Luthman J, Lindqvist E, Kojima H, Shiotani T, Tanaka M, Tachizawa H, Olson L
Department of Neuroscience, Karolinska Institute, Stockholm, Sweden.
Arch Int Pharmacodyn Ther. 1994 Sep-Oct;328(2):125-44.
The pyrrolidone cyclic gamma-aminobutyric acid (GABA) derivative nefiracetam [DM-9384; N-(2,6-dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl)acetamide] has been shown to enhance acquisition and ameliorate amnesia in different learning tasks in rodents. In the present study, the effects of nefiracetam on the brain monoamine systems were studied. Male, adult Sprague-Dawley rats were treated with nefiracetam in single doses (0, 1, 3, 10, 30 or 100 mg/kg, p.o.) and analyzed after 1 and 4 hr, or treated by daily doses (0, 1, 3, 10 or 30 mg/kg, p.o.) for 2 weeks. In general, no or only weak effects were observed on tissue monoamine levels, either following acute or 14 days treatment with nefiracetam. Acute administration of intermediate doses of nefiracetam induced minor increases in dopamine (DA) and homovanillic acid (HVA) tissue levels in the striatum, while hypothalamic 3,4-dihydroxyphenylacetic acid (DOPAC) decreased at 1 hr. Noradrenaline (NA) and serotonin (5-HT) levels increased in some regions after higher doses of nefiracetam. Increases in 5-hydroxyindoleacetic acid (5-HIAA) were also seen at 4 hr, but only after the 3 mg/kg dose. Minor decreases of HVA and DOPAC levels were seen in some regions after treatment with various doses of nefiracetam for 14 days, while an increase in 5-HT levels was observed occasionally. Using in vivo microdialysis in freely moving animals, no significant effects on extracellular levels of HVA, DOPAC and 5-HIAA in the striatum or of HVA, DOPAC and NA levels in the dorsal hippocampus were seen after acute administration of nefiracetam. On the other hand, extracellular hippocampal 5-HIAA levels decreased by 20% after the 1 and 3 mg/kg doses. Nefiracetam, in a concentration range of 1 nM to 10 microM, did not affect the in vitro synaptosomal uptake of [3H]NA and [3H]5-HT in the cortex or of [3H]DA in the striatum. Taken together, nefiracetam appears to exert minor, regionally restricted and not dose-dependent effects on the monoamine systems following either acute or repeated administrations in normal rats. A direct or indirect, possible GABA-mediated, influence of nefiracetam may underlie the modest changes seen on monoamines. The cognitive-enhancing action of nefiracetam does not seem to be related to effects on presynaptic monoamine functions.
吡咯烷酮环状γ-氨基丁酸（GABA）衍生物奈非西坦[DM-9384；N-(2,6-二甲基苯基)-2-(2-氧代-1-吡咯烷基)乙酰胺]已被证明可促进啮齿动物在不同学习任务中的习得并改善失忆。在本研究中，研究了奈非西坦对脑单胺系统的影响。成年雄性Sprague-Dawley大鼠单次给予奈非西坦（0、1、3、10、30或100mg/kg，口服），并在1小时和4小时后进行分析，或每日给予（0、1、3、10或30mg/kg，口服），持续2周。总体而言，无论是急性给予还是14天给予奈非西坦，对组织单胺水平均未观察到或仅观察到微弱影响。急性给予中等剂量的奈非西坦可使纹状体中多巴胺（DA）和高香草酸（HVA）的组织水平略有升高，而下丘脑3,4-二羟基苯乙酸（DOPAC）在1小时时降低。给予较高剂量的奈非西坦后，某些区域的去甲肾上腺素（NA）和5-羟色胺（5-HT）水平升高。在4小时时也观察到5-羟吲哚乙酸（5-HIAA）升高，但仅在3mg/kg剂量后出现。给予各种剂量的奈非西坦14天后，某些区域的HVA和DOPAC水平略有降低，而5-HT水平偶尔会升高。在自由活动的动物中使用体内微透析技术，急性给予奈非西坦后，纹状体中HVA、DOPAC和5-HIAA的细胞外水平或背侧海马中HVA、DOPAC和NA的水平均未观察到显著影响。另一方面，给予1mg/kg和3mg/kg剂量后，海马细胞外5-HIAA水平降低了20%。在1nM至10μM的浓度范围内，奈非西坦不影响皮质中[3H]NA和[3H]5-HT或纹状体中[3H]DA的体外突触体摄取。综上所述，在正常大鼠中，无论是急性给药还是重复给药，奈非西坦对单胺系统似乎都有轻微的、区域受限且非剂量依赖性的影响。奈非西坦可能通过直接或间接的、可能由GABA介导的作用，对单胺产生适度的影响。奈非西坦的认知增强作用似乎与对突触前单胺功能的影响无关。
