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Long-Lasting Effects of a Pegylated Mutant Cocaine Esterase (Coce) on the Reinforcing and Discriminative Stimulus Effects of Cocaine in Rats

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Long-Lasting Effects of a Pegylated Mutant Cocaine Esterase (Coce) on the Reinforcing and Discriminative Stimulus Effects of Cocaine in Rats Neuropsychopharmacology (2012) 37, 1092–1103 & 2012 American College of Neuropsychopharmacology. All rights reserved 0893-133X/12 www.neuropsychopharmacology.org Long-Lasting Effects of a PEGylated Mutant Cocaine Esterase (CocE) on the Reinforcing and Discriminative Stimulus Effects of Cocaine in Rats Gregory T Collins*,1,2, Diwahar Narasimhan1, Alyssa R Cunningham1, Matthew E Zaks1, Joseph Nichols1, Mei-Chuan Ko1, Roger K Sunahara1 and James H Woods1 1 Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, USA Recent mutagenesis studies have identified a mutant G4C/S10C/T172R/G173Q cocaine esterase (CCRQ CocE) with an in vitro duration of action of 440 days. Although the in vivo duration of CCRQ CocE’s action was o24 h, modification of this enzyme with polyethylene glycol (PEG) polymers resulted in a CocE (PEG-CCRQ CocE) capable of preventing cocaine-induced lethality for up to 72 h. The current studies were aimed at providing a detailed characterization of the effectiveness, selectivity, and duration of PEG-CCRQ CocE’s actions in cocaine self-administration and discrimination assays in rats. Pretreatment with PEG-CCRQ CocE produced dose-dependent rightward shifts in the dose–response curves for cocaine self-administration and discrimination, with the highest dose of PEG-CCRQ CocE capable of producing an initial shift of cocaine’s reinforcing and interoceptive effects of 430-fold to the right, with significant inhibition of these effects observed for up to 72 h. Although PEG-CCRQ CocE also produced slight reductions in the rates of methylphenidate- and food- reinforced responding, these effects were short-lived, lasting o24 h. Finally, when taken together with the finding that PEG-CCRQ CocE failed to alter the cocaine-like interoceptive effects of either methylphenidate or d-amphetamine, these results suggest that PEG-CCRQ CocE possesses a high degree of pharmacologic specificity for cocaine and a prolonged in vivo duration of action. In conclusion, these studies provide strong evidence to support the further development of long-lasting, highly efficient CocEs, such as PEG-CCRQ CocE, as a potential therapeutic option for the treatment of cocaine abuse in humans. Neuropsychopharmacology (2012) 37, 1092–1103; doi:10.1038/npp.2011.226; published online 12 October 2011 Keywords: cocaine esterase; PEG-CCRQ CocE; cocaine; methlyphenidate; self-administration; drug discrimination INTRODUCTION is able to reach its central sites of action by altering the pharmacodynamic and/or pharmacokinetic properties of Cocaine abuse remains a significant worldwide public cocaine. Cocaine-specific antibodies achieve this by seques- health problem, with an estimated 20 million individuals tering cocaine in the periphery (eg, Fox et al, 1996; Martell using cocaine during the 2009 calendar year (UNODC, et al, 2005), whereas cocaine-specific enzymes and catalytic 2010). Despite longstanding efforts to identify small antibodies reduce the central effects of cocaine by enhan- molecules capable of selectively inhibiting the reinforcing cing the metabolism and clearance of cocaine, thus reducing effects of cocaine (eg, Dackis and O’Brien, 2003; Grabowski the circulating concentrations of cocaine within both the et al, 2004; Mello, 1990; Platt et al, 2002; Roberts and central and peripheral nervous systems (eg, Landry and Brebner, 2000; Tanda et al, 2009; Vocci et al, 2005), there Yang, 1997; Turner et al, 2002). are currently no approved pharmacotherapies for the Although cocaine-specific antibodies have been shown to treatment of cocaine abuse. Recently, significant efforts reduce the reinforcing and/or subjective effects of cocaine have been made toward developing protein-based pharma- in both preclinical (Carrera et al, 2000; Fox et al, 1996; cotherapies as an alternative approach to treating cocaine Kantak et al, 2000), and clinical studies (Haney et al, 2010; abuse with the goal of reducing the amount of cocaine that Martell et al, 2005), many of these studies also suggest that the protective effects of cocaine-specific antibodies are *Correspondence: Dr GT Collins, Alcohol and Drug Abuse Research easily surmounted by increasing the rate and/or amount of Center, McLean Hospital, Harvard Medical School, 115 Mill Street, cocaine intake. One approach to circumvent these stoichio- Belmont, MA 02478, USA, Tel: + 1 617 855 2611, Fax: 734 764 7118, E-mail: [email protected] metric limitations has been to develop catalytic antibodies, 2Current address: Alcohol and Drug Abuse Research Center, McLean such as mAb 15A10, which not only sequester cocaine in the Hospital, Harvard Medical School, Belmont, MA, USA periphery, but also catalyze its breakdown (Landry et al, Received 26 July 2011; revised 18 August 2011; accepted 18 August 1993). Although this approach has been shown to selectively 2011 decrease cocaine self-administration in rats (Baird et al, Prolonged inhibition of cocaine’s effects by PEG-CCRQ CocE GT Collins et al 1093 2000; Mets et al, 1998), its utility has been limited by the (PEG) moieties has been shown to lengthen in vivo relatively poor efficiency with which mAb 15A10 metabo- residence times by imparting stealth properties (Caliceti lizes cocaine (Kcat/Km B26-fold lower than butyrylcholi- and Veronese, 2003). The addition of two 40 kDa branched nesterase (BChE)). Nevertheless, together with the PEG moieties (one per monomer) to CCRQ CocE (PEG- demonstration that exogenous BChE is capable of reducing CCRQ CocE) dramatically increased its in vivo duration of the toxic effects of cocaine (Lynch et al, 1997), these action in rodents, with a 32.0-mg/kg dose of PEG-CCRQ experiments provided the theoretical basis for the develop- CocE capable of reducing the reinforcing effects of 0.1 mg/ ment of highly efficient cocaine-specific enzymes as kg/inj cocaine for up to 96 h, and the lethal effects of pharmacotherapies for cocaine toxicity and abuse (eg, Zhan 180.0 mg/kg cocaine for up to 72 h (Narasimhan et al, 2011). et al, 2003). Briefly, the current studies were aimed at extending these Cocaine is naturally metabolized by BChE to the inactive findings by providing a detailed characterization of the metabolites ecgonine methyl ester and benzoic acid, with effectiveness, selectivity, and duration of PEG-CCRQ CocE’s elimination half-lives for cocaine of B26 min in rats and actions in cocaine self-administration and discrimination B45 min in non-human and human primates (Carmona assays in rats. Accordingly, the effects of three doses of et al, 2005; Mello et al, 2002; Mendelson et al, 1999). In an PEG-CCRQ CocE were evaluated against at least a 100-fold attempt to improve upon BChE’s catalytic efficiency, Zhan range of cocaine doses in self-administration and drug and colleagues have used site-directed mutagenesis to create discrimination procedures, with the daily assessment of mutant BChEs capable of hydrolyzing cocaine B450–2000 cocaine dose–response curves used to determine the in vivo times more efficiently than native BChE (Pan et al, 2005; duration of PEG-CCRQ CocE’s actions. In addition, Zheng et al, 2008). These mutant BChEs have shown methylphenidate (self-administration and drug discrimina- promising results when evaluated in rodents, effectively tion) and d-amphetamine (drug discrimination only) were reducing the cardiovascular, lethal, and response-reinstat- also used to evaluate PEG-CCRQ CocE’s pharmacologic ing effects of cocaine (Brimijoin et al, 2008; Xue et al, 2010; selectivity, whereas rates of food-reinforced responding Zheng et al, 2008). In addition, an albumin-fused mutant were used to evaluate the behavioral selectivity of PEG- BChE (Albu-CocH) has been shown to decrease progressive CCRQ CocE’s effects. ratio responding for cocaine (Carroll et al, 2011), suggesting that it is also capable of reducing the reinforcing effective- ness of cocaine. METHODS In addition to mutant BChEs, a highly efficient (Kcat/Km Subjects B800-fold greater than BChE; Larsen et al, 2002; Turner et al, 2002), bacterial cocaine esterase (CocE) has been Male Sprague-Dawley rats (325–350 g) were obtained from isolated from a strain of Rhodococcus growing in the soil Harlan (Indianapolis, IN) and maintained in a temperature around coca plants (Bresler et al, 2000) and extensively and humidity controlled environment, on a 12-h dark/light evaluated as a possible treatment for cocaine toxicity and cycle with lights on at 0700 h. All rats were singly housed abuse. Although the wild-type (wt) form of CocE is capable with free access to tap water and B20 g of food per day. All of dose dependently protecting mice and rats against the experimental procedures were approved by the University cardiovascular, convulsant, and lethal effects of cocaine, it is of Michigan Committee on the Use and Care of Animals, rapidly inactivated at body temperature resulting in an and performed in accordance with the Guide for the Care in vivo half-life of B15 min (Cooper et al, 2006; Jutkiewicz and Use of Laboratory Animals as adopted and promul- et al, 2009; Ko et al, 2007, 2009; Wood et al, 2010). Site- gated by the National Institutes of Health. directed mutagenesis studies aimed at improving the thermostability of CocE have identified an equally efficient Surgery mutant CocE (T172R/G173Q CocE, RQ CocE, DM CocE) with an in vivo half-life of B4.5 h in mice (Gao et al, 2009; Rats were prepared with chronic indwelling catheters in the Narasimhan et al, 2010), and a high degree of pharmaco- left femoral vein under ketamine:xylazine (90 : 10 mg/kg; logic specificity (Brim et al, 2011). In addition to dose intraperitoneal (IP)) anesthesia. Catheters were passed dependently inhibiting the cardiovascular, convulsant, under the skin and attached to stainless steel tubing that lethal, and reinforcing effects of cocaine in rats (Collins exited through a metal tether button that was sutured to the et al, 2009, 2011b), DM CocE has also been shown to muscle between the scapulae. A 5–7-day recovery period effectively reverse the cardiovascular effects associated with was provided before experimentation.
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