Author(s): Zhang Y, Butelman ER, Schlussman SD, Ho A, Kreek MJ
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Abstract RATIONALE: 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. CONCLUSION: 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.
This article was published in Psychopharmacology (Berl)
and referenced in Journal of Addiction Research & Therapy