Neuropsychopharmacology (2016) 41, 1166–1178 © 2016 American College of Neuropsychopharmacology. All rights reserved 0893-133X/16 www.neuropsychopharmacology.org Partial mGlu5 Negative Allosteric Modulators Attenuate Cocaine-Mediated Behaviors and Lack Psychotomimetic-Like Effects 1,2,5 1,2,5,6 1,2 1 1,2 Robert W Gould , Russell J Amato , Michael Bubser , Max E Joffe , Michael T Nedelcovych , Analisa D Thompson1,2, Hilary H Nickols2,3, Johannes P Yuh1,2, Xiaoyan Zhan1,2, Andrew S Felts2,4, Alice L Rodriguez1,2, Ryan D Morrison1,2, Frank W Byers1,2, Jerri M Rook1,2, John S Daniels1,2, 1,2 1,2 1,2,4 1,2,4 *,1,2 Colleen M Niswender , P Jeffrey Conn , Kyle A Emmitte , Craig W Lindsley and Carrie K Jones 1Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA; 2Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN, USA; 3Department of Pathology, Microbiology and Immunology, Division of Neuropathology, 4 Vanderbilt University Medical Center, Nashville, TN, USA; Department of Chemistry, Vanderbilt University Medical Center, Nashville, TN, USA Cocaine abuse remains a public health concern for which pharmacotherapies are largely ineffective. Comorbidities between cocaine abuse, depression, and anxiety support the development of novel treatments targeting multiple symptom clusters. Selective negative allosteric modulators (NAMs) targeting the metabotropic glutamate receptor 5 (mGlu ) subtype are currently in clinical trials for the treatment of 5 multiple neuropsychiatric disorders and have shown promise in preclinical models of substance abuse. However, complete blockade or inverse agonist activity by some full mGlu5 NAM chemotypes demonstrated adverse effects, including psychosis in humans and psychotomimetic-like effects in animals, suggesting a narrow therapeutic window. Development of partial mGlu5 NAMs, characterized by their submaximal but saturable levels of blockade, may represent a novel approach to broaden the therapeutic window. To understand potential therapeutic vs adverse effects in preclinical behavioral assays, we examined the partial mGlu5 NAMs, M-5MPEP and Br-5MPEPy, in comparison with the full mGlu5 NAM MTEP across models of addiction and psychotomimetic-like activity. M-5MPEP, Br-5MPEPy, and MTEP dose-dependently decreased cocaine self-administration and attenuated the discriminative stimulus effects of cocaine. M-5MPEP and Br-5MPEPy also demonstrated antidepressant- and anxiolytic-like activity. Dose-dependent effects of partial and full mGlu NAMs in these 5 assays corresponded with increasing in vivo mGlu5 occupancy, demonstrating an orderly occupancy-to-efficacy relationship. PCP-induced hyperlocomotion was potentiated by MTEP, but not by M-5MPEP and Br-5MPEPy. Further, MTEP, but not M-5MPEP, potentiated the discriminative-stimulus effects of PCP. The present data suggest that partial mGlu5 NAM activity is sufficient to produce therapeutic effects similar to full mGlu5 NAMs, but with a broader therapeutic index. Neuropsychopharmacology (2016) 41, 1166–1178; doi:10.1038/npp.2015.265; published online 30 September 2015 INTRODUCTION treating cocaine abuse have been largely unsuccessful (Shorter et al, 2015) and some purported treatment mecha- Cocaine use continues to be a public health concern, with nisms elicit or exacerbate unwanted symptoms (eg, depres- an estimated 1.6 million cocaine users in the United States sion, anxiety, increased impulsivity, cognitive impairments, alone in 2012 (Administration SAMHSA, 2012). Comor- or psychosis) (Homayoun et al, 2004; Kishi et al, 2013; bidity with other psychiatric conditions, including depres- Moore et al, 2014). Developing pharmacotherapies targeting sion and anxiety disorders, is commonly seen in substance cocaine addiction and associated comorbidities while lacking use disorders, including cocaine abuse (Volkow, 2004; adverse effects may provide greater therapeutic efficacy as Vorspan et al, 2015). Pharmacotherapies developed for well as medication compliance, increased abstinence rates and improved overall treatment success. *Correspondence: Dr Carrie K. Jones, Department of Pharmacology One novel treatment mechanism for cocaine addiction and Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt involves modulation of glutamatergic neurotransmission University Medical Center, 418A PRB, 2220 Pierce Avenue, Nashville, through antagonism of the metabotropic glutamate (mGlu) TN 37232-0697, USA, Tel: +615-343-4337, Fax: +615-343-3088, receptor subtype, mGlu (Bird and Lawrence, 2009). E-mail: [email protected] 5 5These authors contributed equally to this work Glutamate binds to and signals through both ionotropic 6Present Address: Department of Neuroscience, Louisiana State and mGlu receptors. mGlu5 is one of eight mGlu receptor University Health Sciences Center, New Orleans, LA 70112, USA. subtypes identified and couples to Gq/11 proteins, resulting in Received 26 May 2015; revised 17 August 2015; accepted 21 August intracellular calcium mobilization and the activation of 2015; accepted article preview online 28 August 2015 phosphoinositide hydrolysis (Niswender and Conn, 2010). Preclinical efficacy of mGlu5 partial NAMs RW Gould et al 1167 Selective inhibitors of mGlu5, known as negative allosteric when compared with a full mGlu5 NAM like MTEP; this modulators (NAMs), have been developed that do not submaximal blockade occurs at concentrations that fully interact with the highly conserved orthosteric binding site occupy the allosteric site on mGlu5 (Rodriguez et al, 2005). of glutamate, but instead bind to an allosteric site in the We previously reported the development and characteriza- seven transmembrane-spanning domain of mGlu5 and tion of two highly selective partial mGlu5 NAMs M-5MPEP inhibit coupling of the receptor to GTP-binding proteins and Br-5MPEPy that, in contrast to MPEP and MTEP, (Conn et al, 2009). These selective mGlu5 NAMs have shown produced only a 50% inhibition of the maximal glutamate exciting efficacy across preclinical models (Emmitte, 2011; response in vitro within a concentration range that fully Christopoulos, 2014; Nickols and Conn, 2014) and in clinical displaces binding of the radioligand [3H]methoxyPEPy to development for the treatment of multiple CNS disorders the MPEP allosteric binding site of mGlu5 (Rodriguez (Berg et al, 2011; Jacquemont et al, 2011; Nickols and Conn, et al, 2005). In the present studies, we compare the 2014; Lindemann et al, 2015). behavioral effects of the partial mGlu5 NAMs M-5MPEP Preclinical studies have shown that the first generation and Br-5MPEPy with the classical full mGlu5 NAM MTEP of selective full mGlu5 NAMs, MPEP and MTEP (Gasparini in preclinical models of cocaine abuse, anxiolytic- and et al, 1999; Cosford et al, 2003), reduced cocaine antidepressant-like activity and psychotomimetic-like effects. self-administration, attenuated drug and cue-mediated Both partial mGlu5 NAMs attenuated cocaine-mediated reinstatement of cocaine-seeking behavior, and/or blocked behaviors and produced antidepressant- and anxiolytic-like cocaine-induced conditioned place preference (CPP) in effects comparable to effects with the full mGlu5 NAM rodents and nonhuman primates (McGeehan and Olive, MTEP. In contrast to full mGlu5 NAMs, the partial mGlu5 2003; Herzig and Schmidt, 2004; Kenny et al, 2005; Lee et al, NAMs did not exacerbate PCP-induced effects, cause 2005; Paterson and Markou, 2005; Backstrom and Hyytia, sedation, or demonstrate inverse agonist activity in vitro. 2006; Kumaresan et al, 2009; Brown et al, 2012). MPEP and The present data suggest that partial mGlu5 NAM activity is MTEP also produced robust anxiolytic- and antidepressant- sufficient to produce similar effects as full mGlu5 NAMs like activity, suggesting that mGlu5 NAMs may be effective across multiple preclinical models of addiction and comorbid in treating the comorbid symptoms observed in cocaine conditions. Importantly, the partial mGlu5 NAMs exhibit addicts (Busse et al, 2004; Ballard et al, 2005). Unfortunately, less adverse effect potential, supporting a role for partial clinical and preclinical studies using full mGlu5 NAMs, with mGlu5 NAM activity for the treatment of neuropsychiatric little chemotype diversity, exhibited a narrow therapeutic disorders, including cocaine abuse. index between doses that produced efficacy and those that induced dose-limiting adverse effects (Kinney et al, 2003; Homayoun et al, 2004; Gravius et al, 2005). In particular, the MATERIALS AND METHODS mGlu5 NAM fenobam (McN-3377) demonstrated anxiolytic- Animals like effects in rodents and humans yet also induced psychotomimetic-like effects in humans (Friedmann et al, Group-housed adult male Sprague-Dawley rats (two to three 1980; Pecknold et al, 1982; Porter et al, 2005). per cage) or CD-1 mice (four to five per cage; Harlan Although the underlying cause of these adverse effects Laboratories, Indianapolis, IN) were maintained on a 12-h remains unknown, one possible mechanism is through light/12-h dark cycle with standard rodent chow and water downstream inhibition of ionotropic N-methyl-D-aspartate available ad libitum except for animals in self-administration receptor subtype of glutamate receptors (NMDARs), to and drug discrimination studies (see below). All studies which mGlu5 is physically and functionally coupled were approved by the Institutional Animal Care and (Mannaioni et al, 2001; Pisani et al, 2001; Marino and Use Committee of Vanderbilt University