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

• Published in: Behavioural brain research Vol. 333; pp. 251 - 257
• Main Authors: Yuan, Menglu, Malagon, Ariana M., Yasuda, Dennis, Belluzzi, James D., Leslie, Frances M., Zaveri, Nurulain T.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 30.08.2017
• Subjects: Adrenergic alpha-2 Receptor Antagonists - toxicity; Animals; AT-1001; Cholinergic Agonists - therapeutic use; Conditioning, Operant - drug effects; Disease Models, Animal; Dose-Response Relationship, Drug; Extinction, Psychological - drug effects; Male; Mecamylamine - pharmacology; Nicotine - administration & dosage; Nicotine reinstatement; Nicotinic acetylcholine receptor; Nicotinic Agonists - administration & dosage; Nicotinic Antagonists - pharmacology; Oligopeptides - therapeutic use; Rats; Rats, Sprague-Dawley; Reinforcement (Psychology); Relapse; Self Administration; Stress, Psychological - drug therapy; Stress, Psychological - physiopathology; Stress-induced reinstatement; Substance Withdrawal Syndrome - etiology; Tobacco Use Disorder - drug therapy; Tobacco Use Disorder - etiology; Yohimbine - pharmacology; α3β4 nAChR; Nicotine reinstatement; Stress-induced reinstatement; Relapse; α3β4 nAChR; Nicotinic acetylcholine receptor; AT-1001
• ISSN: 0166-4328; 1872-7549
• DOI: 10.1016/j.bbr.2017.07.004

•AT-1001, a high affinity, selective α3β4 nAChR partial agonist attenuates reinstatement of nicotine seeking induced by pharmacological stress in a rat model of relapse.•When administered to nicotine-dependent rats, AT-1001 induces minimum withdrawal signs.•The robust efficacy of α3β4 nAChR-selective compounds such as AT-1001 to block reinstatement of nicotine-seeking differentiate it from current smoking cessation medications like bupropion and varenicline which do not attenuate relapse to nicotine seeking.•Targeting the α3β4 nAChR offers a new approach for smoking cessation treatment and improving long term abstinence rates. 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.