title: ABT-089, but not ABT-107, ameliorates nicotine withdrawal-induced cognitive deficits in C57BL6/J mice.
abstract: Nicotine withdrawal produces cognitive deficits that can predict relapse. Amelioration of these cognitive deficits emerges as a target in current smoking cessation therapies. In rodents, withdrawal from chronic nicotine disrupts contextual fear conditioning (CFC), whereas acute nicotine enhances this hippocampus-specific learning and memory. These modifications are mediated by β2-subunit-containing (β2*) nicotinic acetylcholine receptors in the hippocampus. We aimed to test ABT-089, a partial agonist of α4β2*, and ABT-107, an α7 nicotinic acetylcholine receptor agonist, for amelioration of cognitive deficits induced by withdrawal from chronic nicotine in mice. Mice underwent chronic nicotine administration (12.6 mg/kg/day or saline for 12 days), followed by 24 h of withdrawal. At the end of withdrawal, mice received 0.3 or 0.6 mg/kg ABT-089 or 0.3 mg/kg ABT-107 (doses were determined through initial dose-response experiments and prior studies) and were trained and tested for CFC. Nicotine withdrawal produced deficits in CFC that were reversed by acute ABT-089, but not ABT-107. Cued conditioning was not affected. Taken together, our results suggest that modulation of hippocampal learning and memory using ABT-089 may be an effective component of novel therapeutic strategies for nicotine addiction.
authors.affiliation: Department of Psychology, Program in Neuroscience, Temple University, Philadelphia, Pennsylvania, USA.
authors.forename: Emre
authors.initials: E
authors.lastname: Yildirim
authors.forename: David A
authors.initials: DA
authors.lastname: Connor
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Gould
mesh_terms: D000818:Animals; D003071:Cognition / Q000187:drug effects*; D003213:Conditioning, Psychological / Q000187:drug effects; D003463:Cues; D004305:Dose-Response Relationship, Drug; D054333:Drug Partial Agonism; D005239:Fear / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology*; D007858:Learning / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009538:Nicotine / Q000009:adverse effects*; D018722:Nicotinic Agonists / Q000008:administration & dosage / Q000494:pharmacology; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology*; D011759:Pyrrolidines / Q000008:administration & dosage / Q000494:pharmacology*; D011812:Quinuclidines / Q000494:pharmacology*; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000378:metabolism; D013375:Substance Withdrawal Syndrome / Q000150:complications; D014029:Tobacco Use Disorder / Q000188:drug therapy
chemical_list: D007211:Indoles; D009538:Nicotine; D018722:Nicotinic Agonists; D011725:Pyridines; D011759:Pyrrolidines; D011812:Quinuclidines; D011978:Receptors, Nicotinic; C552256:5-(6-(1-azabicyclo(2,2,2)oct-3-yloxy)pyridazin-3-yl)-1H-indole; C403531:nicotinic receptor alpha4beta2; C108326:pozanicline