The α4β2 nicotinic acetylcholine receptor agonist TC-2559 impairs long-term potentiation in the dentate gyrus in vivo

Nicotinic acetylcholine receptors (nAChR) are widely expressed throughout the nervous system, are involved in some fast excitatory neurotransmission, and play an important role in modulating the release of several neurotransmitters, including the major excitatory and inhibitory neurotransmitters, glutamate and GABA. We used a recently characterised α4β2 nAChR subunit selective partial agonist, TC-2559, to study the effect of α4β2 nAChR activation on synaptic plasticity in the medio-dorsal perforant pathway input to the dentate gyrus, in the intact nervous system in vivo. We show for the first time, that the selective activation of α4β2 containing nAChR can reduce the level of long-term potentiation (LTP) induced by high frequency stimulation, an effect that was reversed by the selective antagonist, dihydro-β-erythroidine (DβHE). This modulator role of nAChRs is in contrast to previous findings that used broad spectrum agonists, highlighting the complex actions of nicotine.