, 1991, Marks et al., 1992, Nguyen et al., 2003, Nashmi et al.,

2007 and Doura et al., 2008). In several brain regions, chronic nicotine administration produces ∼50% upregulation of HS nAChRs after just two days. Continued administration then produces additional increases over one to several weeks (Marks et al., 1991 and Pietilä et al., 1998). Within individual brain regions, there is selective upregulation among cell click here types. In the midbrain, both DA neurons (in substantia nigra pars compacta and ventral tegmental area [VTA]) and GABAergic neurons (in substantia nigra pars reticulata and VTA) express high levels of α4β2∗ nAChRs on their somata, but only GABAergic neurons display somatic upregulation (Nashmi et al., 2007 and Xiao et al., 2009). Another example of cell-selective upregulation occurs in the projection from medial entorhinal cortex to dentate gyrus. In the medial perforant path, which mainly arises from layer II stellate cells, chronic nicotine upregulates α4β2∗ nAChRs. However in the temporoammonic pathway, which mainly arises from layer III pyramidal neurons, α4β2∗ nAChRs are present but are

not upregulated (Nashmi et al., 2007). Chronic nicotine also produces selective upregulation between somatodendritic versus axon terminal regions of individual neurons. In midbrain, chronic nicotine treatment elicits a general increase in α4β2∗ nAChRs in GABAergic neurons, but only in axon terminals of DA neurons. Such “tiers of selectivity” in mesostriatal and mesolimbic upregulation have the power to explain two components of nicotine

dependence: Lumacaftor tolerance to some rewarding effects of nicotine and sensitization to others (Nashmi et al., 2007 and Lester et al., 2009). Nicotine also interacts with specific nAChR subtypes, and nicotine-induced upregulation is governed in part by these interactions at agonist binding interfaces (Figure 1). Further work is needed to understand how chronic nicotine differentially upregulates some but not all HS nAChRs. Part of the cell selectivity in upregulation presumably arises because each neuronal type expresses a distinct repertoire of subunits. GABAergic neurons in DA brain regions express mostly α4β2 nAChRs along with a few α4α5β2 nAChRs (McClure-Begley et al., 2009), whereas DA neurons express at least three α4-containing Carnitine palmitoyltransferase II nAChRs (α4α6β2β3, α4α5β2, and a few α4β2) (Salminen et al., 2004 and Gotti et al., 2007). Although α6β3∗ nAChRs are, like α4β2 nAChRs, highly sensitive to nicotine, several studies demonstrate that chronic nicotine treatment elicits either no change or a decrease in α6β3∗ nAChRs in mouse brain ( McCallum et al., 2006a, McCallum et al., 2006b and Mugnaini et al., 2006). Nicotine may also subvert the coordinated regulation in place by other control mechanisms, such as lynx proteins, through the preferential upregulation of one subtype resulting in imbalance in nicotinic receptor signaling.