, 2011). ��4��2 nAChRs can exist in high- and low-sensitivity states, a property attributed to the fact that distinct stoichiometries www.selleckchem.com/products/ganetespib-sta-9090.html of the receptor are possible due to alternative subunit assembly (Nelson, Kuryatov, Choi, Zhou, & Lindstrom, 2003; Zwart & Vijverberg, 1998). Specifically, it has been proposed that the receptor can exit as a (��4)2(��2)3 pentamer that has high sensitivity to agonist stimulation, or a (��4)3(��2)2 pentamer that has low-sensitivity low-agonist stimulation. Interestingly, varenicline and nicotine can activate both the high and low stoichiometries of the ��4��2 nAChR, whereas a wide range of other putatively selective ��4��2 nAChR ligands such as AZD3480, ABT-089, and dianicline only activated the high-sensitivity stoichiometry (Anderson et al., 2009).

The relevance of this finding to the therapeutic effects of nicotine and varenicline is unclear, but it is an intriguing possibility that molecules that modify the low-sensitivity state of the ��4��2*nAChR may be particularly beneficial for smoking cessation. As noted above, ��6* nAChRs are also believed to contribute to the stimulatory effects of nicotine on striatal dopamine transmission (Grady et al., 2007). Interestingly, varenicline-induced increases in dopamine release from striatal or prefrontal cortical tissues was unaffected by the ��3/��6��2* selective antagonist CntxMII (Anderson et al., 2009), consistent with the largely ��4��2 nAChR-specific actions of varenicline and suggesting that ��6* nAChRs are unlikely to play a major role in the therapeutic actions of varenicline.

In addition to ��4��2* and ��6* nAChRs, there is evidence that ��7 nAChRs may also play a role in regulating nicotine intake. Brunzell and McIntosh reported that antagonism of ��7 nAChRs in the NAc or anterior cingulate cortex (ACC), achieved by local infusion of the ��7 nAChR-selective antagonist ��-conotoxin ArIB [V11L,V16D] (ArIB), increased responding for nicotine in rats (Brunzell & McIntosh, 2012). Conversely, NAc infusion of the ��7 nAChR agonist, PNU 282987, decreased the motivation to consume nicotine (Brunzell & McIntosh, 2012). It has also been shown that the stimulatory Dacomitinib effects of nicotine on mesoaccumbens dopamine transmission are potentiated in ��7 nAChR KO mice (Besson et al., 2012). Moreover, ��7 KO mice respond at lower levels for intra-VTA infusions of nicotine, an effect interpreted as increased sensitivity to the reinforcing properties of the drug necessitating lower quantities being required to achieve the desired hedonic state (Besson et al., 2012). Together, these findings suggest that increasing ��7 nAChR signaling in the brains of smokers may decrease the motivation to smoke.