Abstract
Cocaine addiction is characterized by aberrant plasticity of the mesolimbic dopamine circuit, leading to dysregulation of motivation to seek and take drug. Despite the significant toll that cocaine use disorder exacts on society, there are currently no available pharmacotherapies. We have recently identified granulocyte-colony stimulating factor (G-CSF) as a soluble cytokine that alters the behavioral response to cocaine and which increases dopamine release from the ventral tegmental area (VTA). Despite these known effects on behavior and neurophysiology, the molecular mechanisms by which G-CSF affects brain function are unclear. In this study mice were treated with repeated injections of G-CSF, cocaine or a combination and changes in protein expression in the VTA were examined using an unbiased proteomics approach. Repeated G-CSF treatment resulted in alterations in multiple signaling pathways related to synaptic plasticity and neuronal morphology. While the treatment groups had marked overlap in their effect, injections of cocaine and the combination of cocaine and G-CSF lead to distinct patterns of significantly regulated proteins. These experiments provide valuable information as to the molecular pathways that G-CSF activates in an important limbic brain region and will help to guide further characterization of G-CSF function and evaluation as a possible translational target.
Highlights
Pathological substance use disorders are a group of recalcitrant, relapsing and remitting conditions that have deleterious effects on the patient, their family, and society at large
We have previously demonstrated that peripheral injections of granulocyte-colony stimulating factor (G-CSF) alter gene expression in the nucleus accumbens (NAc) in response to cocaine [11]
We have identified G-CSF as a potent regulator of dopamine release from the ventral tegmental area (VTA) into the NAc [12]. These data lead us to the hypothesis that G-CSF may be inducing changes in VTA function that lead to downstream alterations in neuronal responsiveness in the NAc
Summary
Pathological substance use disorders are a group of recalcitrant, relapsing and remitting conditions that have deleterious effects on the patient, their family, and society at large. While there have been attempts made to mitigate the prevalence of substance abuse disorders, the incidences of illicit substance abuse and misuse has remained steady or increased since 1990 [1], and the economic burden created by substance use disorders is tremendous with a societal cost of over 500 billion dollars per year in the United States alone [2] Of these conditions, pathological use of psychostimulants such as cocaine and amphetamine account for a significant portion of the morbidity and mortality. In recent years there has been growing interest in the role that neuroimmune interactions play in the development of psychiatric illness, including addictive disorders [8,9,10] This raises the intriguing possibility that targeting neuroimmune signaling pathways may be a viable translational treatment strategy to reduce the persistence of pathological substance use disorders. Peripheral injections of G-CSF potentiated the development of locomotor sensitization, conditioned place preference, and self-administration of cocaine, and blockade of G-CSF function in the mesolimbic dopamine system abrogated the formation of conditioned place preference
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