Tuning Correlative Heterogeneity and Related Properties in Ni-Nb-Tm (Tm=Zr, Y, Gd) Metallic Glasses

Park, T. G.; Kim, S. Y.; Ahn, Hyeong Sik; Oh, Hyun Seok; Chang, Hye Jung; Park, E. S.

doi:10.2139/ssrn.3315657

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“…Amphetamine and cocaine are euphoric stimulants that cause mania, tachycardia, and hedonia by increasing extracellular dopamine. 1 Despite the high economic and social costs of stimulant abuse, no therapeutics have been approved to treat abuse of these drugs. Our studies suggest that a novel target for reducing amphetamine abuse would be protein kinase Cβ (PKCβ).…”

Section: Introductionmentioning

confidence: 99%

Ruboxistaurin Reduces Cocaine-Stimulated Increases in Extracellular Dopamine by Modifying Dopamine-Autoreceptor Activity

Zestos

Carpenter²,

Kim³

et al. 2018

ACS Chem. Neurosci.

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Cocaine is a highly abused drug and cocaine addiction affects millions of individuals worldwide. Cocaine blocks normal uptake function at the dopamine transporter (DAT), thus increasing extracellular dopamine. Currently, no chemical therapies are available to treat cocaine abuse. Previous works showed that the selective inhibitors of protein kinase Cβ (PKCβ), enzastaurin and ruboxistaurin, attenuate dopamine overflow and locomotion stimulated by another psychostimulant drug, amphetamine. We now test if ruboxistaurin similarly affects cocaine action. Perfusion of 1 μM ruboxistaurin directly into the core of the nucleus accumbens via retrodialysis reduced cocaine-stimulated increases in dopamine overflow, measured using microdialysis sampling, with simultaneous reductions in locomotor behavior. Because cocaine activity is highly regulated by dopamine autoreceptors, we examined whether ruboxistaurin was acting at the level of the D2-autoreceptor. Perfusion of 5 μM raclopride, a selective D2-like receptor antagonist, before addition of ruboxistaurin abrogated the effect of ruboxistaurin on cocaine-stimulated dopamine overflow and hyperlocomotion. Further, ruboxistaurin was inactive against cocainestimulated locomotor activity in mice with a genetic deletion in D2 receptors as compared to wild type mice. In contrast, blockade or deletion of dopamine D2 receptors did not abolish the attenuating effect of ruboxistaurin on amphetamine-stimulated activities. Therefore, the inhibition of PKCβ reduces dopamine overflow and locomotor activity stimulated by both cocaine and amphetamine, but the mechanism of action differs for each stimulant. These data suggest that inhibition of PKCβ would serve as a target to reduce the abuse of either amphetamine or cocaine.

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Section: Introductionmentioning

confidence: 99%