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 (Abeta) is involved in Alzheimer's disease (AD), a neurodegenerative disorder leading to cognitive deficits. Nicotine is also claimed to act as a cognitive enhancer. Abeta is known to bind with high affinity to the alpha7-nicotinic acetylcholine receptor (nAChR). Here we have investigated the effect of intracerebroventricular (icv) injection of the endogenous peptide Abeta(1-40) on LTP in area CA1 of urethananesthetized rats. We also examined the effect of Abeta(12-28) (icv), which binds with high affinity to the alpha7-nAChR and the specific alpha7-nAChR antagonist methyllycaconitine (MLA) on LTP. We found that Abeta(12-28) had no effect on LTP, whereas MLA depressed significantly LTP, suggesting that activation of the alpha7-nAChR is a requirement for LTP. Within the in vivo environment, where other factors may compete with Abeta(12-28) for binding to alpha7-nAChR, it does not appear to modulate LTP. To determine if the depressive action of Abeta(1-40) on LTP could be modulated by nicotine, these agents were also co-applied. Injection of 1 or 10 nmol Abeta(1-40) caused a significant depression of LTP, whereas nicotine alone (3 mg/kg) had no effect on LTP. Co-injection of nicotine with Abeta(1-40) 1 h prior to LTP induction caused a further significant depression of LTP compared with Abeta(1-40) alone. These results demonstrate that nicotine enhances the deficit in LTP produced by Abeta(1-40). This then suggests that nicotine may exacerbate the depressive actions of Abeta on synaptic plasticity in AD.