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

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. Uniterms:Purine nucleotide/quantitative analysis. Purine nucleotide/effects/brain rats. Heroin analysis. Adenosine deaminase analysis. Xanthine oxidase analysis INTRODUCTIONOpiates, 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). Therefore, 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.Properly regulated purine nucleotide (PN) metabolism is necessary for normal brain function (Franke, 2011). Imbalances in purine nucleotide levels lead to a variety of human diseases (Burhans, Weinberger, 2007;El-Hattab, Scaglia, 2013;Kimura et al., 2003). Studies have shown that morphine and heroin can enhance the oxidation of xanthine and hypoxanthine in the lobus temporalis, lobus frontalis, and lobus parietalis of rats (Liu et al., 2007;Yang et al., 2006). 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). Furthermore, it has been reported that morphine may increase UA concentrations in the corpus striatum, as well as in serum and extracellularly, in vitro (Enrico et al., 1997;Sumathi, Niranjali Devaraj, 2009). In patients where morphine was administe...