Parthenolide Blocks Cocaines Effect on Spontaneous Firing Activity of Dopaminergic Neurons in the Ventral Tegmental Area

David Schwarz,C A Jimenez-Rivera,One R Pagan,Rocio Castro,Damaris Bloom

doi:10.2174/157015911795017010

David Schwarz, C A Jimenez-Rivera + Show 3 more

Open Access

https://doi.org/10.2174/157015911795017010

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Abstract

Chronic cocaine administration leads to catecholamine reuptake inhibition which enhances reward and motivational behaviors. Ventral Tegmental Area dopaminergic (VTA DA) neuronal firing is associated with changes in reward predictive signals. Acute cocaine injections inhibit putative VTA DA cell firing in vertebrates. Parthenolide, a compound isolated from the feverfew plant (Tanacetum parthenium), has been shown to substantially inhibit cocaine’s locomotion effects in a planarian animal model (Pagán et al., 2008). Here we investigated the effects of parthenolide on the spontaneous firing activity of putative VTA DA neurons in anesthetized male rats (250-300g). Single-unit recordings were analyzed after intravenous (i.v.) parthenolide administration followed by 1mg/kg i.v. cocaine injection. Results showed that parthenolide at 0.125 mg/kg and 0.250mg/kg significantly blocked cocaine’s inhibitory effect on DA neuronal firing rate and bursting activity (p< 0.05, two way ANOVA). We propose that parthenolide might inhibit cocaine’s effects on VTA DA neurons via its interaction with a common binding site at monoamine transporters. It is suggested that parthenolide could have a potential use as an overdose antidote or therapeutic agent to cocaine intoxication.

Highlights

The mesocorticolimbic circuit functions as the center for reward and motivation [1]
The present study demonstrates that parthenolide administration blocks the acute cocaine’s action on Ventral Tegmental Area dopaminergic (VTA DA) neuronal firing activity
Similar to the behavioral results published by Pagán et al 2008, systemic administration of parthenolide prior to a cocaine injection blocked cocaineinduced firing rate inhibition and bursting activity

Summary

Introduction

The mesocorticolimbic circuit functions as the center for reward and motivation [1]. The Ventral Tegmental Area (VTA) forms part of this circuit, and is identified with modulating want and motivation [2]. Catecholamine reuptake mechanisms are inhibited, causing an increase in neurotransmitters at the synapse [4]. This increased concentration of dopamine, serotonin, or norepinephrine can have lasting effects in the form of neuroadaptations, such as enhanced reward and motivational behaviors, and serious short term effects such as cardiac arrest in susceptible individuals. Studies have shown that parthenolide has potent anti-inflammatory effects, but recent evidence suggests a potential blockade action on cocaine’s effects in an invertebrate animal model [5, 6]. Behavioral evidence in planarians supports that parthenolide can bind to catecholamine reuptake transporters without impairing function, and this binding prevents cocaine’s effect by allosteric competition [4]

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