Effect of chronic nicotine on brain stimulation reward. II. An escalating dose regimen.

This study examined whether repeated nicotine injections, using an escalating dose regimen, would produce brain stimulation reward facilitation indicative of a strong rewarding action. Male, Long-Evans rats with lateral hypothalamic stimulating electrodes were injected daily with escalating doses of nicotine bitartrate across 5-day cycles: 0.5, 1, and 2 mg/kg/day (dose expressed as freebase weight) were administered subcutaneously (s.c.) in consecutive 5-day cycles. Nicotine lowered thresholds across the first two 5-day cycles (i.e. 0.5 and 1 mg/kg/day doses), but thresholds returned to baseline levels during the last 5-day cycle (i.e. 2 mg/kg/day). The maximum threshold lowering produced by nicotine was similar to that previously reported for acute and chronic nicotine and for mild stimulants with a low addiction liability (i.e. caffeine and pseudoephedrine). Forty-eight h after terminating the nicotine injection regimen, thresholds were elevated revealing a nicotine withdrawal reaction. However, the high nicotine dose used during the last 5-day cycle is probably not pharmacologically relevant, thus making the significance of the withdrawal effect unclear. Overall, this study suggests that even under chronic administration using escalating doses, nicotine's profile in this animal model is that of a substance with a low addiction liability.