29-31 Figure 3. Schematic representation subcellular localization of neuronal nicotinic receptors with their postsynaptic, presynaptic, extrasynaptic, and axonal distributions. Multiple functions of nAChRs The broad distribution of nAChRs in the CNS suggests that these

receptors play a major role in brain physiology. Surprisingly, however, bath application of nicotine Inhibitors,research,lifescience,medical to brain slices produces little or no effect, a result that was interpreted as the lack of action of nicotine in the CNS. However, if the neuronal properties are examined more closely, the action of nicotine can be detected in most brain areas. The reason for this discrepancy is mainly due to the method of drug application. When applied in the bath, nicotine provokes both a small activation of the receptors Inhibitors,research,lifescience,medical and their desensitization. Because bath application is rather slow, the short-lasting

activation is essentially masked by the receptor desensitization. In contrast, when an agonist such as ACh or nicotine is briefly applied to neurons the physiological consequences of the nAChRs can be detected. It has been shown that activation of nAChRs causes multiple effects according to Inhibitors,research,lifescience,medical the localization of the receptor. For example, somatic receptors will cause a depolarization of the neuron and therefore modulate its firing activity, while presynaptic receptors modulate the release of other neurotransmitter, such as dopamine, glutamate, and 5-HT.31 To understand the basis of these neurotransmitter

interactions, it should be recalled that a significant fraction of the nAChRs are expressed on presynaptic Inhibitors,research,lifescience,medical boutons. Activation of the nAChRs causes two important mechanisms that are (i) depolarization of the synaptic bouton; and (ii) in the case of α7 nAChRs, a significant calcium influx. Both mechanisms provoke an increase in the intracellular calcium concentration, which is known to be the key step in the liberation of the neurotransmitter contained in the vesicle of the synaptic bouton by exocytosis. While a few experiments have shown that nAChRs can participate Inhibitors,research,lifescience,medical in synaptic transmission, it is generally accepted that these receptors have out more a modulatory role in neuronal function, rather than a determining role in the fast excitatory pathways. In agreement with these observations, knocking out a given nAChR subunit in mice is not lethal, but was shown to alter behavior.32 Nicotine and depression In view of the modulatory role of nAChRs and their multiple interactions with various neurotransmitter systems, such as Crenolanib nmr dopamine or 5-HT, it is not surprising that an association between nicotine and depression is often reported.3,4 The main pathways associating nicotine and depression are summarized in Table I. During the past 5 years, more than 250 scientific publications have discussed the interaction between nicotine and depression.