Effects of the beta-lactam antibiotic ceftriaxone on nicotine withdrawal and nicotine-induced reinstatement of preference in mice

Abstract

Rationale: Several studies suggest that repeated nicotine administration causes alterations in glutaminergic transmission that may play an important role in developing and maintaining nicotine addiction. Chronic nicotine administration in rats decreases the expression of the glutamate transporter-1 (GLT-1) and cysteine-glutamate exchanger (system xC-) in the nucleus accumbens. We hypothesized that ceftriaxone, a GLT-1 and system xC- activator, would decrease murine behavioral aspects of nicotine dependence.

Objective: This study aimed to investigate the effect of repeated ceftriaxone administration on the behavioral effects of nicotine using mouse models of conditioned reward and withdrawal.

Method: Using male ICR mice, the ability of repeated ceftriaxone injections to modulate the development and reinstatement of a nicotine-conditioned place preference (CPP) was evaluated. Additionally, nicotine withdrawal-associated signs were assessed. These included both physical (somatic signs and hyperalgesia) and affective (anxiety-related behaviors) withdrawal signs in mice. Finally, the effects of ceftriaxone on nicotine-induced antinociception and hypothermia after acute nicotine injection were measured.

Result: Ceftriaxone had no effect on the development of nicotine preference but significantly attenuated nicotine-induced reinstatement of CPP. Furthermore, ceftriaxone reversed all nicotine withdrawal signs measured in mice.

Conclusion: Altogether, these findings show that a β-lactam antibiotic reduces nicotine withdrawal and nicotine-seeking behavior. Our results suggest that the documented efficacy of ceftriaxone against cocaine and morphine dependence-related behaviors effects extends to nicotine.

Fig. 1

Effects of ceftriaxone on the development of nicotine-induced CPP in the mouse. Nicotine (0.5 mg/kg, s.c.) induced a significant CPP in mice. Ceftriaxone had no effect on the development of nicotine CPP in mice conditioned with 0.5 mg/kg nicotine. Each point represents the mean ± SEM of eight mice per group. *p<0.05 vs. the saline and ceftriaxone control groups. CEF ceftriaxone, NIC nicotine, SAL saline

Fig. 2

Effects of ceftriaxone on nicotine-primed reinstatement of nicotine CPP in the mouse. Mice conditioned with 0.5 mg/kg nicotine (s.c.) expressed a significant CPP on test day. Nicotine CPP was extinguished by extinction day 3. On day 8, nicotine CPP was reinstated by nicotine (0.1 mg/kg, s.c.). Ceftriaxone pretreatment blocked the reinstatement of CPP. Each point represents the mean ± SEM of five to seven mice per group. *p<0.05 vs. the corresponding saline group; ^p<0.05 vs. SAL–NIC(0.1) group. CEF ceftriaxone, NIC nicotine, SAL saline

Fig. 3

Effects of ceftriaxone pretreatment on nicotine withdrawal in the mouse. Mice chronically infused with nicotine for 7 days (36 mg/kg/day) were withdrawn on day 8 after injection of mecamylamine (2 mg/kg, s.c.). Significant a anxiety-related response, b increase in somatic withdrawal signs, and c hyperalgesia response were observed in nicotine-withdrawn mice. Ceftriaxone (200 mg/kg, i.p.) significantly attenuated the expression of both the physical and affective nicotine withdrawal responses in mice. Each point represents the mean ±SEM of six to eight mice per group. *p<0.05 vs. the SAL–SAL–MEC and SAL–CEF(200)–MEC control groups; ^p<0.05 vs. NIC–SAL–MEC group. CEF ceftriaxone, NIC nicotine, SAL saline

Fig. 4

Effects of ceftriaxone on nicotine-induced hypothermia and antinociception. Mice received single injection of either saline or nicotine (0.5 or 2.5 mg/kg, s.c.) and were tested 5 min later for antinociception in the a tail flick and b hot plate tests; c changes in body temperature were measured 30 min later. A 4-day pretreatment with ceftriaxone failed to enhance or block the responses of the low and high doses of nicotine, respectively. Each point represents the mean ± SEM of six mice per group. *p<0.05 vs. the SAL–SAL, SAL–NIC(0.5), and CEF(200)–NIC(0.5) groups. CEF ceftriaxone, NIC nicotine, SAL saline