Effect of the kappa opioid agonist R-84760 on cocaine-induced increases in striatal dopamine levels and cocaine-induced place preference in C57BL/6J mice.
BACKGROUND
While the effects of several kappa opioid receptor agonists on cocaine-induced reward have been studied, such effects of R-84760, a novel non-peptidic, potent and selective kappa opioid agonist that has been studied in humans, are not yet known.


OBJECTIVE
To study the effects of R-84760 on basal levels of dopamine, cocaine-induced increases in dopamine levels, cocaine-induced conditioned place preference and locomotor activity in mice.


METHODS
In the first experiment, R-84760 was administered i.p. (0, 0.01, 0.05 or 0.1 mg/kg) to C57BL/6J mice. Its effect on basal dopamine levels in the caudate putamen was measured with in vivo microdialysis. In the second experiment, the effect of pretreatment with 0.1 mg/kg R-84760 on cocaine-induced increases in dopamine levels was studied. The third experiment examined the effect of R-84760 (0.1 mg/kg) on the development of cocaine-induced conditioned place preference and locomotor activity in the conditioning chamber.


RESULTS
R-84760 decreased dopamine levels in a dose-dependent manner. The highest dose of R-84760 (0.1 mg/kg, i.p.) significantly decreased dopamine levels relative to vehicle, an effect completely blocked by pre-injection with 10 mg/kg of the kappa-opioid receptor antagonist nor-binaltorphimine (nor-BNI). The same dose of R-84760 blocked cocaine-induced increases in dopamine levels, cocaine-induced conditioned place preference and attenuated cocaine-induced locomotor response.


CONCLUSIONS
These findings suggest that R-84760 decreases dopamine levels in the caudate putamen through kappa-opioid receptors. The inhibitory effect of R-84760 on striatal dopamine may contribute to its blockade of cocaine-induced increases in dopamine levels, cocaine-induced conditioned place preference and the associated increases in locomotor activity.
Zhang
Yong
Y
The Laboratory of the Biology of Addictive Diseases, The Rockefeller University, 1230 York Avenue, Box 171, New York, NY 10021, USA. zhangyo@mail.rockefeller.edu
Butelman
Eduardo R
ER
Schlussman
Stefan D
SD
Ho
Ann
A
Kreek
Mary Jeanne
MJ
D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D003042:Cocaine / Q000494:pharmacology*; D003216:Conditioning, Operant / Q000187:drug effects*; D004298:Dopamine / Q000378:metabolism*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005502:Food; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017551:Microdialysis; D009043:Motor Activity / Q000187:drug effects; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D017072:Neostriatum / Q000187:drug effects* / Q000378:metabolism; D011759:Pyrrolidines / Q000494:pharmacology*; D017473:Receptors, Opioid, kappa / Q000819:agonists*; D013843:Thiazines / Q000494:pharmacology*
D018765:Dopamine Uptake Inhibitors; D009292:Narcotic Antagonists; D011759:Pyrrolidines; D017473:Receptors, Opioid, kappa; D013843:Thiazines; C091101:R 84760; C051844:norbinaltorphimine; D009271:Naltrexone; D003042:Cocaine; D004298:Dopamine