Behavioral and Biochemical Impact of Chronic Unpredictable Mild Stress on the Acquisition of Nicotine Conditioned Place Preference in Rats

Abstract

Addiction is a chronic psychiatric disease which represents a global problem, and stress can increase drug addiction and relapse. Taking into account frequent concomitance of nicotine dependence and stress, the purpose of the present study was to assess behavioral and biochemical effects of chronic unpredictable mild stress (CUMS) exposure on nicotine reward in rats measured in the conditioned place preference (CPP) paradigm. Rats were submitted to the CUMS for 3 weeks and conditioned with nicotine (0.175 mg/kg) for 2 or 3 days. Our results revealed that only CUMS-exposed animals exhibited the CPP after 2 days of conditioning indicating that stressed rats were more sensitive to the rewarding properties of nicotine and that chronic stress exacerbates nicotine preference. Administration of metyrapone (50 mg/kg), a glucocorticosteroid antagonist, and imipramine (15 mg/kg), an antidepressant, abolished nicotine CPP in stressed rats after 2 days of conditioning. The biochemical experiments showed increased markers of oxidative stress after nicotine conditioning for 2 and 3 days, while the CUMS further potentiated pro-oxidative effects of nicotine. Moreover, metyrapone reversed oxidative changes caused by stress and nicotine, while imipramine was not able to overwhelm nicotine- and stress-induced oxidative damages; however, it could exert antioxidant effect if administered repeatedly. The results suggest that recent exposure to a stressor may augment the rewarding effects of nicotine through anhedonia- and stress-related mechanisms. Our study contributes to the understanding of behavioral and biochemical stress-induced modification of the rewarding effects of nicotine on the basis of the development of nicotine dependence.

Keywords: Chronic mild stress; Conditioned place preference; Nicotine; Oxidative stress; Rats.

Fig. 1

Influence of the CUMS on the expression of nicotine-induced CPP in rats after 2 days of conditioning. Rats were subjected to the CUMS protocol for 21 days. Place preference procedure consisted of pre-conditioning, two conditioning sessions with nicotine (0.175 mg/kg, i.p.), and post-conditioning test. Data represent means ± S.E.M. and are expressed as the difference (in s) between post-conditioning and pre-conditioning time spent in the drug-associated compartment. n = 8–12 rats per group; **P < 0.01 vs. unstressed nicotine treated rats; ^P < 0.05 vs. stressed saline-conditioned rats (Tukey’s test)

Fig. 2

Influence of metyrapone on the expression of nicotine-induced CPP in stressed rats after 2 days of conditioning. Rats were subjected to the CUMS protocol for 21 days. Place preference procedure consisted of pre-conditioning, two conditioning sessions with nicotine (0.175 mg/kg, i.p.) and post-conditioning test. Metyrapone (50 mg/kg) was administered on the test day 60 min before the test. Data represent means ± S.E.M. and are expressed as the difference (in s) between post-conditioning and pre-conditioning time spent in the drug-associated compartment. n = 8–12 rats per group; ***P < 0.001 vs. stressed saline-conditioned rats; #P < 0.05 vs. stressed nicotine-conditioned rats (Tukey’s test)

Fig. 3

Influence of imipramine on the expression of nicotine-induced CPP in stressed rats after 2 days of conditioning. Rats were subjected to the CUMS protocol for 21 days. Place preference procedure consisted of pre-conditioning, two conditioning sessions with nicotine (0.175 mg/kg, i.p.) and post-conditioning test. Imipramine (15 mg/kg) was administered on the test day 15 min before the test. Data represent means ± S.E.M. and are expressed as the difference (in s) between post-conditioning and pre-conditioning time spent in the drug-associated compartment. n = 8–12 rats per group; **P < 0.01 vs. stressed saline-conditioned rats; #P < 0.05 vs. stressed nicotine-conditioned rats (Tukey’s test)

Fig. 4

Influence of imipramine on the expression of nicotine-induced CPP in unstressed rats after 3 days of conditioning. Place preference procedure consisted of pre-conditioning, three conditioning sessions with nicotine (0.175 mg/kg, i.p.), and post-conditioning test. Imipramine (15 mg/kg) was administered on the test day 15 min before the test. Data represent means ± S.E.M. and are expressed as the difference (in s) between post-conditioning and pre-conditioning time spent in the drug-associated compartment. n = 8–12 rats per group; **P < 0.01 vs. saline-conditioned rats (Tukey’s test)

Fig. 5

Influence of the CUMS on the expression of nicotine-induced CPP in rats after 3 days of conditioning. Rats were subjected to the CUMS protocol for 21 days. Place preference procedure consisted of pre-conditioning, three conditioning sessions with nicotine (0.175 mg/kg, i.p.), and post-conditioning test. Data represent means ± S.E.M. and are expressed as the difference (in s) between post-conditioning and pre-conditioning time spent in the drug-associated compartment. n = 8–12 rats per group; ***P < 0.001 vs. unstressed saline-conditioned rats; ^P < 0.05 vs. stressed saline-conditioned rats (Tukey’s test)