6-methyl-2-(phenylethynyl)pyridine and Tobacco-Use-Disorder

Nicotine dependence is the primary motivational factor perpetuating the tobacco smoking habit that is one of the leading preventable causes of morbidity throughout the world. This Neuroscience Perspectives article summarizes and discusses recent evidence demonstrating the critical role of glutamate transmission in nicotine dependence and emerging data suggesting that compounds acting as antagonists at metabotropic glutamate receptors may be useful therapeutics to assist people in achieving and maintaining abstinence from tobacco smoking. Metabotropic glutamate 5 receptor antagonists may be useful in decreasing the reinforcing effects of nicotine, reducing motivation for nicotine and preventing relapse during protracted abstinence, whereas metabotropic glutamate 2/3 receptor antagonists may alleviate the depression observed during the early nicotine withdrawal phase. Metabotropic glutamate 2/3 receptor antagonists may also be therapeutics for non-drug-induced depressions.

Topics: Animals; Depression; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Humans; Models, Biological; Nicotine; Pyridines; Receptors, Metabotropic Glutamate; Reinforcement, Psychology; Time Factors; Tobacco Use Disorder

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.

Topics: Animals; Behavior, Animal; Conditioning, Operant; Disease Models, Animal; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Male; Nicotine; Nicotinic Agonists; Photic Stimulation; Pyridines; Rats; Rats, Sprague-Dawley; Reinforcement, Psychology; Self Administration; Thiazoles; Tobacco Use Disorder

Topics: Animals; Brain; Cocaine; Cocaine-Related Disorders; Dose-Response Relationship, Drug; Nicotine; Nicotinic Agonists; Pyridines; Rats; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate; Reward; Tobacco Use Disorder