Administration of the nicotinic acetylcholine receptor agonists ABT-089 and ABT-107 attenuates the reinstatement of nicotine-seeking behavior in rats

Abstract

Current smoking cessation pharmacotherapies have modest efficacy, and most smokers relapse within the first few days after a quit attempt. Nicotine withdrawal-induced craving and cognitive impairments predict smoking relapse during abstinence and suggest that cognitive-enhancing drugs may prevent relapse. ABT-089 and ABT-107 are subtype-selective nAChR agonists that improve cognitive performance in laboratory animals. However, there are no studies examining the effects of ABT-089 and ABT-107 on nicotine self-administration and the reinstatement of nicotine-seeking behavior, an animal model of relapse in human smokers. The goal of the present study was to determine the effects of the α4β2*/α6β2* nAChR agonist ABT-089 and the α7 nAChR agonist ABT-107 on nicotine taking and seeking in rats. The effects of acute ABT-089 and ABT-107 pretreatment on nicotine self-administration and reinstatement were tested in male Sprague Dawley rats. Parallel studies of ABT-089 and ABT-107 on sucrose self-administration and reinstatement were tested in separate groups of rats to determine if the effects of these drug treatments generalized to other reinforced behaviors. Nicotine and sucrose self-administration behaviors were not altered following acute administration of ABT-089 (0, 0.12, 1.2 and 12.0 mg/kg) or ABT-107 (0, 0.03 and 0.3 mg/kg). In contrast, both ABT-089 and ABT-107 pretreatment dose-dependently attenuated nicotine reinstatement. These effects were reinforcer-specific as no effects of ABT-089 or ABT-107 pretreatment on sucrose seeking were noted. Taken together, these findings suggest that ABT-089 and ABT-107 do not affect nicotine consumption, but may reduce the likelihood that a smoking lapse will lead to relapse.

α6-Containing nicotinic acetylcholine receptors in midbrain dopamine neurons are poised to govern dopamine-mediated behaviors and synaptic plasticity

“…Indeed, ABT-089 has cognition-enhancing properties (Decker et al, 1997, Lin et al, 1997), improves attention (Prendergast et al, 1998), reduces nicotine intake (Lee et al, 2014), reduces L-Dopa-induced dyskinesias in Parkinson’s disease models (Zhang et al, 2014), and has shown efficacy in human clinical trials for attention deficit hyperactivity disorder (Wilens et al, 2006). Although originally characterized as an α4β2-specific ligand, later pharmacology studies demonstrated significant activity at α6* nAChRs.…”

Repeated administration of an acetylcholinesterase inhibitor attenuates nicotine taking in rats and smoking behavior in human smokers

“…Details regarding animals, housing, surgery and acquisition of nicotine and sucrose self-administration can be found in Supplementary Materials and Methods and are identical to those described in our previously published studies. 10 , 11 , 23 …”

Nicotine self-administration research: the legacy of Steven R. Goldberg and implications for regulation, health policy, and research

“…However, his contributions extended to other neural targets including α -type peroxisome proliferator-activated receptors (PPAR α ) (Justinova et al 2015; Panlilio et al 2012), group II metabotropic glutamate receptors (mGluR2 and mGluR3) (Justinova et al 2015, 2016), dopamine receptors (Yan et al 2012), and α1-adrenoreceptors (Forget et al 2010). Clearly, the SA model has emerged as the gold standard for medication development (Chang et al 2015; Cippitelli et al 2015; George et al 2011; Lee et al 2014; Le Foll et al 2012; Levin et al 2008, 2010, 2011 O’Connor et al 2010; Rollema et al 2007a, 2007b; Shoaib and Buhidma 2016). …”