[3H] cocaine labels a binding site associated with the serotonin transporter in guinea pig brain: allosteric modulation by paroxetine

Neurochem Res. 1992 Dec;17(12):1275-83. doi: 10.1007/BF00968412.


We studied the characteristics of [3H]cocaine binding to membranes prepared from whole guinea pig brain. Cocaine binding was specific and saturable. A one-site binding model fit the data adequately: the Kd value of [3H]cocaine was 44 nM with a Bmax value of 280 fmol/mg protein. The rank order of potency for the [3H]cocaine binding site was paroxetine > clomipramine > (-)-cocaine > fluoxetine > mazindol > desipramine > GBR12909 > phencyclidine > benztropine > GBR12935 > (+)-cocaine. The IC50 values of these drugs for inhibition of [3H]cocaine binding were highly correlated with their IC50 values for inhibition of [3H]5-HT uptake into synaptosomes prepared from whole guinea pig brain. High affinity 5-HT uptake inhibitors produced dose-dependent wash-resistant (pseudoirreversible) inhibition of [3H]cocaine binding. The wash-resistant inhibition produced by paroxetine was due to an increase in the Kd of [3H]cocaine binding sites, and was accompanied by an increase in the dissociation rate, consistent with an allosteric mechanism. These studies suggest that, using membranes prepared from whole guinea pig brain, [3H]cocaine labels a binding site associated with serotonin transporter and that paroxetine and cocaine bind to different sites on the serotonin transporter.

Publication types

  • Comparative Study

MeSH terms

  • Allosteric Regulation
  • Animals
  • Binding Sites / drug effects
  • Brain / metabolism*
  • Carrier Proteins / antagonists & inhibitors
  • Carrier Proteins / metabolism*
  • Cell Membrane / metabolism
  • Cocaine / metabolism*
  • Guinea Pigs
  • Membrane Glycoproteins / antagonists & inhibitors
  • Membrane Glycoproteins / metabolism*
  • Membrane Transport Proteins*
  • Nerve Tissue Proteins*
  • Paroxetine / pharmacology*
  • Piperazines / pharmacology
  • Serotonin / metabolism
  • Serotonin Plasma Membrane Transport Proteins
  • Synaptosomes / metabolism
  • Tritium


  • Carrier Proteins
  • Membrane Glycoproteins
  • Membrane Transport Proteins
  • Nerve Tissue Proteins
  • Piperazines
  • Serotonin Plasma Membrane Transport Proteins
  • Tritium
  • Serotonin
  • Paroxetine
  • vanoxerine
  • Cocaine