The α3β4 nAChR partial agonist AT-1001 attenuates stress-induced reinstatement of nicotine seeking in a rat model of relapse and induces minimal withdrawal in dependent rats

Abstract

The strong reinforcing effects of nicotine and the negative symptoms such as anxiety experienced during a quit attempt often lead to relapse and low success rates for smoking cessation. Treatments that not only block the reinforcing effects of nicotine but also attenuate the motivation to relapse are needed to improve cessation rates. Recent genetic and preclinical studies have highlighted the involvement of the α3, β4, and α5 nicotinic acetylcholine receptor (nAChR) subunits and the α3β4 nAChR subtype in nicotine dependence and withdrawal. However, the involvement of these nAChR in relapse is not fully understood. We previously reported that the α3β4 nAChR partial agonist AT-1001 selectively decreases nicotine self-administration in rats without affecting food responding. In the present experiments, we examined the efficacy of AT-1001 in attenuating reinstatement of nicotine-seeking behavior in a model of stress-induced relapse. Rats extinguished from nicotine self-administration were treated with the pharmacological stressor yohimbine prior to AT-1001 treatment and reinstatement testing. We also examined whether AT-1001 produced any withdrawal-related effects when administered to nicotine-dependent rats. We found that AT-1001 dose-dependently reduced yohimbine stress-induced reinstatement of nicotine seeking. When administered to nicotine-dependent rats at the dose that significantly blocked nicotine reinstatement, AT-1001 elicited minimal somatic withdrawal signs in comparison to the nicotinic antagonist mecamylamine, which is known to produce robust withdrawal. Our data suggest that α3β4 nAChR-targeted compounds may be a promising approach for nicotine addiction treatment because they can not only block nicotine’s reinforcing effects, but also decrease motivation to relapse without producing significant withdrawal effects.

Activation of nicotinic acetylcholine receptors induces potentiation and synchronization within in vitro hippocampal networks

“…This result is consistent with evidence that shows that these receptors are found on the axonal terminals of GABAergic interneurons and that the release of GABA via this mechanism is slow but long‐lasting (Tang et al, ). Moreover AT‐1001, which selectively activates β4‐containing receptors, was recently shown to have anxiolytic properties (Cippitelli, Brunori, Gaiolini, Zaveri, & Toll, ; Yuan et al, ), further suggesting a role for GABA in mediating effects of AT‐1001.…”

More than Smoke and Patches: The Quest for Pharmacotherapies to Treat Tobacco Use Disorder

“…Specifically, receptors containing these subunits can mediate seizure and hypolocomotor effects of nicotine in mice (Salas et al, 2004a). A partial agonist at nAChRs containing a3b4 was found to decrease reinstatement of nicotine seeking in a rat model of stress-induced relapse (Yuan et al, 2017). Furthermore, mice lacking the b4 subunit display a decrease in behaviors associated with nicotine withdrawal (Salas et al, 2004b).…”

Molecular Mechanisms Associated with Nicotine Pharmacology and Dependence

“…Since α5Ã nAChRs in the MHb-IPN pathway have been demonstrated to mediate the aversive properties of nicotine that limit intake (Fowler et al 2011), drug development efforts are focused on generating positive allosteric modulators of these receptors, with the idea of enhancing aversive processing in the presence of nicotine to decrease further drug intake (Jin et al 2014). Another compound, AT-1001, which is an α3β4 partial agonist, has been shown to reduce nicotine relapse-related behaviors in rodents (Yuan et al 2017), likely through action on the α3β4Ã nAChRs expressed in the MHb. GLP-1 receptor signaling has also been implicated in MHb-IPN modulation of nicotine intake (Tuesta et al 2017), and a GLP-1 receptor agonist, liraglutide, is currently being tested for smoking cessation in a clinical trial (Ashare 2019).…”