Nicotine Relieves Anxiogenic-Like Behavior in Mice that Overexpress the Read-Through Variant of Acetylcholinesterase but Not in Wild-Type Mice

• Published in: Molecular pharmacology Vol. 74; no. 6; pp. 1641 - 1648
• Main Authors: Salas, R, Main, A, Gangitano, D A, Zimmerman, G, Ben-Ari, S, Soreq, H, De Biasi, M
• Format: Journal Article
• Language: English
• Published: United States American Society for Pharmacology and Experimental Therapeutics 01.12.2008
• Subjects: Acetylcholinesterase - biosynthesis; Acetylcholinesterase - genetics; Animals; Anxiety - metabolism; Anxiety - psychology; Behavior, Animal - drug effects; Brain - drug effects; Brain - metabolism; Bridged Bicyclo Compounds, Heterocyclic - pharmacology; Corpus Striatum - drug effects; Corpus Striatum - metabolism; Isoenzymes - biosynthesis; Isoenzymes - genetics; Maze Learning - drug effects; Mice; Mice, Transgenic; Motor Activity - drug effects; Nicotine - pharmacology; Nicotinic Agonists - pharmacology; Oligonucleotide Array Sequence Analysis; Pyridines - pharmacology; Radioligand Assay; Receptors, Nicotinic - biosynthesis; Reverse Transcriptase Polymerase Chain Reaction; Time Factors; Up-Regulation
• ISSN: 0026-895X; 1521-0111
• DOI: 10.1124/mol.108.048454

Stress increases vulnerability and causes relapse to drugs of abuse. The usually rare read-through variant of acetylcholinesterase (AChE-R) is causally involved in stress-related behaviors, and transgenic mice constitutively overexpressing AChE-R (TgR) show behaviors characteristic of chronic stress. We measured anxiety-like behavior on TgR and control mice under normal conditions and under long-term nicotine treatment. In addition, we measured epibatidine binding in the brain and transcription status in the striatum, using microarrays, in wild-type and TgR mice. TgR mice behaved as more anxious than controls, an effect normalized by long-term nicotine intake. In control mice, long-term nicotine augmented epibatidine binding in several areas of the brain, including the hippocampus and striatum. In TgR transgenics, long-term nicotine increased epibatidine binding in some areas but not in the hippocampus or the striatum. Because the striatum is involved in the mechanisms of drug addiction, we studied how the transgene affected striatal gene expression. Whole-genome DNA microarray showed that 23 transcripts were differentially expressed in TgR mouse striata, including 15 known genes, 7 of which are anxiety-related. Subsequent reverse-transcriptase polymerase chain reaction validated changes in 7 of those 15 genes, confirmed the increase trend in 5 more transcripts, and further revealed changes in 5 genes involved in cholinergic signaling. In summary, we found that nicotine acts as an anxiolytic in TgR mice but not in control mice and that continuously overexpressed AChE-R regulates striatal gene expression, modulating cholinergic signaling and stress-related pathways.