The anxiolytic-like effect of nicotine undergoes rapid tolerance in a model of contextual fear conditioning in rats.

The effects of repeated administration of nicotine on contextual fear conditioning, locomotor activity, and pain threshold, were examined in rats. It was found that a single injection of nicotine prior to the training session (three 0.7-mA footshocks, each 0.5 s long), decreased the freezing reaction during the retest 24 h later. The locomotor activity was moderately enhanced, and the pain threshold remained unchanged. The baseline freezing measured immediately after administration of a single dose of nicotine was not significantly different from the saline-treated group. The anxiolytic-like effect of nicotine was as potent as that of midazolam, a benzodiazepine derivative. After five day-by-day injections, the anxiolytic-like effect of nicotine (0.6 mg/kg, sc) was no longer present, independently whether the last drug injection was given 24 h or 5 min (i.e., the sixth, additional, nicotine injection), prior to the training session. Thus, it appeared that the expression of tolerance to the nicotine-induced anxiolytic-like action did not require a direct stimulation of nicotinic receptors. Simultaneously, in this group of animals, nicotine caused a potent stimulation of locomotor activity in the open field test. The applied dosage and regimen of nicotine administration did not change rat pain threshold (flinch-jump test). Collectively, the present data showed for the first time, that short-term, intermittent, administration of nicotine was sufficient to induce tolerance to the anxiolytic-like effect of this drug, in the model of fear conditioning to context. Importantly, a clear dissociation between the locomotor and anxiolytic-like effects of nicotine was present. This effect appeared independent also of changes in rat pain threshold. The possible mechanisms of this phenomenon are discussed.