title: The 5-HT3 receptor agonist 1-(m-chlorophenyl)-biguanide interacts with the dopamine transporter in rat brain synaptosomes.
abstract: 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.
authors.affiliation: Department of Medical and Molecular Genetics, Indiana University Medical Center, Indianapolis, USA.
authors.forename: A D
authors.initials: AD
authors.lastname: Campbell
authors.forename: D E
authors.initials: DE
authors.lastname: Womer
authors.forename: J R
authors.initials: JR
authors.lastname: Simon
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001645:Biguanides / Q000494:pharmacology*; D001667:Binding, Competitive; D001693:Biological Transport, Active / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002352:Carrier Proteins / Q000187:drug effects* / Q000378:metabolism; D002421:Caudate Nucleus / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D005260:Female; D066298:In Vitro Techniques; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D009714:Nucleus Accumbens / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012702:Serotonin Antagonists / Q000494:pharmacology*; D013574:Synaptosomes / Q000187:drug effects* / Q000378:metabolism
chemical_list: D001645:Biguanides; D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D012702:Serotonin Antagonists; C065734:1-(3-chlorophenyl)biguanide; D004298:Dopamine