Abstract
BACKGROUND: Understanding the role of non-nicotine constituents in tobacco use disorder (TUD) could inform the development of more effective treatments for TUD and tobacco control policies. Cigarette smoke contains considerable levels of various volatile organic compounds (VOCs) including acetaldehyde, toluene, and benzene. While acetaldehyde and toluene can have substance use disorder (SUD)-related effects and/or potentiate the TUD-related effects of nicotine in some preclinical models, their role in TUD is not fully understood, and effects of benzene have not been evaluated in any preclinical model of SUDs. This study evaluated the SUD-related effects of parenteral (s.c.) administration of these VOCs in an intracranial self-stimulation (ICSS) model in male and female rats. The ability of acetaldehyde and benzene to influence nicotine's effects on ICSS was also examined. METHODS AND RESULTS: In Experiment 1, acetaldehyde (10-150mg/kg) did not lower ICSS thresholds, suggesting a lack of SUD-related effects. Rather, 100mg/kg acetaldehyde elevated ICSS thresholds, indicating aversive/anhedonic effects. Benzene (600-1500mg/kg) reduced ICSS thresholds, while toluene (100-1500mg/kg) did not affect ICSS. Nicotine (1.0mg/kg) and methamphetamine (0.3 or 0.56mg/kg) (positive controls) increased and decreased ICSS thresholds, respectively. In Experiment 2, acetaldehyde (60mg/kg) did not influence nicotine's (0.125-1.0mg/kg) effects on ICSS, whereas benzene (600mg/kg) produced a downward shift in the nicotine ICSS dose-response function in males but not in females. CONCLUSIONS: Benzene, but not acetaldehyde or toluene, had SUD-related effects in an ICSS model. As such, benzene may contribute to the TUD-related effects of combusted tobacco products, particularly in males.