Effects of purine nucleotide administration on purine nucleotide metabolism in brains of heroin-dependent rats

Kun Li,Fengying Guan,Ping Zhang,Li Chen

doi:10.1590/s1984-82502016000400024

Abstract

Heroin is known to enhance catabolism and inhibit anabolism of purine nucleotides, leading to purine nucleotide deficiencies in rat brains. Here, we determined the effect of exogenous purine nucleotide administration on purine nucleotide metabolism in the brains of heroin-dependent rats. Heroin was administrated in increasing doses for 9 consecutive days to induce addiction, and the biochemical changes associated with heroin and purine nucleotide administration were compared among the treated groups. HPLC was performed to detect the absolute concentrations of purine nucleotides in the rat brain cortices. The enzymatic activities of adenosine deaminase (ADA) and xanthine oxidase (XO) in the treated rat cortices were analyzed, and qRT-PCR was performed to determine the relative expression of ADA, XO, adenine phosphoribosyl transferase (APRT), hypoxanthine-guaninephosphoribosyl transferase (HGPRT), and adenosine kinase (AK). Heroin increased the enzymatic activity of ADA and XO, and up-regulated the transcription of ADA and XO. Alternatively, heroin decreased the transcription of AK, APRT, and HGPRT in the rat cortices. Furthermore, purine nucleotide administration alleviated the effect of heroin on purine nucleotide content, activity of essential purine nucleotide metabolic enzymes, and transcript levels of these genes. Our findings therefore represent a novel, putative approach to the treatment of heroin addiction.

Highlights

Opiates, such as morphine and heroin, are illegally used as recreational drugs worldwide, and can significantly impair the user’s physical and mental health (Chu et al, 2009; Li et al, 2014)
This study shows that the administration of purine nucleotides, in combination with heroin, reduces adenosine deaminase (ADA) and xanthine oxidase (XO) levels dramatically (P
Our results reveal that heroin inhibits the transcription of these three key enzymes involved in the purine nucleotide synthesis pathway in the rat cortex, the inhibitory effects of heroin on these enzymes could be negated with the administration of exogenous purine nucleotides

Summary

Introduction

Opiates, such as morphine and heroin, are illegally used as recreational drugs worldwide, and can significantly impair the user’s physical and mental health (Chu et al, 2009; Li et al, 2014). Opioid dependence is a significant public health concern, underscoring the need for effective treatment options (Kresina, Bruce, Mulvey, 2013; Nutt, King, Phillips, 2010). The exploration of the effects of repeated exposure to these compounds is important for understanding the mechanisms of drug dependency and developing new treatment options. Imbalances in purine nucleotide levels lead to a variety of human diseases (Burhans, Weinberger, 2007; El-Hattab, Scaglia, 2013; Kimura et al, 2003). Uric acid (UA) is the final oxidation product of purine metabolism in humans and higher primates, and changes in UA levels may reflect the catabolism of purine nucleotides (Liang, Clark, 2004). Morphine may increase ATP catabolic products, including nucleotides and oxypurines, in BALB/c mouse strains (Di Francesco et al, 1998)

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