Mifepristone decreases nicotine intake in dependent and non-dependent adult rats

Abstract

Background: Addiction to tobacco and nicotine products has adverse health effects and afflicts more than a billion people worldwide. Therefore, there is an urgent need for new treatments to reduce tobacco and nicotine use. Glucocorticoid receptor blockade shows promise as a novel treatment for drug abuse and stress-related disorders.

Aim: These studies aim to investigate whether glucocorticoid receptor blockade with mifepristone diminishes the reinforcing properties of nicotine in rats with intermittent or daily long access to nicotine.

Methods: The rats self-administered 0.06 mg/kg/inf of nicotine for 6 h per day, with either intermittent or daily access for 4 weeks before treatment with mifepristone. Daily nicotine self-administration models regular smoking, while intermittent nicotine self-administration models occasional smoking. To determine whether the rats were dependent, they were treated with the nicotinic acetylcholine receptor antagonist mecamylamine, and somatic signs were recorded.

Results: The rats with intermittent access to nicotine had a higher level of nicotine intake per session than those with daily access but only the rats with daily access to nicotine showed signs of physical dependence. Furthermore, mecamylamine increased nicotine intake during the first hour of access in rats with daily access but not in those with intermittent access. Mifepristone decreased total nicotine intake in rats with intermittent and daily access to nicotine. Moreover, mifepristone decreased the distance traveled and rearing in the open field test and operant responding for food pellets.

Conclusion: These findings indicate that mifepristone decreases nicotine intake but this effect may be partially attributed to the sedative effects of mifepristone.

Keywords: Smoking; glucocorticoid receptors; mecamylamine; mifepristone; nicotine; rats.

Figure 1.. Schematic overview of the experiment.

In experiment 1, rats were trained to respond for food pellets and were then prepared with IV catheters. The rats were then allowed to self-administer nicotine in five 1 h sessions and then either in 29 daily sessions or 13 intermittent sessions. After these sessions, the effects of mifepristone on nicotine self-administration were investigated. Subsequently, the effects of mecamylamine and nicotine pre-treatment on nicotine self-administration were investigated. Catheter patency was assessed following the completion of the mifepristone, mecamylamine, and nicotine treatments. In experiment 2, the rats were trained to respond for food pellets and then the effects of mifepristone on operant responding for food was investigated, and subsequently, the effects of mifepristone on locomotor activity, rearing, and stereotypies in the small open field were investigated. Abbreviations: W, weeks; IVSA, intravenous self-administration.

Figure 2.. Baseline nicotine intake in rats with daily and intermittent access.

The rats with daily access self-administered 0.06 mg/kg/inf of nicotine for 29 sessions and the rats with intermittent access self-administered the same dose of nicotine for 13 sessions (A, daily; B, intermittent). All the sessions lasted 6 h. Nicotine intake (0.06 mg/kg/inf) was the same during the first and the last session in rats with intermittent access, but nicotine intake was lower during the last session in rats with daily access (C-E). Rats with daily, but not intermittent access to nicotine displayed somatic withdrawal signs (F). Asterisks indicate lower nicotine intake during the last than the first session in rats with daily access (C-E), and more somatic signs after treatment with mecamylamine than vehicle in rats with daily access to nicotine (F). Plus signs indicate lower nicotine intake compared to rats with intermittent access during the last session (C), lower nicotine intake compared to the first hour of nicotine intake during the first and last session in rats with the same access schedule (D), and more somatic signs compared to rats with intermittent access treated with mecamylamine (F). * P<0.05; ***, +++ P<0.001. Daily n=13, Intermittent, n=13. Data are expressed as means ± SEM.

Figure 3.. Mifepristone decreases nicotine intake.

The effects of mifepristone on nicotine intake (A), active lever presses (B), and inactive lever presses (C) were investigated. Mifepristone decreased nicotine intake, responding on the active lever, but not responding on the inactive lever. Asterisks indicate lower nicotine intake and fewer lever presses compared to rats on the same access schedule and treated with vehicle. * P<0.05, *** P<0.001. Daily n=13, Intermittent, n=13. Data are expressed as means ± SEM.

Figure 4.. Time course effects of mifepristone on nicotine intake.

Mifepristone decreased nicotine intake at the onset of the nicotine self-administration period in rats with daily (A) and intermittent (B) access. The heatmap shows the time course effects of mifepristone on nicotine intake in rats with daily and intermittent access (C). Asterisks indicate lower nicotine intake in rats treated with 30 mg/kg of mifepristone than in vehicle-treated rats with the same access schedule and at the same time point. Plus sign indicate lower nicotine intake in rats treated with 60 mg/kg of mifepristone than in vehicle-treated rats with the same access schedule and at the same time point. * P<0.05; ***, +++ P<0.001. Daily n=13, Intermittent, n=13. Data are expressed as means ± SEM.

Figure 5.. Effects of mecamylamine and nicotine pre-treatment on nicotine intake.

The effects of mecamylamine (A, total intake; B, time-course) and nicotine (C, total intake; D, time-course) on nicotine intake was investigated. Mecamylamine did not affect total nicotine intake over the 6 h nicotine self-administration period in rats with daily and intermittent access to nicotine (A). Mecamylamine increased nicotine intake during the first hour of the self-administration session in the rats with daily access but not with intermittent access (B). Pre-treatment with nicotine decreased nicotine intake during the 6 h nicotine self-administration period in rats with daily and intermittent access to nicotine (C). Pre-treatment with nicotine also induced a decrease in nicotine intake during the first hour of the self-administration session in the rats with daily and intermittent access (D). Plus signs indicate higher nicotine intake in rats treated with 2 mg/kg of mecamylamine than in vehicle-treated rats with the same access schedule and at the same time point. Asterisks indicate lower nicotine intake in rats treated with 0.4 mg/kg of nicotine than in vehicle-treated rats with the same access schedule and at the same time point. ++ P<0.01; *** P<0.001. Daily n=10, Intermittent, n=13. Data are expressed as means ± SEM.

Figure 6.. Mifepristone decreases operant responding for food, total distance traveled, and rearing.

The effects of mifepristone on food pellets received (A), active lever presses (B), and inactive lever presses (C) was investigated. Furthermore, the effects of mifepristone on the total distance traveled (D), horizontal beam breaks (E), vertical beam breaks (F), and stereotypies (G) was investigated. Mifepristone decreased food intake, responding on the active lever, and responding on the inactive lever (A-C). Mifepristone also decreased the total distance traveled (D) and vertical beam breaks (F) and did not affect horizontal beam breaks (C) and stereotypies (G). N=10. Asterisks indicate significantly different compared to rats treated with vehicle. * P<0.05; ** P<0.01. Data are expressed as means ± SEM.