Contribution of Harman and Norharman to the Reinforcing Efficacy of Aqueous Tobacco Smoke Extract Self-Administered by Rats

Background: Animal models of drug abuse treat nicotine as the primary reinforcing agent that promotes tobacco addiction. However, rodents demonstrate poor self-administration of nicotine despite evidence of tobacco's high abuse potential in humans. This discrepancy has been attributed to other constituents of tobacco smoke that facilitate the development of nicotine dependence. Objectives: This study aimed to determine whether rats would self-administer intravenous an aqueous tobacco smoke extract (TPM) to find evidence if it was more reinforcing than nicotine alone. The study also evaluated the role of tobacco smoke constituent’s harman and norharman in any differences observed. Methods: Firstly, male Sprague-Dawley rats (n=29) were assigned to treatment groups: nicotine (30.0μg/kg/infusion), TPM (containing 30.0μg/kg/infusion nicotine) or saline vehicle. Ability for each treatment to support intravenous self-administration was assessed using spontaneous acquisition of responding on gradually increasing fixed ratio schedules (FR1, FR2, FR5). Subsequent progressive ratio (PR) testing was employed to determine reinforcing efficacy of each treatment. Then a second group of rats (N = 56) were assigned to treatment groups: nicotine alone (30.0 or 75.0μg/kg/infusion) or nicotine combined with norharman (0, 0.4, 2.5 or 6.25μg/kg/infusion) and harman (0.0, 1.6 or 10.0μg/kg, IP), and tested using a similar protocol. Results: Animals readily acquired self-administration responding for TPM and produced higher PR breakpoints (BP) than rats treated with nicotine alone or vehicle. Rats trained to respond for a larger dose of nicotine demonstrated significantly greater response rates than those receiving the lower dose of nicotine. Finally, the addition of harman and norharman to nicotine significantly reduced BP at the lower unit dose of nicotine tested. Conclusions: These findings support the hypothesis that TPM is more reinforcing than nicotine alone. However, the increased reinforcing efficacy of TPM cannot be attributed to the actions of harman and norharman. The potential role of serotonin inhibition in tobacco reward processes is discussed.