Impact of the nicotinergic alpha7 receptor on cortical plasticity in smokers and nonsmokers
Zusammenfassung der Projektergebnisse
Nicotine is the main neuroactive component of tobacco. It improves cognitive functions and neuroplasticity probably by enhancing the signal to noise ratio in cortical networks. Accordingly, increasing cholinergic activity or applying nicotine in healthy non-smoking humans enhances focal, but suppresses nonfocal plasticity. In contrast, plasticity is absent without, but re-established with acute nicotine intake in smokers. These results are in accordance with a compensatory role of acute nicotine consumption in smokers for establishing neuroplasticity. This need for acute compensation sheds light on the neurophysiological and -psychological addiction causes of nicotine consumption. Further differentiation is needed regarding the impact of specific nicotinic receptors on these effects. We aimed to explore the impact of nicotinic receptor subtypes, and calcium-dependent mechanisms, on cortical plasticity in smokers and non-smoking individuals. Plasticity induced by transcranial direct current stimulation (tDCS) and paired associative stimulation (PAS) in the human brain is calcium-dependent, and some nicotinic receptor subtypes, e.g. alpha4beta2- and alpha7-receptors, have calcium channel properties. Moreover, neuroplastic effects depend on the amount of calcium influx to the post-synaptic neuron. High calcium influx results in long term potentiation (LTP), whereas low calcium influx result in long term depression (LTD). Furthermore, between LTD- and LTP-inducing calcium concentrations, and moreover for very high calcium concentrations, respective "no-man´s lands" do exist, where no plasticity is induced. These calcium-dependent mechanisms can explain the results of the above-mentioned studies. For smokers, tDCS and PAS might have not induced plasticity under nicotine withdrawal because of desensitized nicotinic receptors and thus reduced calcium influx. Nicotine would have activated these receptors and hereby, via enhanced intraneuronal calcium, enabled LTP-like processes. For the non-smokers, however, intraneuronal calcium should have been already sufficiently elevated without nicotine to induce LTP. In the present project, we explored these proposed mechanisms in two groups of studies. In the first group, we specifically activated nicotinic receptor subtypes with calcium channel properties via administration of the alpha4beta2- and alpha7-receptor agonist varenicline. In healthy non-smokers, a dosage-dependent effect of varenicline on LTP-like plasticity emerged. Specifically, medium-dosage varenicline abolished tDCS-induced non-focal, but preserved PAS-induced focal plasticity. This effect mirrors that of nicotine application and is in accordance with a calcium-dependent mechanism. We have furthermore conducted a companion study in smokers, which also resulted in similar results as those accomplished by nicotine. In the second group of studies, we were directly modulating calcium influx via block of NMDA receptors, which have calcium channel properties, by dextromethorphan (DMO). DMO - when given alone - reduces or blocks tDCS- and PAS-induced plasticity, presumably via reducing calcium influx. We hypothesized that, if abolishment of tDCS-induced LTP-like plasticity is caused by nicotinic receptor-generated calcium overflow in non-smokers, gradual block of calcium influx should re-establish plasticity. In accordance with our hypothesis, medium dosage DMO, which, when given alone, abolished LTP, re-installed it under nicotine, which, when given alone, also abolished LTP. Similar effects were accomplished via calcium channel block, which stresses the calcium dependency of respective nicotinic plasticity regulation mechanisms. Taken together, the main results of these studies show that nicotine exerts ist discernable effects on plasticity in smokers and non-smokers primarily via nicotinic receptors with calcium channel properties. Nicotine has modulatory effects on plasticity, which are clearly state-dependent, i.e. affected by smoking state of individuals. Nicotine deprivation in smokers impairs plasticity-dependent cognitive functions, such as long-term memory formation, which are restituted by nicotine exposure. Thus the results of our studies might be relevant for improving knowledge about the physiological foundation of nicotine addiction, and perspective lead to targeted intervention protocols.
