Methamphetamine induces neuroinflammation and neuronal
dysfunction in the mice hippocampus
Joana
Goncalves1, 2*,
Sofia
Baptista1, 3,
Tania
Martins1, 2,
Nuno
Milhazes4,
Fernanda
Borges4,
Carlos
Fontes-Ribeiro1, 2,
Joao
O.
Malva3, 5 and
Ana
P.
Silva1, 2
-
1
University of Coimbra, Institute of Pharmacology and Experimental Therapeutics, Faculty of Medicine, Portugal
-
2
University of Coimbra, Institute of Biomedical Research on Light and Image (IBILI), Faculty of Medicine, Portugal
-
3
University of Coimbra, Center for Neuroscience and Cell Biology, Portugal
-
4
University of Porto, Chemistry Department, Faculty of Pharmacy, Portugal
-
5
University of Coimbra, Institute of Biochemistry, Faculty of Medicine, Portugal
It has been suggested that the activation of microglial cells and astrocytes, beyond neuronal dysfunction, may also contribute to methamphetamine (METH)-induced neuropathology. In the present study, we first demonstrate that a single acute METH administration (30 mg/kg; intraperitoneal injection), in male C57BL/6J wild-type mice, causes an inflammatory process in the hippocampus. This was characterized by astrocytes reactivity, microglia activation and alterations in the tumor necrosis factor (TNF) system. In fact, we observed an upregulation of glial fibrillary acidic protein (GFAP) levels at 1 h and 24 h post-METH injection and an increase in macrophage-1 (Mac-1; CD11b) immunoreactivity at 24 h and 3 days post-METH injection. Since METH induced a significant gliosis, and knowing that these cells are the main source of pro-inflammatory cytokines, we further evaluated possible changes in protein levels of TNF-α and their receptors. We verified that, post-METH treatment, both TNF-α and TNF receptor 1 (TNFR1) protein levels were upregulated at 7 days and 1 h and 24 h, respectively. However, we did not observe any changes in the TNF receptor 2 (TNFR2) protein levels. Furthermore, we investigated the effect of METH on hippocampal neurons and we observed a significant decrease in β-tubulin III (Tuj-1) protein levels following 24 h, 3 d and 7 d of METH treatment. Thus, to evaluate if all these changes observed after an acute administration of METH cause cell death, we analyzed the protein levels of caspase-3, but no alterations were observed. Moreover, we also examined the changes in the levels of several presynaptic and postsynaptic proteins, and our results corroborate the hypothesis of neuronal dysfunction. Indeed, syntaxin-1 protein levels were found to be decreased in the hippocampus following 3 days and 7 days of METH administration. In contrast, METH induced a significant increase in synaptophysin protein levels after 1 h and 24 h, but with no alterations in the levels of synaptosome-associated protein of 25000 daltons (SNAP25) and postsynaptic density 95 (PSD-95). In addition, we also observed that METH decreased calbindin D28k protein levels at the all time-points analyzed (1 h, 24 h, 3 days and 7 days), whereas tau levels only decreased 7 days post-administration. Taken together, our results demonstrate that a single acute administration of METH induces an inflammatory process and neuronal dysfunction.
This work was supported by FCT, Portugal, Project PTDC/SAU-FCF/67053/2006 and Fellowship SFRH/BD/35893/2007
Conference:
11th Meeting of the Portuguese Society for Neuroscience, Braga, Portugal, 4 Jun - 6 Jun, 2009.
Presentation Type:
Poster Presentation
Topic:
Neuronal Communication
Citation:
Goncalves
J,
Baptista
S,
Martins
T,
Milhazes
N,
Borges
F,
Fontes-Ribeiro
C,
Malva
JO and
Silva
AP
(2009). Methamphetamine induces neuroinflammation and neuronal
dysfunction in the mice hippocampus.
Front. Neurosci.
Conference Abstract:
11th Meeting of the Portuguese Society for Neuroscience.
doi: 10.3389/conf.neuro.01.2009.11.116
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Received:
11 Aug 2009;
Published Online:
11 Aug 2009.
*
Correspondence:
Joana Goncalves, University of Coimbra, Institute of Pharmacology and Experimental Therapeutics, Faculty of Medicine, Alicante, Portugal, jgoncalves@cnc.cj.uc.pt