GBR12909 antagonizes the ability of cocaine to elevate extracellular levels of dopamine

Pharmacol Biochem Behav. 1991 Oct;40(2):387-97. doi: 10.1016/0091-3057(91)90570-r.


Rats were administered various IP doses of the high-affinity dopamine (DA) reuptake inhibitor 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-[3-phenylpropyl]piperazine (GBR12909). The caudate nuclei were removed 60 min after drug administration and stored at -70 degrees C. Striatal membranes were prepared later. The results demonstrated that GBR12909 produced a dose-dependent decrease in the binding of [3H]cocaine or [3H]GBR12935 to the DA transporter (ED50 about 10 mg/kg). Saturation binding studies with [3H]GBR12935 showed that this was due to both an increase in the Kd, due to residual drug, and to a decrease in the Bmax. At a dose of 25 mg/kg IP, GBR12909 produced a 50% decrease in the Bmax, and a 3.4-fold increase in the Kd. In the in vivo microdialysis studies, GBR12909 (25 mg/kg IP) produced a modest, long-lasting and stable elevation of extracellular DA. Administration of cocaine through the microdialysis probe to rats pretreated with either saline or GBR12909 (25 mg/kg IP) produced a dose-dependent increase in extracellular DA in both groups. GBR12909 inhibited cocaine-induced increases in extracellular DA by about 50% at all doses. These data collectively indicate that at a dose sufficient to decrease by 50% the Bmax of [3H]GBR12935 binding sites, GBR12909 antagonizes the ability of cocaine to elevate extracellular DA by 50%. Further studies will be needed to evaluate a possible role for GBR12909 in the medical treatment of cocaine addiction.

MeSH terms

  • Animals
  • Carrier Proteins / metabolism
  • Caudate Nucleus / drug effects
  • Caudate Nucleus / metabolism
  • Chromatography, High Pressure Liquid
  • Cocaine / antagonists & inhibitors*
  • Dialysis
  • Dopamine / metabolism*
  • Dopamine / pharmacology
  • Dopamine Plasma Membrane Transport Proteins
  • Electrochemistry
  • Extracellular Space / drug effects
  • Extracellular Space / metabolism
  • Kinetics
  • Male
  • Mazindol / pharmacology
  • Membrane Glycoproteins*
  • Membrane Transport Proteins*
  • Nerve Tissue Proteins*
  • Neurotransmitter Uptake Inhibitors / pharmacology*
  • Piperazines / pharmacology*
  • Radioligand Assay
  • Rats
  • Rats, Inbred Strains


  • Carrier Proteins
  • Dopamine Plasma Membrane Transport Proteins
  • Membrane Glycoproteins
  • Membrane Transport Proteins
  • Nerve Tissue Proteins
  • Neurotransmitter Uptake Inhibitors
  • Piperazines
  • vanoxerine
  • Mazindol
  • Cocaine
  • Dopamine