title: GBR12909 antagonizes the ability of cocaine to elevate extracellular levels of dopamine.
abstract: 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.
authors.affiliation: Unit on Receptor Studies, NIDDK, Bethesda, MD 20892.
authors.forename: R B
authors.initials: RB
authors.lastname: Rothman
authors.forename: A
authors.initials: A
authors.lastname: Mele
authors.forename: A A
authors.initials: AA
authors.lastname: Reid
authors.forename: H C
authors.initials: HC
authors.lastname: Akunne
authors.forename: N
authors.initials: N
authors.lastname: Greig
authors.forename: A
authors.initials: A
authors.lastname: Thurkauf
authors.forename: B R
authors.initials: BR
authors.lastname: de Costa
authors.forename: K C
authors.initials: KC
authors.lastname: Rice
authors.forename: A
authors.initials: A
authors.lastname: Pert
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D002421:Caudate Nucleus / Q000187:drug effects / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D003042:Cocaine / Q000037:antagonists & inhibitors*; D003956:Dialysis; D004298:Dopamine / Q000378:metabolism* / Q000494:pharmacology; D050483:Dopamine Plasma Membrane Transport Proteins; D004563:Electrochemistry; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D007700:Kinetics; D008297:Male; D008454:Mazindol / Q000494:pharmacology; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D011919:Rats, Inbred Strains
chemical_list: D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D014179:Neurotransmitter Uptake Inhibitors; D010879:Piperazines; C043425:vanoxerine; D008454:Mazindol; D003042:Cocaine; D004298:Dopamine