The mGluR2 Positive Allosteric Modulator BINA Decreases Cocaine Self-Administration and Cue-Induced Cocaine-Seeking and Counteracts Cocaine-Induced Enhancement of Brain Reward Function in Rats

Neuropsychopharmacology (2010) 35, 2021–2036 & 2010 Nature Publishing Group All rights reserved 0893-133X/10 $32.00 www.neuropsychopharmacology.org The mGluR2 Positive Allosteric Modulator BINA Decreases Cocaine Self-Administration and Cue-Induced Cocaine-Seeking and Counteracts Cocaine-Induced Enhancement of Brain Reward Function in Rats Xinchun Jin1,4, Svetlana Semenova1,4, Li Yang2, Robert Ardecky2, Douglas J Sheffler3, Russell Dahl2, P Jeffrey Conn3, Nicholas DP Cosford2 and Athina Markou*,1 1 Department of Psychiatry, School of Medicine, University of California San Diego, La Jolla, CA, USA; 2Program on Apoptosis and Cell Death, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA; 3Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA Metabotropic glutamate receptor 2/3 (mGluR2/3) agonists were shown previously to nonselectively decrease both cocaine- and food-maintained responding in rats. mGluR2 positive allosteric modulators (PAMs) may represent improved therapeutic compounds because of their modulatory properties and higher selectivity for mGluR2. We analyzed the effects of the selective, brain penetrant, and systemically active mGluR2 PAM potassium 30 -([(2-cyclopentyl-6-7-dimethyl-1-oxo-2,3-dihydro-1H-inden-5-yl)oxy]methyl)biphenyl l-4-carboxylate (BINA) and the mGluR2/3 agonist LY379268 on intravenous cocaine self-administration and cocaine-seeking behavior in rats that had short (1 h, ShA) or long (6 h, LgA) access to cocaine. The effects of BINA on food responding and food-seeking behavior were also analyzed. Finally, we examined the effects of BINA on brain reward function and cocaine-induced reward enhancement using the intracranial self-stimulation procedure. BINA decreased cocaine self-administration in both ShA and LgA rats, with no effect on food self-administration. Alternatively, LY379268 nonselectively decreased both cocaine and food self-administration. BINA decreased cue-induced reinstatement of cocaine seeking with no effect on food seeking. The cocaine-induced enhancement of brain reward function was blocked by BINA, although the highest doses of BINA decreased brain reward function when administered alone, suggesting additive, rather than interactive, effects of BINA and cocaine. In conclusion, BINA attenuated the reinforcing and counteracted the reward-enhancing effects of cocaine and decreased cue-induced cocaine-seeking behavior, without affecting behaviors motivated by food reinforcement. The higher selectivity of BINA compared with an mGluR2/3 agonist for drug- vs food-motivated behaviors suggests a therapeutic role for mGluR2 PAMs for the treatment of cocaine addiction and possibly other drugs of abuse. Neuropsychopharmacology (2010) 35, 2021–2036; doi:10.1038/npp.2010.82; published online 16 June 2010 Keywords: glutamate; LY379268; intracranial self-stimulation; food seeking; food responding; BINA INTRODUCTION Cocaine addiction, a chronic relapsing disorder, remains a major public health problem in the United States (O’Brien and McLellan, 1996; Leshner, 1997; Ohishi et al, 1998; Dackis and O’Brien, 2001), showing the unmet need for novel treatments for cocaine addiction (O’Brien and Gardner, 2005). Several sources of motivation contribute to the maintenance of cocaine abuse. Specifically, the *Correspondence: Dr A Markou, Department of Psychiatry, M/C 0603, School of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0603, USA, Tel: + 1 858 534 1572, Fax: + 1 858 534 9917, E-mail: 4 These authors contributed equally to this work. Received 26 January 2010; revised 11 May 2010; accepted 11 May 2010 rewarding properties of abused drugs lead to a progressive escalation in the frequency and intensity of drug use, one of the major behavioral phenomena characterizing the development of addiction (American Psychiatric Association, 1994; for review, see Koob et al, 2004; Koob, 2009). In animal experiments, rats that have extended/long access to intravenous cocaine self-administration increase their intake over days, closely mimicking the human condition of increased compulsive drug use (Ahmed and Koob, 1998; Ahmed et al, 2002). In addition, cocaine amplifies reward signals in the brain, an effect common with other drugs of abuse (Robbins et al, 1983; Taylor and Robbins, 1986; Phillips and Fibiger, 1990; Rice and Cragg, 2004). Furthermore, the reward-enhancing actions of cocaine may partially account for its intrinsic rewarding properties and reflect how psychostimulant mGluR2 positive allosteric modulator and cocaine X Jin et al 2022 drugs, including cocaine, increase sensitivity to non-drug rewarding environmental stimuli (Harrison et al, 2002; Chaudhri et al, 2006; Kenny and Markou, 2006; Kenny, 2007). Specifically, in the intracranial self-stimulation (ICSS) procedure, cocaine administration lowers reward thresholds in rats (Esposito et al, 1978; Frank et al, 1988; Kokkinidis and McCarter, 1990; Markou and Koob, 1992; Kenny et al, 2003, 2006), reflecting cocaine-induced enhancement of the rewarding effects of the stimulation. Finally, chronic vulnerability to relapse contributes to the maintenance of cocaine abuse (Weiss, 2005; Epstein et al, 2006). The presentation of environmental stimuli previously associated with drug taking can precipitate drug craving and relapse to drug use in humans (O’Brien and McLellan, 1996; O’Brien et al, 1998; Dackis and O’Brien, 2001) and may elicit cocaine-seeking behaviors, leading to the reinstatement of cocaine self-administration in animals (eg, Markou et al, 1993; Katz and Higgins, 2003; Epstein et al, 2006). Recent findings suggest that the neuronal mechanisms underlying drug self-administration are different from those mediating relapse vulnerability during abstinence (Shalev et al, 2002; Kalivas and Volkow, 2005; Shiffman et al, 2006). Therefore, in the assessment of the putative therapeutic effects of new compounds, examining the effects of the compounds on the different aspects of cocaine dependence is important. Recent findings suggest that neuroadaptations in glutamatergic transmission induced by repeated exposure to cocaine or other drugs of abuse are likely to contribute to the maintenance of addictive behaviors, including drug use, craving, and relapse to drug taking in humans (Kalivas and Duffy, 1998; Mansvelder and McGehee, 2000; Ungless et al, 2001; Kalivas, 2004, 2009; Kenny and Markou, 2004; Markou, 2007; Gass and Olive, 2008; Knackstedt and Kalivas, 2009). Specifically, repeated cocaine exposure alters the function of group II metabotropic glutamate receptors (mGluRs). Group II mGluRs, comprising mGluR2 and mGluR3, are predominantly found presynaptically (Schoepp, 2001) and modulate presynaptic glutamate release (Conn and Pin, 1997; Anwyl, 1999; Cartmell and Schoepp, 2000). High levels of group II receptor binding are found in brain regions implicated in different aspects of drug abuse and dependence, sug (...truncated)