Paterson NE, Markou A. The metabotropic glutamate receptor 5 antagonist MPEP decreased break points for nicotine, cocaine and food in rats. Psychopharmacology (Berl) 179: 255-261
Department of Neuropharmacology, CVN-7, The Scripps Research Institute, La Jolla, CA 92037, USA. Psychopharmacology
(Impact Factor: 3.88).
05/2005; 179(1):255-61. DOI: 10.1007/s00213-004-2070-9
The metabotropic glutamate (mGlu5) receptor subtype 5 antagonist MPEP attenuates self-administration of numerous drugs of abuse.
The purpose of the present study was to explore whether MPEP-induced decreases in nicotine and cocaine self-administration reflect attenuation of the reinforcing and incentive motivational effects of nicotine and cocaine. The effects of MPEP on breaking points maintained by nicotine, cocaine or food were assessed using a progressive ratio schedule of reinforcement. Breaking points obtained under such schedules are postulated to reflect both the reinforcing and incentive motivational properties of reinforcers.
Rats were allowed to respond for nicotine (0.05 mg/kg per infusion, free base), cocaine (0.18 mg/kg per infusion, salt), or food (45 mg pellets) under a progressive ratio schedule of reinforcement. After establishing stable and equivalent levels of responding for all three reinforcers, rats underwent one test session where no rewards were presented to assess the effects of 1-day extinction, similar to 1-day pharmacological-induced extinction, on performance in this schedule. Subsequently, rats were again allowed to respond for nicotine, cocaine or food until reestablishment of stable levels of responding. Then, MPEP (1-9 mg/kg) was administered intraperitoneally according to a within-subjects Latin square design, 30 min prior to the testing sessions.
Responding in the absence of a primary reinforcer was significantly decreased compared to responding under baseline conditions. Further, MPEP decreased break points maintained by nicotine, cocaine and food.
The mGlu5 receptor is implicated in mediating the reinforcing and incentive motivational properties of nicotine, cocaine and food.
Available from: Gregor Hasler
- "In reinstatement studies, self-administration training was followed by extinction and, subsequently, reinstatement of drug seeking by either a priming administration of the reinforcer (substance-induced reinstatement) or a response-contingent administration of the conditioned cues which had been delivered together with the reinforcer during selfadministration training (cue-induced reinstatement). Thus, the main experimental paradigms were consumption under direct access to the reinforcer, self-administration maintenance under a fixed reinforcement schedule, substance-, or cue-induced reinstatement of drug seeking.A total of 125 reports (Chiamulera et al., 2001;Paterson et al., 2003;Backstrom et al., 2004;Tessari et al., 2004;Bespalov et al., 2005;Bradbury et al., 2005;Cowen et al., 2005;Kenny et al., 2005;Lee et al., 2005;McMillen et al., 2005;Olive et al., 2005;Paterson and Markou, 2005;Schroeder et al., 2005;Varty et al., 2005;Backstrom and Hyytia, 2006;Hodge et al., 2006;Iso et al., 2006;Lominac et al., 2006;Cowen et al., 2007;Liechti and Markou, 2007;Semenova and Markou, 2007;van der Kam et al., 2007;Adams et al., 2008;Besheer et al., 2008;Gupta et al., 2008;Osborne and Olive, 2008;Palmatier et al., 2008;Platt et al., 2008;Schroeder et al., 2008;Gass et al., 2009;Kumaresan et al., 2009;Martin-Fardon et al., 2009;Moussawi et al., 2009;Hao et al., 2010;Ploj et al., 2010;Sidhpura et al., 2010;Tronci et al., 2010;Eiler et al., 2011;Popik et al., 2011;Tronci and Balfour, 2011;Martin-Fardon and Weiss, 2012;Varga et al., 2012;Keck et al., 2013;Watterson et al., 2013;Keck et al., 2014)on the effects of mGluR5 NAMs were extracted and classified with respect to the following parameters: publication (source of the report), mGluR5 NAM (MPEP, MTEP, fenobam, or MFZ 10-7), species (rats, mice, or monkeys), administration route (i.p., s.c., i.m., or i.v.), administered dose (mg/kg), and experimental paradigm (Supplementary Figures S1-4). Furthermore, the alpha error correction-method reported was extracted for each study (Supplementary Table S1). "
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Abundant evidence at the anatomical, electrophysiological, and molecular level implicates metabotropic glutamate receptors subtype 5 (mGluR5) in addiction. Consistently, the effects of a wide range of doses of different mGluR5 negative allosteric modulators (NAMs) have been tested in various animal models of addiction. Here, these studies were subjected to a systematic review to find out if mGluR5 NAMs have a therapeutic potential which can be translated to the clinic.
Literature on consumption/self-administration and reinstatement of drug seeking as outcomes of interest published up to April 2015 was retrieved via PubMed. The review focused on the effects of systemic (i.p., i.v., s.c.) administration of the mGluR5 NAMs MTEP and MPEP on paradigms with cocaine, ethanol, nicotine, and food in rats.
MTEP and MPEP were found to reduce self-administration of cocaine, ethanol, and nicotine, at doses equal to or higher than 1 mg/kg and 2.5 mg/kg, respectively. Dose-response relationship resembled a sigmoidal curve, with low doses not reaching statistical significance and high doses reliably inhibiting self-administration of drugs of abuse. Importantly, self-administration of cocaine, ethanol, and nicotine but not food was reduced by MTEP and MPEP in the dose range 1-2 mg/kg and 2.5-3.2mg/kg, respectively. This dose range corresponds to approximately 50%-80% mGluR5 occupancy. Interestingly, the limited data found in mice and monkeys showed a similar therapeutic window.
Altogether, this review suggests a therapeutic window for mGluR5 NAMs which can be translated to the treatment of substance-related and addictive disorders.
Available from: Manoranjan S D'Souza
- "In other words, break point, reflects the maximum work an animal will perform to obtain another infusion/delivery of the drug. Several studies have demonstrated reliable intravenous self-administration of cocaine, nicotine, and heroin under both fixed-and progressive-ratio schedules (e.g., Roberts and Bennett, 1993; Duvauchelle et al., 1998; Paterson and Markou, 2005). Additionally, several studies have demonstrated oral self-administration of alcohol using the two bottle choice paradigm (e.g., Grant and Samson, 1985; Pfeffer and Samson, 1985; Samson and Doyle, 1985; Suzuki et al., 1988). "
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ABSTRACT: Individuals addicted to drugs of abuse such as alcohol, nicotine, cocaine, and heroin are a significant burden on healthcare systems all over the world. The positive reinforcing (rewarding) effects of the above mentioned drugs play a major role in the initiation and maintenance of the drug-taking habit. Thus, understanding the neurochemical mechanisms underlying the reinforcing effects of drugs of abuse is critical to reducing the burden of drug addiction in society. Over the last two decades, there has been an increasing focus on the role of the excitatory neurotransmitter glutamate in drug addiction. In this review, pharmacological and genetic evidence supporting the role of glutamate in mediating the rewarding effects of the above described drugs of abuse will be discussed. Further, the review will discuss the role of glutamate transmission in two complex heterogeneous brain regions, namely the nucleus accumbens (NAcc) and the ventral tegmental area (VTA), which mediate the rewarding effects of drugs of abuse. In addition, several medications approved by the Food and Drug Administration that act by blocking glutamate transmission will be discussed in the context of drug reward. Finally, this review will discuss future studies needed to address currently unanswered gaps in knowledge, which will further elucidate the role of glutamate in the rewarding effects of drugs of abuse.
Available from: Matthias E Liechti
- "Nicotine increases glutamatergic transmission by activating excitatory nicotinic receptors located on presynaptic glutamatergic terminals (Fu et al, 2000; Mansvelder and McGehee, 2002; Reid et al, 2000). Blockade of glutamatergic neurotransmission by systemic administration of receptor antagonists that act at postsynaptically located ionotropic or metabotropic glutamate (mGlu) receptors attenuated both nicotine selfadministration (Kenny et al, 2009, 2003; Liechti and Markou, 2007; Palmatier et al, 2008; Paterson and Markou, 2005; "
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