Chronic cocaine increases kappa-opioid receptor density: lack of effect by selective dopamine uptake inhibitors.
Continuous infusion of cocaine or the selective dopamine uptake inhibitors GBR 12909 or RTI-117 increases locomotor stimulation, to which partial tolerance occurs. In addition, all three drugs produce significant decreases in tyrosine hydroxylase immunoreactivity in caudate putamen and nucleus accumbens core, suggesting a decreased dopaminergic tone. An interaction between cocaine and opioids has long been documented. Chronic cocaine significantly increases mu and kappa-opioid receptors and treatment with a kappa-opioid agonist markedly reduces the behavioral effects of cocaine. In addition, chronic cocaine, but not GBR 12909, increases prodynorphin gene expression in caudate putamen. To further understand the interaction between cocaine and the kappa-opioid system, the effects of a chronic continuous infusion for 14 days of cocaine or one of the selective dopamine uptake inhibitors GBR 12909 or RTI-117 via osmotic minipump were examined on kappa-opioid receptors using the selective kappa-opioid ligand [3H] U-69593. [3H] U-69593 binding density was significantly increased in caudate putamen, nucleus accumbens shell, claustrum, and endopiriform nucleus after cocaine, while neither GBR 12909 nor RTI-117 had any effect. The increased kappa-opioid receptor densities observed following cocaine are likely not related to dopamine uptake inhibition, since they were not produced by selective dopamine uptake inhibitors. These findings suggest that regulation of kappa-opioid receptors by cocaine may be via inhibition of serotonin or norepinephrine uptake, by a combination of effects on two or three monoamine transporters, or by a mechanism unrelated to transporter inhibition.
Department of Psychiatry and Behavioral Sciences, University of Miami School of Medicine, Miami, Florida 33136, USA.
Stephanie L
SL
Collins
Paul M
PM
Kunko
Bruce
B
Ladenheim
Jean-Lud
JL
Cadet
F Ivy
FI
Carroll
Sari
S
Izenwasser
D000818:Animals; D002421:Caudate Nucleus / Q000187:drug effects / Q000378:metabolism; D003042:Cocaine / Q000008:administration & dosage* / Q000031:analogs & derivatives*; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage*; D004334:Drug Administration Schedule; D015918:Infusion Pumps, Implantable; D007279:Injections, Subcutaneous; D008297:Male; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D010879:Piperazines / Q000008:administration & dosage; D011699:Putamen / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017473:Receptors, Opioid, kappa / Q000096:biosynthesis / Q000378:metabolism*
D018765:Dopamine Uptake Inhibitors; D010879:Piperazines; C121918:RTI 117; D017473:Receptors, Opioid, kappa; C043425:vanoxerine; D003042:Cocaine