Elsevier

Neuroscience

Volume 150, Issue 2, 5 December 2007, Pages 433-441
Neuroscience

Neuropharmacology
Methamphetamine induces alterations on hippocampal NMDA and AMPA receptor subunit levels and impairs spatial working memory

https://doi.org/10.1016/j.neuroscience.2007.09.044Get rights and content

Abstract

Methamphetamine (METH) is a powerful psychostimulant that increases glutamate (Glu) levels in the mammalian brain and it is currently known that hippocampi are particularly susceptible to METH. Moreover, it is well established that the overactivation of N-methyl-d-aspartate (NMDA) and AMPA ionotropic Glu receptors causes excitotoxicity. In the present study, we investigated the effect of acute (30 mg/kg) versus escalating dose (ED) administration of METH on NMDA receptor 1, NMDA receptor 2 and glutamate receptor 2 (GluR2) subunit expression in the hippocampus and on memory. Adult Sprague–Dawley rats were injected s.c. during six consecutive days with saline (control and acute groups) or with a growing dose of METH (10, 15, 15, 20, 20, 25 mg/kg/day; ED group). On the 7th day, both METH groups were injected with a ‘bolus’ of 30 mg/kg METH whereas controls received saline. Western blot analysis showed an increase of GluR2 and NR2A expression levels and no alterations on NR1 subunit in the acute group. On the other hand, in the ED group, GluR2 and NR2A expression levels were unaltered and there was a decrease on NR1 levels. Moreover, we did not observe neurodegeneration with both administration paradigms, as assessed by Fluoro-Jade C staining, but we did observe a strong astrogliosis in the acute administration group by using both immunohistochemistry and Western blot analysis. The impact of METH on working memory was evaluated using the Y maze test and revealed significant mnemonic deficit in the rats acutely treated with the drug. Overall, our results suggest a protection mechanism under conditions of METH administration by decreasing permeability and/or functionality of NMDA and AMPA receptors, which has implications on memory. So, the participation of the glutamatergic system should be considered as an important pharmacological target to design new strategies to prevent or diminish the harmful effect of drug consumption.

Section snippets

Animals and METH treatments

Male, 8-week-old, Sprague–Dawley rats (Charles River Laboratories Inc., Barcelona, Spain) weighting between 250 and 300 g were housed one per cage under controlled environmental conditions (12-h light/dark schedule, at room temperature of 21±1 °C) with food and water supplied ad libitum. A group of animals (the ED group) received a subchronic administration, being injected for seven consecutive days with increasing doses of METH (10, 15, 15, 20, 20, 25, 30 mg/kg, s.c.). The total daily doses

Effect of acute versus ED of METH on neurodegeneration and astrocytes activation in the hippocampus

It was recently proposed that besides dopaminergic and serotonergic terminal degeneration, METH also causes cell death in different brain areas, including non-monoaminergic systems (see Cadet et al., 2007 for a review). Astrogliosis frequently accompany METH and several other toxic insults effects in the brain, therefore, glial response is considered an indicative of neurotoxicity (O’Callaghan and Sriram, 2005). In order to evaluate the neurotoxic impact of the presently studied METH

Discussion

The present work revealed that METH treatment induced a significant astrogliosis in the rat hippocampus, without, however, signs of neurodegeneration. Astrogliosis is considered a measure of neurotoxicity and can be evaluated by assessing GFAP expression (O’Callaghan and Sriram, 2005). Indeed, we observed that acute administration of METH induced a significant reactivity of the astrocytes in the hippocampal subregions, and this observation is in line with previous reports (Hebert and

Conclusion

Both METH regimens induced alteration of Glu NMDA and AMPA receptor subunits levels. The acute treatment with METH decreased permeability to Ca2+ of AMPA receptors, due to increased GluR2 subunit levels. ED treatment with METH has induced a decrease of NMDA receptors’ functionality, given the decrease in NR1 subunit levels. These effects of METH in the hippocampus suggest a protection mechanism from Glu receptors’ overactivation and might have contributed to the absence of neurodegeneration at

Acknowledgments

This work was supported, in part, by GAI project 23/06 and by IPDT, Portugal. We thank to the PhD student Paula Canas for helping us in the immunohistochemistry studies. We also would like to acknowledge Dr. João Malva for the important suggestions and discussions of the present work.

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