INTRODUCTION: It is unknown how the timing between doses might affect nicotine's impact on neural activity. Our objective was to examine how the interdose interval affects nicotine's impact on resting-state functional connectivity (rsFC).

MATERIALS AND METHODS: Adult male Sprague-Dawley rats were administered nicotine daily (0.4 mg/kg) over 6 days while control animals received saline vehicle. Functional magnetic resonance imaging was used to measure rsFC before and after a challenge dose of nicotine (0.4 mg/kg) delivered for the first time and 3, 6, 12, or 24hr after the previous dose.

RESULTS: As the interval between nicotine doses increased from 3 to 24hr, the strength of rsFC increased in some circuits, particularly the nucleus accumbens and prefrontal circuits, and decreased in others, namely the interpeduncular nucleus, hippocampus, caudoputamen, retrosplenial cortex, ventral tegmental, and the insular circuits.

CONCLUSIONS: These data indicate that the effect that nicotine has on the brain is affected by the amount of time that has passed since the previous dose. The effect on rsFC of cumulative doses is not additive. This may have important implications for the study of nicotine addiction as it implies that the same dose of nicotine might have a different impact on the brain depending on the time elapsed from the previous exposure.