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.2008 Aug;33(9):2139-47.
doi: 10.1038/sj.npp.1301623. Epub 2007 Nov 28.

Metabotropic glutamate 5 receptor (mGluR5) antagonists decrease nicotine seeking, but do not affect the reinforcement enhancing effects of nicotine

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Metabotropic glutamate 5 receptor (mGluR5) antagonists decrease nicotine seeking, but do not affect the reinforcement enhancing effects of nicotine

Matthew I Palmatier et al. Neuropsychopharmacology.2008 Aug.

Abstract

Nicotine self-administration models typically evaluate the effects of smoking cessation aides on 'primary reinforcement' engendered by nicotine. However, the more recently described reinforcement enhancing effects of the drug are not always included in experimental analyses of potential therapeutics. We evaluated the effects of pretreatment with noncompetitive antagonists of the metabotropic glutamate 5 receptor (mGluR5) on each reinforcement-related effect of nicotine using a model in which a reinforcing visual stimulus (VS) and nicotine infusions were concurrently available. Five groups (2-lever, VS-only, NIC+VS, NIC-only, or SAL-only) were instrumented for self-administration. The 2-lever group could earn a nicotine infusion (0.06 mg/kg per infusion free base) for meeting the schedule on one lever (eg right), or VS for meeting the schedule on the other lever (eg left). The VS-only group could earn VS or saline under similar contingencies. Remaining rats could press one lever to earn both reinforcers (NIC+VS), nicotine infusions (NIC-only), or saline infusions (SAL-only); the other lever was 'inactive'. Responding on the VS lever in the 2-lever group was greater than that of the VS-only group, reflecting the reinforcement-enhancing effect of nicotine. Pretreatment with 2-methyl-6-(phenylethynyl)-pyridine (MPEP) or 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) decreased nicotine intake as well as the enhanced responding for the concurrently available VS. In follow-up studies, replacing nicotine via experimenter-administered infusions sustained the drugs reinforcement enhancing effect; neither MPEP nor MTEP decreased the enhancing effects of nicotine. These findings are consistent with other studies suggesting that mGlu5 receptors mediate nicotine seeking, but do not alter the reinforcement enhancing effects of nicotine.

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Conflict of interest statement

DISCLOSURE/CONFLICT OF INTEREST

The research presented in this manuscript was supported by NIH Grants DA-10464, DA-19278, and DA-17288. For Experiments 1, 3, and 4, pretreatment drugs were donated by the National Institute on Drug Abuse (MPEP) and Eli Lilly & Company (MTEP). The authors declare that, except for income received from our primary employers, no financial support or compensation has been received from any individual or corporate entity over the past 3 years for research or professional service and there are no personal financial holdings that could be perceived as constituting a potential conflict of interest.

Figures

Figure 1
Figure 1
Mean (± SEM) active lever responding for rats with concurrent access to nicotine and a reinforcing visual stimulus (VS, 2-lever group), rats that received both reinforcers for pressing a single active lever (NIC + VS group), groups that only received access to one of the reinforcers (VS-only or NIC-only groups), and a nonreinforced control condition (SAL-only group). Nicotine (NIC-onlyvs SAL-only) and VS (VS-onlyvs SAL-only) both served as primary reinforcers when they were self-administered in isolation (sessions 12–22), and self-administered nicotine enhanced responding for VS (VS-onlyvs 2-lever).
Figure 2
Figure 2
Panel (a) illustrates mean (+ SEM) active lever responding for groups tested with various doses of MPEP (Experiment 1). Panel (b) illustrates mean (+ SEM) active lever responding for groups tested with various doses of MTEP (Experiment 3). Both metabotropic glutamate 5 receptor (mGluR5) antagonists dose dependently decreased nicotine seeking. Neither antagonist decreased responding for VS (VS-only group), unless VS-derived reinforcement was inflated by concurrent (2-lever group) or contingent (NIC + VS group) access to nicotine.
Figure 3
Figure 3
Panel (a) illustrates mean (+ SEM) active lever responding for groups tested with nicotine replacement and 0 or 12 mg/kg MPEP (Experiment 2). Panel (b) illustrates mean (+ SEM) active lever responding for groups tested with nicotine replacement and 0 or 2 mg/kg MTEP (Experiment 4). Since both mGluR5 antagonists reduced voluntary nicotine-intake (see Figure 2), evaluating their impact on the reinforcement enhancing effects of nicotine required experimenter-administered infusions. Thus, rats in the 2-lever, NIC + VS, and NIC-only groups were given eight experimenter-administered infusions of nicotine during the 60-min test period, the VS-only group received eight saline infusions (hatched and solid bars, see Method). The antagonists decreased nicotine seeking but did not affect the reinforcement enhancing effects of nicotine. Both metabotropic glutamate 5 receptor (mGluR5) antagonists dose dependently decreased nicotine seeking. Neither antagonist decreased VS seeking when VS was presented in isolation (VS-only group), or when VS seeking and nicotine seeking were measured with separate/concurrent responses (2-lever group). Rats in the saline-only (Experiment 2) were not included in pharmacological tests.
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