Behavioral sensitization, behavioral tolerance, and increased [3H]WIN 35,428 binding in rabbit caudate nucleus after repeated injections of cocaine.
This study examined whether changes in the behavioral response to repeated intravenous injections of cocaine hydrochloride (4 mg/kg, twice daily for 22 days) might be related to alterations in the dopamine (DA) transporter as measured by the binding of the potent cocaine analog [3H]WIN 35,428 to membranes derived from fresh caudate tissue. Rabbits demonstrated both tolerance and sensitization. Tolerance occurred for cocaine elicited convulsions, whereas sensitization occurred to the ability of cocaine to elicit motor activity, facial twitches, and head bobbing. Cocaine-exposed animals demonstrated a significant 17% increase in the Bmax of specific [3H]WIN 35,428 binding to caudate membranes with no change in Kd. The increase in Bmax was observed at 42 but not 96 h after the last chronic cocaine administration. There was no change in [3H]WIN 35,428 binding at 42 h after a single injection of cocaine. We suggest that the upregulation of the dopamine transporter in the caudate nucleus reflected the mechanisms involved in tolerance rather than sensitization.
Aloyo
V J
VJ
Department of Pharmacology, Medical College of Pennsylvania, Philadelphia 19129, USA.
Pazdalski
P S
PS
Kirifides
A L
AL
Harvey
J A
JA
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001665:Binding Sites / Q000187:drug effects; D002352:Carrier Proteins / Q000378:metabolism; D002421:Caudate Nucleus / Q000187:drug effects / Q000378:metabolism*; D003042:Cocaine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology*; D050483:Dopamine Plasma Membrane Transport Proteins; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D005260:Female; D007275:Injections, Intravenous; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D008566:Membranes / Q000187:drug effects / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects; D009294:Narcotics / Q000008:administration & dosage / Q000494:pharmacology*; D009419:Nerve Tissue Proteins; D011817:Rabbits; D012640:Seizures / Q000139:chemically induced; D015854:Up-Regulation / Q000187:drug effects
D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009294:Narcotics; D009419:Nerve Tissue Proteins; C021279:(1R-(exo,exo))-3-(4-fluorophenyl)-8-methyl-8- azabicyclo(3.2.1)octane-2-carboxylic acid, methyl ester; D003042:Cocaine