of escape latencies revealed significant effects of time [F(3,36) = 25.347, p < 0.001], but not group [F(1,12) = 0.078, p > 0.05] and their interaction [F(3,36) = 0.714, p > 0.05] (Fig. 1A). All mice gradually learned to locate

Discussion

As a highly addictive drug (Herrold et al., 2009; Mizoguchi et al., 2004), METH was proved to induce cognitive functional alterations in both humans (Mahoney III et al., 2010) and rodents (Belcher et al., 2007; Kamei et al., 2006; Skelton et al., 2008; Vorhees et al., 2009; Williams et al., 2003). Previous studies mainly focused on the neurotoxic effects of METH, which found that high doses of METH in binge (4–25 mg/kg given 4 times a day) or escalating (10 mg/kg–30 mg/kg) treatment regimens

Conclusions

In conclusion, our current results demonstrated that 1.0 mg/kg dose of METH facilitated spatial memory consolidation but not retrieval or reconsolidation, and the ERK and CREB signaling pathway in the hippocampus might be involved in METH-induced spatial memory changes.

Acknowledgments

We do not have any conflict of interest. Guofen Cao, Jie Zhu, Qing Zhong, Chaofeng Shi, Yonghui Dang, Wei Han, Xinshe Liu performed the described experiments and data analyses. Ming Xu and Teng Chen designed the experiments and helped to analyze the results. Guofen Cao, Jie Zhu, Ming Xu and Teng Chen wrote the manuscript. This project was supported by a grant from the National Natural Science Foundation of China (No. 30973365), and a grant from the Ministry of Science and Technology of China (

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