Varenicline and Cytisine Diminish the Dysphoric-Like State Associated with Spontaneous Nicotine Withdrawal in Rats

Abstract

Tobacco addiction is characterized by a negative mood state upon smoking cessation and relapse after periods of abstinence. Clinical studies indicate that negative mood states lead to craving and relapse. The partial a4/a6/b2* nicotinic acetylcholine receptor (nAChR) agonists varenicline and cytisine are widely used as smoking cessation treatments. Varenicline has been approved in the United States for smoking cessation and cytisine is used in Eastern European countries. Despite the widespread use of these compounds, very little is known about their effects on mood states. These studies investigated the effects of varenicline, cytisine, and the cytisine-derivative 3-(pyridin-3 0 -yl)-cytisine (3-pyr-Cyt) on brain reward function in nicotine-naive and nicotine-withdrawing rats. The cytisine-derivative 3-pyr-Cyt is a very weak a4b2* nAChR partial agonist and like cytisine and varenicline has antidepressant-like effects in animal models. The intracranial self-stimulation (ICSS) procedure was used to investigate the effects of these compounds on brain reward function. Elevations in ICSS thresholds reflect a dysphoric state and a lowering of thresholds is indicative of a potentiation of brain reward function. It was shown that acute administration of nicotine and varenicline lowered ICSS thresholds. Acute administration of cytisine or 3-pyr-Cyt did not affect ICSS thresholds. Discontinuation of chronic, 14 days, nicotine administration led to elevations in ICSS thresholds that lasted for about 2 days. Varenicline and cytisine, but not 3-pyr-Cyt, diminished the nicotine withdrawal-induced elevations in ICSS thresholds. In conclusion, these studies indicate that varenicline and cytisine diminish the dysphoric-like state associated with nicotine withdrawal and may thereby prevent relapse to smoking in humans.

Effects of Acute and Repeated Administration of Oxycodone and Naloxone-Precipitated Withdrawal on Intracranial Self-Stimulation in Rats

“…Although people may not always experience the full spectrum of the physical signs of oxycodone withdrawal, they still may be inflicted with those unpleasant enough to promote escalation of self-dosing, with the drug obtained either through legitimate or illegitimate channels. ICSS has been proposed as a preclinical model that can be used to model affective-like withdrawal symptoms, because many drugs, including morphine (Schaefer and Michael, 1986;Easterling et al, 2000;Liu and Schulteis, 2004;Altarifi and Negus, 2011;Holtz et al, 2015), nicotine (Epping-Jordan et al, 1998;Cryan et al, 2003;Kenny and Markou, 2005;Igari et al, 2014;Manbeck et al, 2014;Qi et al, 2015), ethanol (Schulteis et al, 1995;Chester et al, 2006;Rylkova et al, 2009;Boutros et al, 2014), and cocaine (Markou and Koob, 1991;Stoker and Markou, 2011), produce decreases in ICSS after either spontaneous or precipitated withdrawal. Furthermore, withdrawal from nicotine and morphine has been associated with decreased ventral tegmental area dopaminergic activity, which correlates with ICSS deficits (Liu and Jin, 2004;Kaufling and Aston-Jones, 2015).…”

Nicotinic Receptor Contributions to Smoking: Insights from Human Studies and Animal Models

“…DHβE-precipitated withdrawal results in somatic signs [113, 115, 119] and increased anxiety in the EPM [115] following chronic nicotine exposure. It is interesting that administration of the partial β2*nAChR agonist varenicline relieved increases in ICSS thresholds instigated by spontaneous nicotine withdrawal [122], presumably due to stimulation of β2*nAChRs since DHβE administration promotes withdrawal-induced increases in ICSS thresholds [119]. Contrary to pharmacological data, however, studies utilizing β2KO mice show that withdrawal-associated anxiety is absent in the β2KO mice but that somatic signs remain intact [116, 118], suggesting a strong role for β2*nAChRs in mediating the affective signs of nicotine withdrawal but indicating that β2*nAChR mediation of physical withdrawal symptoms requires further validation.…”

Bupropion–varenicline interactions and nicotine self-administration behavior in rats

“…The different mechanisms of action of each drug make them ideal candidates for use as a combination therapy for tobacco addiction, both to reduce craving for nicotine as well as to alleviate the somatic and affective symptoms of tobacco withdrawal. Indeed, both drugs have previously been shown, when administered individually, to reduce nicotine self-administration in rats and reduce withdrawal symptoms associated with nicotine (Cryan et al , 2003, Igari et al , 2014, Malin et al , 2006, Paterson et al , 2007). It is currently unknown whether the effects of a combination of varenicline and bupropion would be additive, synergistic, or time-course dependent and what the optimal dose combinations of these drugs would be.…”