Hippocampal long-term potentiation (LTP) is a form of synaptic plasticity used as a cellular model of memory. Beta amyloid (A beta) is involved in Alzheimer's disease (AD), a neurode-generative disorder leading to cognitive deficits. Nicotine is also claimed to act as a cognitive enhancer. A beta is known to bind with high affinity to the alpha 7-nicotinic acetylcholine receptor (nAChR). Here we have investigated the effect of intracerebroventricular (i.c.v.) injection of the endogenous peptide A beta 1-40 on LTP in area CA1 of urethananesthetized rats. We also examined the effect of A beta 12-28 (i.c.v.), which binds with high affinity to the alpha 7-nAChR and the specific alpha 7-nAChR antagonist methyllycaconitine (MLA) on LTP. We found that A beta 12-28 had no effect on LTP, whereas MLA depressed significantly LTP, suggesting that activation of the alpha 7-nAChR is a requirement for LTP. Within the in vivo environment, where other factors may compete with A beta 12-28 for binding to alpha 7-nAChR, it does not appear to modulate LTP. To determine if the depressive action of A beta 1-40 on LTP could be modulated by nicotine, these agents were also co-applied. Injection of 1 or 10 nmol A beta 1-40 caused a significant depression of LTP, whereas nicotine alone (3 mg/kg) had no effect on LTP. Co-injection of nicotine with A beta 1-40 1 h prior to LTP induction caused a further significant depression of LTP compared with A beta 1-40 alone. These results demonstrate that nicotine enhances the deficit in LTP produced by A beta 1-40. This then suggests that nicotine may exacerbate the depressive actions of A beta on synaptic plasticity in AD.