Pereira Frederico C, Rolo Marta R, Marques Elsa, Mendes Vera M, Ribeiro Carlos F, Ali Syed F, Morgadinho Teresa, Macedo Tice R
Institute of Pharmacology and Therapeutics and Biomedical Institute for Research in Light and Image (IBILI), Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
Ann N Y Acad Sci. 2008 Oct;1139:212-21. doi: 10.1196/annals.1432.040.
The glutamate-glutamine cycle between neurons and glia is tightly related to excitatory glutamatergic and inhibitory GABAergic regulation in brain. The role of this neuron-astrocyte cross-talk on the neurotoxicity induced by amphetamines is not understood. Also, the impact of neurotoxic doses of amphetamines on the balance between glutamatergic and GABAergic circuits is largely unknown. The aim of this work was to assess the acute effect of a neurotoxic regimen of amphetamine (AMPH) on glutamine (GLN, an astrocytic marker) levels and on glutamine/glutamate (an index for glutamate-glutamine cycle) and GABA/glutamate ratios in rat brain. Sprague-Dawley rats were sacrificed 4 and 24 h after a single-dose regimen of AMPH (30 mg/kg, i.p.), and the caudate-putamen (CPu), frontal cortex (FC), and hippocampus (Hp) were dissected for analysis of glutamate (GLU), gamma-aminobutyric acid (GABA), and GLN. The total content of these amino acids was measured using a microbore HPLC electrochemical detector. Although AMPH did not change GLU levels, it increased both GLN content and GLN/GLU ratio (160-469%) at 4 h, but not at 24 h, in all regions after injection. Striatal GABA levels and GABA/GLU ratio were increased (46 and 100%, respectively) at 24 h. In hippocampus the GABA/GLU increase (60%) occurred as early as 4 h after treatment. To the contrary, AMPH exerted no effect in GABA/GLU balance in frontal cortex. These data strongly suggest that this neurotoxic AMPH regimen provoked an early increase in the glutamate-glutamine cycle between neurons and glia. This increase may ultimately lead to an upregulation of the inhibitory system as a compensatory response.
神经元与神经胶质细胞之间的谷氨酸 - 谷氨酰胺循环与大脑中兴奋性谷氨酸能和抑制性γ-氨基丁酸能调节密切相关。这种神经元 - 星形胶质细胞间相互作用对苯丙胺诱导的神经毒性的作用尚不清楚。此外，神经毒性剂量的苯丙胺对谷氨酸能和γ-氨基丁酸能回路平衡的影响也大多未知。本研究的目的是评估苯丙胺（AMPH）神经毒性方案对大鼠脑内谷氨酰胺（GLN，一种星形胶质细胞标志物）水平以及谷氨酰胺/谷氨酸（谷氨酸 - 谷氨酰胺循环指标）和γ-氨基丁酸/谷氨酸比值的急性影响。在给予单次剂量的AMPH（30 mg/kg，腹腔注射）后4小时和24小时处死Sprague-Dawley大鼠，并解剖尾状核 - 壳核（CPu）、额叶皮质（FC）和海马体（Hp），用于分析谷氨酸（GLU）、γ-氨基丁酸（GABA）和GLN。使用微径高效液相色谱电化学检测器测量这些氨基酸的总含量。尽管AMPH没有改变GLU水平，但在注射后4小时，所有区域的GLN含量和GLN/GLU比值均增加（160 - 469%），而在24小时时未增加。纹状体GABA水平和GABA/GLU比值在24小时时增加（分别为46%和100%）。在海马体中，GABA/GLU比值在治疗后4小时就开始增加（60%）。相反，AMPH对额叶皮质的GABA/GLU平衡没有影响。这些数据强烈表明，这种神经毒性AMPH方案引发了神经元与神经胶质细胞之间谷氨酸 - 谷氨酰胺循环的早期增加。这种增加最终可能导致抑制系统上调作为一种代偿反应。
