Nicotine has previously been shown to facilitate the induction of long-term potentiation (LTP), long-term depression (LTD) and depotentiation (Fujii et al. 1999; Fujii & Sumikara, 2001), as well as reversing age-related impairments of LTP in the hippocampus. However the relative contribution of nicotine to hippocampal synaptic transmission and plasticity is disputed. Previously we have shown that IL-1β and IL-18 inhibition of LTP can be reversed by selective inhibition of the p38 mitogen-activated protein kinase (O’Connor & Coogan, 1999). As nicotine has been demonstrated to facilitate the induction of LTP and to reverse age-related impairments in LTP which are associated with increased levels of pro-inflammatory cytokine production, we hypothesized that these cytokines would not affect the induction of LTP in the presence of nicotine.

Experiments were performed on slices of dentate gyrus (350 µm) of young Wistar rats (50-100 g) humanely killed. Recordings of field excitatory post-synaptic potentials (EPSPs) were made from the medial perforant path using standard methods. LTP was induced by a high frequency stimulation (HFS) consisting of eight trains of eight pulses at 200 Hz separated by 2 s intervals, at a voltage corresponding to 50 % maximum EPSP slope. Data are expressed as means ± S.E.M. and were statistically analysed using Student’s paired t test. P < 0.05 was considered significant.

HFS in hippocampal slices with picrotoxin (100 µM) present gave rise to robust LTP (151.1 ± 7.0 %, n = 9 at 50-60 min post tetanus; P < 0.01 compared to baseline). In the presence of nicotine (50 µM) LTP was 197.2 ± 3.5 % of baseline levels at 50-60 min post tetanus (P < 0.01 compared to slices without nicotine, n = 5-6). LTP in the presence of picrotoxin was fully depotentiated to 109.7 ± 0.6 %, n = 9 at 20 min post low-frequency stimulation (LFS). However LTP in the presence of picrotoxin and nicotine was not significantly depotentiated (169.4 ± 1.4 % at 20 min post LFS; P < 0.01 compared to slices without nicotine). Treatment of slices with IL-1β (4 ng ml^-1), IL-18 (100 ng ml^-1) or tumour necrosis factor-α (4 ng ml^-1) for 20 min prior to treatment with nicotine (50 µM) led to a robust LTP when HFS was applied (206.3 ± 14.9 %, 200.9 ± 9.8 % and 208.5 ± 7.9 % of baseline respectively 50-60 min post HFS). These were all significantly different from slices treated with cytokine alone (P < 0.05; n = 4-6 for all). Application of LFS 1 h post HFS did not significantly depotentiate the LTP in all three cases (P < 0.01 for all).

These results report for the first time a modulatory role for nicotine on cytokine-induced inhibition of LTP. These effects of nicotine may have an important role to play in the neuro-immune effects of cytokines in the central nervous system.

This work was supported by Enterprise Ireland.