腺苷A_1受体阻断剂对学习记忆的影响与胆碱能神经的关系

目的：研究腺苷A1受体阻断剂对学习记忆的影响与中枢胆碱能神经的关系。方法：采用离体蟾蜍腹直肌生物测定法，通过离体器官测定仪，观察腺苷A，受体特异性阻断剂8-环戊-1，3-二丙基黄嘌呤（DPCPX）对小鼠脑内乙酰胆碱含量的影响；采用在体记录麻醉大鼠LTP的电生理学方法，观察DPCPX与东莨菪碱在海马齿状回基础突触传递活动和高频刺激诱导的LTP中作用的相关性。结果：DPCPX（0．3μg，icv）可显著增加小鼠脑内ACh含量，使蟾蜍腹直肌收缩幅度增强，该作用可被预先给予筒箭毒碱所拮抗；DPCPX（0．03μg）不影响大鼠海马齿状回突触传递活动，但可拮抗或取消东莨菪碱对高频刺激诱导LTP的抑制作用。结论：腺苷A；受体特异性阻断剂DPCPX可影响中枢胆碱能神经递质水平并改善东莨菪碱所致的记忆障碍。     

Adenosinergic modulation of the discriminative-stimulus effects of methamphetamine in rats

RATIONALE: A(1) and A(2A) adenosine receptors are co-localized with dopamine D(1) and D(2) receptors, respectively, and their stimulation attenuates dopaminergic functioning.OBJECTIVE: To test whether adenosine antagonists with different selectivities for A(1) and A(2A) receptors mimic the discriminative-stimulus effects of dopamine releaser methamphetamine.METHODS: Effects of the A(1) antagonist DPCPX, the preferential A(2A) antagonist DMPX and the non-selective adenosine antagonist caffeine were evaluated in Sprague-Dawley rats trained to discriminate 1.0 mg/kg, IP, methamphetamine from saline under a fixed-ratio 10 schedule of food presentation.RESULTS: The A(1) antagonist DPCPX (1.0-10.0 mg/kg) failed to substitute for methamphetamine. However, 5.6 mg/kg DPCPX shifted the methamphetamine dose-response curve to the left. The A(2A) antagonist DMPX (1.8-18.0 mg/kg) produced about 70% methamphetamine-appropriate responding and the non-selective antagonist caffeine (3.0-56.0 mg/kg) about 50% methamphetamine-appropriate responding at the highest tested doses. Both DMPX (5.6 mg/kg) and caffeine (30.0 mg/kg) shifted the methamphetamine dose-response curve to the left. Methamphetamine-like effects of DMPX were blocked fully by the D(2) antagonist spiperone (0.18 mg/kg) and partially by the D(1) antagonist SCH-23390 (0.018 mg/kg).CONCLUSIONS: Antagonism at A(2A) adenosine receptors directly mimics the discriminative-stimulus effects of methamphetamine through the interaction with dopamine receptors. Antagonism at A(1) adenosine receptors potentiates effects of lower methamphetamine doses and thus plays a rather indirect, modulatory role.     

Pyruvate incubation enhances glycogen stores and sustains neuronal function during subsequent glucose deprivation

The use of energy substrates, such as lactate and pyruvate, has been shown to improve synaptic function when administered during glucose deprivation. In the present study, we investigated whether prolonged incubation with monocarboxylate (pyruvate or lactate) prior rather than during glucose deprivation can also sustain synaptic and metabolic function. Pyruvate pre-incubation(3-4 h) significantly prolonged (> 25 min) the tolerance of rat hippocampal slices to delayed glucose deprivation compared to control and lactate pre-incubated slices, as revealed by field excitatory post synaptic potentials (fEPSPs); pre-incubation with pyruvate also reduced the marked decrease in NAD(P)H fluorescence resulting from glucose deprivation. Moreover, pyruvate exposure led to the enhancement of glycogen stores with time, compared to glucose alone (12 μmol/g tissue at 4 h vs. 3.5 μmol/g tissue). Prolonged resistance to glucose deprivation following exogenous pyruvate incubation was prevented by glycogenolysis inhibitors, suggesting that enhanced glycogen mediates the delay in synaptic activity failure. The application of an adenosine A1 receptor antagonist enhanced glycogen utilization and prolonged the time to synaptic failure, further confirming this hypothesis of the importance of glycogen. Moreover, tissue levels of ATP were also significantly maintained during glucose deprivation in pyruvate pretreated slices compared to control and lactate. In summary, these experiments indicate that pyruvate exposure prior to glucose deprivation significantly increased the energy buffering capacity of hippocampal slices, particularly by enhancing internal glycogen stores, delaying synaptic failure during glucose deprivation by maintaining ATP levels, and minimizing the decrease in the levels of NAD(P)H.