Campbell A D, Womer D E, Simon J R
Department of Medical and Molecular Genetics, Indiana University Medical Center, Indianapolis, USA.
Eur J Pharmacol. 1995 Jul 18;290(2):157-62. doi: 10.1016/0922-4106(95)90029-2.
The ability of the 5-HT3 receptor agonist 1-(m-chlorophenyl)-biguanide to bind to the dopamine transporter and inhibit [3H]dopamine uptake was investigated in rat brain synaptosomes from the nucleus accumbens and caudate putamen. Competitive displacement experiments showed that 1-(m-chlorophenyl)-biguanide inhibited the binding of [3H]GBR-12935 in a biphasic manner (IC50 values of 0.4 and 2.0 microM [high affinity] and 34.8 and 52.7 microM [low affinity] for caudate putamen and nucleus accumbens, respectively), and the high affinity binding site differed between brain regions. Serotonin was ineffective at competing for [3H]GBR-12935 binding, while the selective 5-HT3 receptor antagonist ICS 205-930 exhibited an IC50 > 100 microM. The maximum density of [3H]GBR-12935 binding sites was more than two-fold greater in the caudate putamen than in the nucleus accumbens (6.9 vs. 2.7 pmol/mg protein), and KD values were similar (4.7 and 4.2 nM). 1-(m-chlorophenyl)-biguanide was able to inhibit [3H]dopamine uptake into synaptosomes of both brain regions, however it was significantly more potent in the caudate putamen (IC50: 5.1 vs. 6.5 microM). The results demonstrate that some of the reported dopamine releasing effects of 1-(m-chlorophenyl)-biguanide may be due in part to activity at the dopamine transporter, and further suggest a possible difference in dopamine uptake parameters between the caudate putamen and nucleus accumbens.
在来自伏隔核和尾状核壳核的大鼠脑突触体中，研究了5-羟色胺3（5-HT3）受体激动剂1-（间氯苯基）-双胍与多巴胺转运体结合并抑制[3H]多巴胺摄取的能力。竞争性置换实验表明，1-（间氯苯基）-双胍以双相方式抑制[3H]GBR-12935的结合（尾状核壳核和伏隔核的半数抑制浓度[IC50]值分别为0.4和2.0微摩尔[高亲和力]以及34.8和52.7微摩尔[低亲和力]），并且脑区之间的高亲和力结合位点不同。血清素在竞争[3H]GBR-12935结合方面无效，而选择性5-HT3受体拮抗剂ICS 205-930的IC50>100微摩尔。[3H]GBR-12935结合位点的最大密度在尾状核壳核中比在伏隔核中高出两倍多（6.9对2.7皮摩尔/毫克蛋白质），解离常数（KD）值相似（4.7和4.2纳摩尔）。1-（间氯苯基）-双胍能够抑制[3H]多巴胺摄取到两个脑区的突触体中，然而它在尾状核壳核中效力显著更高（IC50：5.1对6.5微摩尔）。结果表明，1-（间氯苯基）-双胍的一些报道的多巴胺释放作用可能部分归因于其对多巴胺转运体的活性，并进一步表明尾状核壳核和伏隔核之间多巴胺摄取参数可能存在差异。
