In the PFC, the relative timing of action potentials in pre- and post-synaptic neurons is critically important for determining the direction of synaptic plasticity, either LTP or LTD, and is referred to as spike-timing-dependent plasticity (STDP) (Markram et al., 1997; Bi and Poo, 1998; Couey et al., 2007). When the pre-synaptic spike occurs before the post-synaptic spike in a time-sensitive manner, robust LTP is induced; in contrast, reversing the order of stimulation will result in LTD. Nicotine will increase the threshold for induction of STDP under the same stimulus conditions by reducing dendritic calcium signals that normally occur with action potential propagation. Pyramidal neurons in the PFC lack nAChRs but GABAergic inhibitory control of these cells is modulated by nicotinic receptors (Couey et al., 2007). The ability of nicotine to eliminate the induction of LTP is attributed to activation of nAChRs on GABA interneurons and glutamatergic cells, which both ultimately increase the excitation of GABA interneurons and enhance inhibition of layer V pyramidal neurons. Application of a GABAA receptor antagonist or increasing dendritic calcium signals with burst-like, post-synaptic stimulation blocked
