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Cellular mechanisms of addiction (468.2)
Author(s) -
Kenny Paul
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.468.2
Subject(s) - nicotine , stimulation , pharmacology , brain stimulation reward , neuroscience , interpeduncular nucleus , nicotine withdrawal , medicine , chemistry , endocrinology , receptor , central nervous system , nucleus accumbens , biology , midbrain
Smokers consume tobacco to obtain rewarding effects of nicotine, but to successfully maintain the habit they must titrate their intake to avoid noxious effects of nicotine. In contrast to nicotine reward, very little is known about brain circuitries that regulate nicotine avoidance. I will present evidence that nicotine activates neurons in the nucleus tractus solitarius (NTS) that synthesize the neuropeptide glucagon‐like peptide 1 (GLP‐1). The antidiabetic drugs sitagliptin (Januvia) and exenatide (Byetta), which inhibit GLP‐1 breakdown and stimulate GLP‐1 receptors (GLP‐1Rs), respectively, will be shown to decrease nicotine intake in mice. Chemicogenetic stimulation of GLP‐1 neurons in NTS using DREADDs also decreases nicotine intake. Conversely, GLP‐1R knockout mice are more sensitive to nicotine reward and consume greater quantities of nicotine than wildtype mice. The interpeduncular nucleus (IPN) densely expresses GLP‐1Rs and GLP‐1‐containing neurons project from NTS to IPN. Using optogenetic and electrical stimulation combined with single‐cell recordings, I will show that GLP‐1 activates excitatory inputs from medial habenula to IPN. Pharmacological stimulation of GLP‐1Rs in IPN will be shown to abolish nicotine reward and decrease intake, whereas their blockade is shown to increase intake. It is concluded that GLP‐1 neurons act as “satiety sensors” that regulate nicotine intake by controlling the activity of the habenulo‐interpeduncular aversion system.