Cannabinoid functions in the amygdala contribute to conditioned fear memory in streptozotocin-induced diabetic mice: Interaction with glutamatergic functions
Cannabinoid functions in the amygdala contribute to conditioned fear memory in streptozotocin-induced diabetic mice: Interaction with glutamatergic functions
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DOI：
10.1016/j.expneurol.2015.04.012
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发表时间：
2015-07-01
影响因子：
5.3
通讯作者：
Kamei, Junzo
中科院分区：
文献类型：
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作者：
Ikeda, Hiroko;Ikegami, Megumi;Kamei, Junzo
在链脲佐菌素（STZ）诱导的糖尿病小鼠中研究大麻素系统在条件性恐惧记忆中的作用。大麻素受体激动剂WIN-55，212 -2（1 mg/kg，腹膜内），当注射到正常小鼠条件反射后，显著延长了冻结行为的持续时间。这种作用被大麻素CB 1受体拮抗剂AM 251（3 mg/kg，s.c.）显著抑制，而大麻素CB 2受体拮抗剂AM 630（1 mg/kg，s.c.）则不能。STZ诱导的糖尿病小鼠的冻结时间显著长于非糖尿病小鼠。注射WIN-55，212 -2（lmg/kg，i. p.）在非糖尿病小鼠中，预处理后显著延长了冷冻持续时间，但在STZ诱导的糖尿病小鼠中没有。相反，注射AM 251（3 mg/kg，s.c.）在STZ诱导的糖尿病小鼠中，预处理后显著缩短了冷冻持续时间，但在非糖尿病小鼠中没有。注射AM 251（3 mg/kg，s.c.）在调节前或测试前对STZ诱导的糖尿病小鼠的冷冻持续时间没有显著影响。STZ诱导的糖尿病小鼠杏仁核中大麻素CB 1受体的蛋白水平增加。相比之下，杏仁核中大麻素CB 2受体和二酰基甘油脂肪酶等（合成内源性大麻素2-花生四烯酰甘油的酶）的蛋白质水平在非糖尿病小鼠和STZ诱导的糖尿病小鼠之间没有差异。这些蛋白质在非糖尿病和STZ诱导的糖尿病小鼠之间没有差异。基底外侧杏仁核注射AM 251（50 ng/侧）可显著抑制STZ诱导的糖尿病小鼠的冻结持续时间。由于内源性大麻素是由多巴胺能功能控制的，我们进一步研究了多巴胺能功能在STZ诱导的糖尿病小鼠恐惧记忆增加中的作用。STZ诱导的糖尿病小鼠杏仁核中谷氨酰胺和谷氨酸的含量显著高于非糖尿病小鼠。AMPA受体拮抗剂NBQX（40 ng/侧），当注射到基底外侧杏仁核，显着抑制STZ诱导的糖尿病小鼠冻结的持续时间。最后，AMPA（40 ng，冰。）AM 251（3 mg/kg，s.c.）可显著延长正常小鼠的冷冻时间，并可抑制AM 251的这种作用。这些结果表明，杏仁核中的大麻素功能在糖尿病小鼠中增加，并且糖尿病小鼠的杏仁核中增强的多巴胺能功能激活内源性大麻素系统，其通过大麻素CB受体增强恐惧记忆。(C)2015 Elsevier Inc. All rights reserved.
The role of cannabinoid systems in conditioned fear memory was investigated in streptozotocin (STZ)-induced diabetic mice. The cannabinoid receptor agonist WIN-55,212-2 (1 mg/kg, i.p.), when injected into normal mice after conditioning, significantly prolonged the duration of freezing behavior. This effect was significantly inhibited by the cannabinoid CB1 receptor antagonist AM 251 (3 mg/kg, s.c.), but not by the cannabinoid CB2 receptor antagonist AM 630 (1 mg/kg, s.c.). The duration of freezing in STZ-induced diabetic mice was significantly longer than that in non-diabetic mice. The injection of WIN-55,212-2 (1 mg/kg, i.p.) after conditioning significantly prolonged the duration of freezing in non-diabetic mice, but not in STZ-induced diabetic mice. In contrast, the injection of AM 251 (3 mg/kg, s.c.) after conditioning significantly shortened the duration of freezing in STZ-induced diabetic mice, but not in non-diabetic mice. The injection of AM 251 (3 mg/kg, s.c.) before conditioning or before testing did not significantly affect the duration of freezing in STZ-induced diabetic mice. The protein levels of cannabinoid CB1 receptors in the amygdala were increased in STZ-induced diabetic mice. In contrast, the protein levels of cannabinoid CB2 receptors and diacylglycerol lipase et, the enzyme that synthesizes endocannabinoid 2-arachidonoylglycerol, in the amygdala did not differ between non-diabetic and STZ-induced diabetic mice. None of these proteins in the hippocampus was different between non-diabetic and STZ-induced diabetic mice. The injection of AM 251 (50 ng/side) into the basolateral amygdala significantly inhibited the duration of freezing in STZ-induced diabetic mice. Since endocannabinoid is controlled by glutamatergic function, we further examined the role of glutamatergic function in the increased fear memory in STZ-induced diabetic mice. The amounts of glutamine and glutamic acid in the amygdala of STZ-induced diabetic mice were significantly increased compared to those in non-diabetic mice. The AMPA receptor antagonist NBQX (40 ng/side), when injected into the basolateral amygdala, significantly inhibited the duration of freezing in STZ-induced diabetic mice. Finally, AMPA (40 ng, icy.) significantly prolonged the duration of freezing in normal mice, and this effect was inhibited by AM 251 (3 mg/kg, s.c.). These results suggest that cannabinoid functions in the amygdala are increased in diabetic mice and that enhanced glutamatergic function in the amygdala of diabetic mice activates the endocannabinoid system, which enhances fear memory via cannabinoid CB, receptors. (C) 2015 Elsevier Inc. All rights reserved.