Key Laboratory of Tropical Biological Resources of Ministry of Education, Key Laboratory for Marine Drugs of Haikou, School of Life and Pharmaceutical Sciences, Hainan University, Haikou 570228, China.
Mar Drugs. 2019 Aug 22;17(9):490. doi: 10.3390/md17090490.
bstract: α-Conotoxin TxIB is a specific antagonist of α6/α3β2β3(α6β2*) nicotinic acetylcholine receptor (nAChR) with an IC of 28 nM. Previous studies have shown that α6β2* nAChRs are abundantly expressed in midbrain dopaminergic neurons and play an important role in mediating the mechanism of nicotine and other drugs reward effect. It provided important targets for the development of anti-addiction drugs. The present study evaluated the pharmacological activity of TxIB in vivo with conditioned place preference (CPP) model, which were induced by subcutaneous injection (s.c.) of nicotine (NIC, 0.5 mg/kg). α-Conotoxin TxIB inhibited the expression and reinstatement of CPP in mice dose-dependently, but had no significant effect on locomotor activity. The concentrations of dopamine (DA), γ-aminobutyric acid (GABA) and noradrenaline (NE) in different brain regions were measured by enzyme-linked immunosorbent assay (ELISA). We found that TxIB could inhibit the concentrations of DA, GABA and NE in different brain regions (such as nucleus accumbens (NAc), hippocampus (HIP) and prefrontal cortex (PFC)) in NIC-induced mice. The concentrations of DA and NE were decreased in ventral tegmental area (VTA), while GABA had little change. The current work described the inhibition activity of TxIB in NIC-induced CPP, suggesting that α6β2* nAChR-targeted compound may be a promising drug for nicotine addiction treatment.
α-芋螺毒素 TxIB 是一种特异性的 α6/α3β2β3（α6β2*）烟碱型乙酰胆碱受体（nAChR）拮抗剂，其半数抑制浓度（IC）为 28 nM。先前的研究表明，α6β2* nAChR 大量表达于中脑多巴胺能神经元，在介导尼古丁和其他药物奖赏效应的机制中发挥重要作用。这为开发抗成瘾药物提供了重要靶点。本研究采用条件位置偏爱（CPP）模型，评估了 TxIB 在体内的药理学活性，该模型是通过皮下注射（s.c.）尼古丁（NIC，0.5mg/kg）诱导产生的。α-芋螺毒素 TxIB 可剂量依赖性地抑制 CPP 的表达和复现，但对运动活动没有显著影响。通过酶联免疫吸附测定（ELISA）测量不同脑区多巴胺（DA）、γ-氨基丁酸（GABA）和去甲肾上腺素（NE）的浓度。我们发现 TxIB 可抑制 NIC 诱导的小鼠不同脑区（如伏隔核（NAc）、海马（HIP）和前额叶皮层（PFC））中 DA、GABA 和 NE 的浓度。腹侧被盖区（VTA）中 DA 和 NE 的浓度降低，而 GABA 变化不大。目前的工作描述了 TxIB 在 NIC 诱导的 CPP 中的抑制活性，表明靶向 α6β2* nAChR 的化合物可能是治疗尼古丁成瘾的有前途的药物。
