The Effect of Ventral Hippocampal lesion and Role of Astrocyte on Methamphetamine Sensitization

• Main Authors: Shang Ru You, 游尚儒
• Other Authors: J. C. Chen
• Format: Others
• Published: 2009
• Online Access: http://ndltd.ncl.edu.tw/handle/76925508917997418377

碩士 === 長庚大學 === 生物醫學研究所 === 97 === We hypothesized that canonical Wnt signaling pathway could participate in the METH sensitization since its activation would affect glycogen synthase kinase 3beta(GSK-3beta) phosphorylation, which is known to participate in the METH sensitization. In addition, suprachiasmatic nucleus circadian oscillatory protein (SCOP), an upstream regulator of pERK1/2, played a role in limbic system-dependent novelty learning. Because above signalings could cross-talk with addiction circuits, the expression of beta-catenin, dishellved-3 and SCOP in the nucleus accumbens (NAc) were analyzed after chronic METH treatment via immunoblot. The results showed that expression of beta-catenin, disheveled-3 and SCOP did not alter in the NAc of METH sensitized mice, and seemed to explain beta-catenin/disheveled-3 and SCOP signals could not participate in the development of behavioral sensitization. Second, astrocytes constitute approximately one-half of total cells in the brain, serve as supporting cells and modulate synaptic plasticity in the central nervous system. Based on that METH sensitization is one kind of alterations in the neuronal plasticity, we intended to examine if reactive astrocytosis in the NAc involves in METH sensitization. We did not find significant alteration in expression of GFAP from NAc after METH sensitized mice. However, administration of propentofylline (PPF), a glial modulator, significantly suppressed the behavioral METH sensitization but not METH-induced conditioned place preference; the results suggested that astrocytes may partially play a role on METH sensitization. Since astrocytes predominantly express two specific glutamate transporters, the L-glutamate/l-aspartate transporter (GLAST) and the glial L-glutamate transporter (GLT-1), and previous studies also indicated that after chronic amphetamine treatment, altered glutamatergic transmission in the NAc contributes significantly the development of behavioral sensitization. Thus, we next explored if chronic METH treatment would affect the expression of GLAST and GLT-1.Our results showed that mRNA levels of GLAST increased significantly in the NAc of METH-sensitized mice, but not for GLT-1 and glutamate receptor, GluR2. Ventral subiculum (vSub) represents one of the major glutamatergic projection to the NAc, thus we investigate effect of the vSub lesion on METH sensitization, with the help of ibotenic acid. We found there was a tendency to decrease the METH-induced locomotor sensitization after vSub lesion. We found that expression of GLAST and GLT-1 did not change after vSub lesion with or without chronic METH treatment via IHC analyses and/or real-time PCR. However, vSub lesion significantly increased the protein levels of NR2A in both NAc-core and shell subregion in saline-treated mice, but reversed the METH-induced GluR2/3 over-expression in both NAc-core and shell subreginos, but treatment itself did not affect the protein levels of GluR2/3. Overall, this study excluded the participation of beta-catenin/disheveled-3 and SCOP signals of the NAc in the development of behavioral sensitization. Second, it is likely that either glial activation or adenosine system contributes to the effect of PPF on METH sensitization, and remain to be clarified. Most importantly, we demonstrate that vSub glutamate innervation in the NAc plays a differential role in the development of behavioral METH sensitization, i.e. lesion in vSub appears to affect specific post-synaptic glutamate receptor subtype(s) but not glial-type glutamate transporters. Functional dissection of vSub glutamate innervation in the NAc during chronic treatment of METH could provide valuable information in delineating the complex neural circuitry reformed during METH addiction.