title: The effects of galantamine on nicotine withdrawal-induced deficits in contextual fear conditioning in C57BL/6 mice.
abstract: Current smoking cessation aids are relatively ineffective at maintaining abstinence during withdrawal. Nicotine withdrawal is associated with a variety of symptoms including cognitive deficits and targeting these deficits may be a useful strategy for maintaining abstinence. Galantamine is an acetylcholinesterase inhibitor and allosteric modulator of nicotinic acetylcholine receptors (nAChRs) with cognitive enhancing effects that may alleviate cognitive deficits associated with nicotine withdrawal. The effects of galantamine on nicotine withdrawal-induced deficits in contextual fear conditioning in C57BL/6 mice were examined. An initial acute dose-response experiment revealed that 0.5 and 1mg/kg galantamine had no effect on fear conditioning. To determine if galantamine would reverse nicotine withdrawal-related deficits in contextual fear conditioning, mice were implanted with osmotic mini-pumps that delivered chronic saline or 6.3mg/kg/d nicotine for 12 days and then pumps were removed. Training and testing of fear conditioning occurred 24 and 48 h later, respectively. Nicotine withdrawal disrupted contextual fear conditioning, which was reversed with 1 but not 0.5mg/kg galantamine. Across all conditions in both studies 2mg/kg galantamine led to high levels of freezing that were likely due to nonspecific effects. The ability of galantamine to reverse nicotine withdrawal-deficits in contextual conditioning is likely mediated through enhanced levels of acetylcholine via inhibition of acetylcholinesterase, potentiation of hippocampal α4β2* nAChRs, or both. The present study suggests that acetylcholinesterase inhibitors and/or drugs that act as allosteric modulators of nAChRs might be targets for smoking cessation aids because they may alleviate withdrawal symptoms such as cognitive deficits that can lead to relapse.
authors.affiliation: Temple University, Department of Psychology, Neuroscience Program, Philadelphia, PA 19122, USA.
authors.forename: Derek S
authors.initials: DS
authors.lastname: Wilkinson
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Gould
mesh_terms: D000818:Animals; D002800:Cholinesterase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D003214:Conditioning, Classical / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005239:Fear / Q000187:drug effects*; D005702:Galantamine / Q000494:pharmacology / Q000627:therapeutic use*; D015918:Infusion Pumps, Implantable; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009538:Nicotine / Q000008:administration & dosage / Q000009:adverse effects*; D018722:Nicotinic Agonists / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy*
chemical_list: D002800:Cholinesterase Inhibitors; D018722:Nicotinic Agonists; D005702:Galantamine; D009538:Nicotine