Tobacco smoke exposure induces nicotine dependence in rats

Abstract

Rationale: Tobacco smoke contains nicotine and many other compounds that act in concert on the brain reward system. Therefore, animal models are needed that allow the investigation of chronic exposure to the full spectrum of tobacco smoke constituents.

Objectives: The aim of these studies was to investigate if exposure to tobacco smoke leads to nicotine dependence in rats.

Methods: The intracranial self-stimulation procedure was used to assess the negative affective aspects of nicotine withdrawal. Somatic signs were recorded from a checklist of nicotine abstinence signs. Nicotine self-administration sessions were conducted to investigate if tobacco smoke exposure affects the motivation to self-administer nicotine. Nicotinic receptor autoradiography was used to investigate if exposure to tobacco smoke affects central alpha7 nicotinic acetylcholine receptor (nAChR) and non-alpha7 nAChR levels (primarily alpha4beta2 nAChRs).

Results: The nAChR antagonist mecamylamine dose-dependently elevated the brain reward thresholds of the rats exposed to tobacco smoke and did not affect the brain reward thresholds of the untreated control rats. Furthermore, mecamylamine induced more somatic withdrawal signs in the smoke-exposed rats than in the control rats. Nicotine self-administration was decreased 1 day after the last tobacco smoke exposure sessions and was returned to control levels 5 days later. Tobacco smoke exposure increased the alpha7 nAChR density in the CA2/3 area and the stratum oriens and increased the non-alpha7 nAChR density in the dentate gyrus.

Conclusion: Tobacco smoke exposure leads to nicotine dependence as indicated by precipitated affective and somatic withdrawal signs and induces an upregulation of nAChRs in the hippocampus.

Figure 1

Experimental protocols for experiment 1–4. The thick black lines indicate tobacco smoke exposure. Abbreviations: ICSS, intracranial self-stimulation; Food, food responding; IVSA, intravenous self-administration; with, withdrawal.

Figure 2

Effect of the nAChR antagonist mecamylamine on the brain reward thresholds (A) and response latencies (B) of rats exposed to tobacco smoke (n=10) and control rats (n=10). In figure 1A, asterisks (* P<0.05, ** P<0.01) indicate elevated brain reward thresholds compared to the corresponding control group. Pound signs (#P<0.05) indicate elevated brain reward thresholds compared to the tobacco smoke group treated with 1 mg/kg of mecamylamine. Plus signs (++ P<0.01) indicate elevated brain reward thresholds compared to the tobacco smoke group treated with vehicle. In figure 1B, asterisks (* P<0.05) indicate increased or decreased response latencies compared to the corresponding control group. Pound signs (#P<0.05) indicate increased latencies compared to the tobacco smoke group treated with 1 mg/kg of mecamylamine. Plus signs (++ P<0.01) indicate increased latencies compared to the tobacco smoke group treated with vehicle.

Figure 2

Effect of the nAChR antagonist mecamylamine on the brain reward thresholds (A) and response latencies (B) of rats exposed to tobacco smoke (n=10) and control rats (n=10). In figure 1A, asterisks (* P<0.05, ** P<0.01) indicate elevated brain reward thresholds compared to the corresponding control group. Pound signs (#P<0.05) indicate elevated brain reward thresholds compared to the tobacco smoke group treated with 1 mg/kg of mecamylamine. Plus signs (++ P<0.01) indicate elevated brain reward thresholds compared to the tobacco smoke group treated with vehicle. In figure 1B, asterisks (* P<0.05) indicate increased or decreased response latencies compared to the corresponding control group. Pound signs (#P<0.05) indicate increased latencies compared to the tobacco smoke group treated with 1 mg/kg of mecamylamine. Plus signs (++ P<0.01) indicate increased latencies compared to the tobacco smoke group treated with vehicle.

Figure 3

Nicotine self-administration (3-hrs) in rats chronically exposed to tobacco smoke (n=8) and control rats (n=10). Nicotine self-administration was investigated 1 day after tobacco smoke exposure after 3 weeks (Day 22, A) and 4 weeks (Day 29, B) of exposure to tobacco smoke (4 hours/day). A final self-administration session was conducted 5 days after the last tobacco smoke exposure session (Day 33, C). Asterisks (** P<0.01) indicate a decrease in responding on the active lever compared to the control group. Data are expressed as means ± SEM.

Figure 3

Nicotine self-administration (3-hrs) in rats chronically exposed to tobacco smoke (n=8) and control rats (n=10). Nicotine self-administration was investigated 1 day after tobacco smoke exposure after 3 weeks (Day 22, A) and 4 weeks (Day 29, B) of exposure to tobacco smoke (4 hours/day). A final self-administration session was conducted 5 days after the last tobacco smoke exposure session (Day 33, C). Asterisks (** P<0.01) indicate a decrease in responding on the active lever compared to the control group. Data are expressed as means ± SEM.

Figure 4

Responding for food pellets (20-min) in rats chronically exposed to tobacco smoke (n=10) and control rats (n=10). Tobacco smoke exposure was discontinued after 32 days and food responding was recorded for 7 days post tobacco smoke exposure (Day 33 – 39). Asterisks (** P<0.01) indicate a decrease in responding on the active lever compared to the control group. Data are expressed as means ± SEM.