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Nicotine Enhances the Depressive Actions of A_1–40 on Long-Term Potentiation in the Rat Hippocampal CA1 Region In Vivo

Department of Human Anatomy and Physiology, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin 2, Ireland

Submitted 1 November 2002; accepted in final form 6 January 2003

Hippocampal long-term potentiation (LTP) is a form of synaptic plasticity used as a cellular model of memory. Beta amyloid (A) 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 is known to bind with high affinity to the 7-nicotinic acetylcholine receptor (nAChR). Here we have investigated the effect of intracerebroventricular (icv) injection of the endogenous peptide A_1–40 on LTP in area CA1 of urethananesthetized rats. We also examined the effect of A_12–28 (icv), which binds with high affinity to the 7-nAChR and the specific 7-nAChR antagonist methyllycaconitine (MLA) on LTP. We found that A_12–28 had no effect on LTP, whereas MLA depressed significantly LTP, suggesting that activation of the 7-nAChR is a requirement for LTP. Within the in vivo environment, where other factors may compete with A_12–28 for binding to 7-nAChR, it does not appear to modulate LTP. To determine if the depressive action of A_1–40 on LTP could be modulated by nicotine, these agents were also co-applied. Injection of 1 or 10 nmol A_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_1–40 1 h prior to LTP induction caused a further significant depression of LTP compared with A_1–40 alone. These results demonstrate that nicotine enhances the deficit in LTP produced by A_1–40. This then suggests that nicotine may exacerbate the depressive actions of A on synaptic plasticity in AD.

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