Nicotine reverses GABAergic inhibition of long-term potentiation induction in the hippocampal CA1 region

Nicotine is known to enhance cognitive function but the mechanism is unknown. The present study examined the modulatory effect of nicotine on the induction of long-term potentiation (LTP), a synaptic model of learning and memory. A weak tetanic stimulation consisting of 20 pulses at 100 Hz induced stable LTP in the hippocampal CA1. The induction of LTP was completely blocked if the tetanus was delivered in the presence of muscimol (2.5 mu M), a gamma-aminobutyric acid (GABA) receptor agonist. This inhibition was sensitive to, and reversed by, not only nicotinic acetylcholine receptor (nAChR) agonists (nicotine and epibatidine), but also the alpha 7 nAChR-selective antagonist methyllycaconitine (MLA). Furthermore, ACh-puff activation of alpha 7 nAChRs on feedforward interneurons induced inhibitory postsynaptic currents in pyramidal cells that were blocked by nicotine or MLA. In addition, nicotine reduced held monosynaptic inhibitory postsynaptic potentials in the presence of MLA. These results suggest not only two pathways of nicotine-induced disinhibition of pyramidal cells, one involving desensitization of alpha 7 nAChRs and the other involving non-alpha 7 nAChRs, but also two potential mechanisms underlying the modulatory effect of nicotine on LTP induction, both reducing GABAergic inhibition, thereby indirectly increasing the excitability of pyramidal cells. (C) 2000 Elsevier Science B.V. All rights reserved.