Department of Medical Sciences, University of Ferrara, Italy.
Synapse. 2013 Oct;67(10):678-91. doi: 10.1002/syn.21672. Epub 2013 May 21.
N-[(4-trifluoromethyl) benzyl] 4-methoxybutyramide (GET73) is a newly synthesized compound displaying anti-alcohol and anxiolytic properties. In light of the importance of the hippocampal CA1 subregion in alcohol addiction and anxiety-like behaviors-this in vivo microdialysis study characterized the effect of GET73 on extracellular GABA levels in the hippocampal CA1 region of the freely moving rat-including a possible role for mGlu5 receptor in mediating this effect. Both intraperitoneal administration (2-10 mg/kg) and local intra-hippocampal CA1 perfusion with GET73 (50-1000 nM) were associated with a transient, step-wise increase in dialysate hippocampal CA1 GABA levels. The GET73 (10 mg/kg)-induced increase in GABA levels was not affected by intra-CA1 perfusion with either the GABA reuptake inhibitor SKF89976A (0.5 mM) or by local GABAA (bicuculline; 1μM) and GABAB (CGP35348; 500 μM) receptor antagonists. On the contrary, the GET73-induced increase in GABA levels was partially counteracted by the intra-CA1 perfusion with the mGlu5 receptor negative allosteric modulator MPEP (300 µM). Interestingly, GET73 at the lowest (2 mg/kg) dose tested, by itself ineffective, fully counteracted the increase in GABA levels induced by the mGlu5 receptor agonist CHPG (1000 µM). Taken together, these findings suggest that the GET73-induced increase in hippocampal CA1 GABA levels operates independently of local GABA reuptake and/or GABAA or GABAB receptors. Furthermore, the present data lead to hypothesize a possible interaction between GET73 and mGluR5-mediated regulation of hippocampal CA1 GABA transmission, an effect which may be relevant to the ability of GET73 to reduce alcohol intake in an alcohol-preferring rat strain.
N-[(4-三氟甲基)苄基]4-甲氧基丁酰胺（GET73）是一种新合成的化合物，具有抗酒精和抗焦虑特性。鉴于海马 CA1 亚区在酒精成瘾和焦虑样行为中的重要性-这项在体微透析研究描述了 GET73 对自由活动大鼠海马 CA1 区细胞外 GABA 水平的影响-包括 mGlu5 受体在介导这种作用中的可能作用。腹腔内给药（2-10mg/kg）和局部海马 CA1 内灌流 GET73（50-1000 nM）均与透析液海马 CA1 GABA 水平的短暂、逐步增加有关。CA1 内灌流 GABA 再摄取抑制剂 SKF89976A（0.5mM）或局部 GABA A（bicuculline；1μM）和 GABA B（CGP35348；500μM）受体拮抗剂均不影响 GET73（10mg/kg）诱导的 GABA 水平增加。相反，CA1 内灌流 mGlu5 受体负变构调节剂 MPEP（300µM）部分拮抗了 GET73 诱导的 GABA 水平增加。有趣的是，在测试的最低剂量（2mg/kg）下，GET73 本身无效，但完全拮抗了 mGlu5 受体激动剂 CHPG（1000µM）诱导的 GABA 水平增加。综上所述，这些发现表明，GET73 诱导的海马 CA1 GABA 水平增加与局部 GABA 再摄取和/或 GABA A 或 GABA B 受体无关。此外，目前的数据假设 GET73 与 mGluR5 介导的海马 CA1 GABA 传递调节之间可能存在相互作用，这种作用可能与 GET73 降低酒精偏好大鼠饮酒量的能力有关。
