Spermine interacts with cocaine binding sites on dopamine transporters.
These studies were designed to assess the potential interaction of the polyamine spermine with cocaine binding to dopamine and serotonin transporters. The results of the experiments presented here indicate that spermine inhibits binding of the cocaine congener [3H] CFT to striatal synaptosomal membranes. Further, although [3H] CFT is known to interact with both dopamine and serotonin transporters, our results indicate that the observed inhibition of [3H] CFT binding is likely to reflect a specific inhibition of binding to dopamine transporters. Spermine significantly inhibited the binding of both [3H] CFT and [3H] mazindol to dopamine transporters, while it had no apparent effects on the binding of the potent serotonin uptake inhibitor [3H] paroxetine. Finally, saturation experiments show that the inhibition of ligand binding to the cocaine binding site on dopamine transporters appears not to be due to a modification of ligand affinity for the transporter, but to a decrease in the apparent density of ligand binding sites. The results of these experiments indicate that endogenously produced polyamines can alter cocaine binding to the dopamine transporter. The results are discussed in terms of possible impact on novel approaches for pharmacologically manipulating cocaine reinforcement and craving in clinical treatments for cocaine addiction, as well as for emergency treatment of cocaine overdose.
Ritz
M C
MC
Center on Alcoholism, Substance Abuse and Addictions, University of New Mexico, Albuquerque 87131.
Mantione
C R
CR
London
E D
ED
D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D002352:Carrier Proteins / Q000187:drug effects* / Q000378:metabolism*; D003042:Cocaine / Q000031:analogs & derivatives / Q000493:pharmacokinetics* / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins; D066298:In Vitro Techniques; D008297:Male; D008454:Mazindol / Q000493:pharmacokinetics; D008562:Membrane Glycoproteins / Q000378:metabolism; D026901:Membrane Transport Proteins; D017072:Neostriatum / Q000378:metabolism; D009419:Nerve Tissue Proteins; D017374:Paroxetine / Q000493:pharmacokinetics; D051381:Rats; D011916:Rats, Inbred F344; D011955:Receptors, Drug / Q000187:drug effects*; D012701:Serotonin / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins; D013096:Spermine / Q000494:pharmacology*
D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D011955:Receptors, Drug; D050486:Serotonin Plasma Membrane Transport Proteins; C493232:Slc6a4 protein, rat; C061445:cocaine receptor; D013096:Spermine; D012701:Serotonin; D017374:Paroxetine; C021279:(1R-(exo,exo))-3-(4-fluorophenyl)-8-methyl-8- azabicyclo(3.2.1)octane-2-carboxylic acid, methyl ester; D008454:Mazindol; D003042:Cocaine; D004298:Dopamine