Nicotine enhances the depressive actions of Aβ1-40 on long-term potentiation in the rat hippocampal CA1 region in vivo

Hippocampal long-term potentiation (LTP) is a form of synaptic plasticity used as a cellular model of memory. Beta amyloid (Aβ) is involved in Alzheimer’s disease (AD), a neurodegenerative disorder leading to cognitive deficits. Nicotine, is also claimed to act as a cognitive enhancer. Aβ is known to bind with high affinity to the α7-nicotinic acetylcholine receptor (nAChR). Here we have investigated the effect of intracerebroventricular (i.c.v.) injection of the endogenous peptide Aβ1-40 on LTP in area CA1 of urethane-anaesthetised rats. We also examined the effect of Aβ12-28 (i.c.v.), which binds with high affinity to the α7-nAChR and the specific α7-nAChR antagonist methyllycaconitine (MLA) on LTP. We found that Aβ12-28 had no effect on LTP while MLA depressed significantly LTP suggesting that activation of the α7-nAChR is a requirement for LTP. Within the in vivo environment, where other factors may compete with Aβ12-28 for binding to α7-nAChR it does not appear to modulate LTP. To determine if the depressive action of Aβ1-40 on LTP could be modulated by nicotine, these agents were also co-applied. Injection of 1 or 10nmol Aβ1-40 caused a significant depression of LTP while nicotine alone (3mg/kg) had no effect on LTP. Co-injection of nicotine with Aβ1-40 1 hour prior to LTP induction caused a further significant depression of LTP compared to Aβ1-40 alone. These results demonstrate that nicotine enhances the deficit in LTP produced by Aβ1-40. This then suggests that nicotine may exacerbate the depressive actions of Aβ on synaptic plasticity in AD.