Pharmacological and molecular mechanism on amino acid neural transmission in brain of animal model for drug abuse

长期使用可卡因或苯环利定可导致类似于偏执型精神分裂症的精神状态的诱导。反复服用可卡因引起的行为敏感化在动物实验中得到了很好的证明。虽然多巴胺能系统可能负责敏化的发展，但谷氨酸或GABA能神经系统也影响这些行为异常。我们观察了可卡因或苯环利定对大鼠脑内离子型或代谢型谷氨酸受体和GABA受体亚单位基因表达的影响。结果显示：(1)单次注射可卡因(20 mg/kg)后，大鼠海马区NMDA受体NR1亚单位mRNA的表达显著增加。长期服用可卡因可导致纹状体NR1亚单位mRNA水平下降，海马区增加。(2)单次注射可卡因后，大脑皮层和海马区α1、β2、β3、γ2亚单位的表达水平明显降低。慢性给药大鼠大脑皮层和尾壳核β-BZD受体GABA3亚单位表达水平显著降低。此外，反复给予可卡因后，伏隔核、海马体和丘脑的GABAB(1)基因表达水平显著升高。(3)苯环利定多次给药后，皮质mGluR2和mGluR4mRNA表达显著降低，单次给药后皮质mGluR mRNA表达下降。这些结果表明，单次和反复给予可卡因和苯环利定独立地调节大脑中谷氨酸和GABA-BZD受体亚单位的mRNA表达。

Chronic use of cocaine or phencyclidine can result in the induction of a psychotic state resembling paranoid schizophrenia. Behavioral sensitization resulting from repeated administration of cocaine has been well documented in animal experiments. While dopaminergic systems may be responsible for the development of sensitization, glutamatergic or GABAergic neural system also influences these behavioral abnormalities. We investigated the effects of intraperitoneal administration of cocaine or phencyclidine on the mRNA levels of ionotropic or metabotropic glutamate receptor and GABA receptor subunits in rat brain. As a result, (1) The amount of the NR1 subunit mRNA of the NMDA receptor significantly increased in the hippocampus following a single administration of cocaine (20 mg/kg). Chronic cocaine administration caused a reduction in the level of NR1 subunit mRNA in the striatum and an increase in the hippocampus. (2) A level of α1, β2, β3, γ2 subunit of GABA-benzodiazepine complex was decreased in the cortex and hippocampus following a single injection of cocaine. In chronically treated rats, the level of β3 subunit of GABA-BZD receptor was significantly reduced in the cortex and caudate-putamen. In addition, the nucleus accumbens, hippocampus and thalamus showed a significant increase in the level of GABAB(1) mRNA following repeated administration of cocaine. (3) After repeated phencyclidine administration, mGluR2 and mGluR4 mRNA expression was significantly decreased in the cortex, while a single administration resulted in a decrease in the mGluR mRNA in the cortex. These findings suggested that single and repeated administration of cocaine and phencyclidine independently regulate the mRNA expression of subunits of glutamate and GABA-BZD receptors in the brain.