Nevertheless, there are inconsistencies in the literature with re

Nevertheless, there are inconsistencies in the literature with regard to the role for ��7 nAChRs in nicotine reinforcement, with a number of reports suggesting that the ��7 subunit KO mice, or rodents treated with ��7 nAChR antagonists, demonstrate either unaltered selleck chemicals or reduced nicotine consumption (Grottick et al., 2000; Levin et al., 2009; Markou & Paterson, 2001). Hence, the precise role for ��7 nAChRs in nicotine reinforcement remains unclear. Table 1. Novel Small Molecule Therapeutic Agents in Clinical Testing for Smoking Cessation The above findings demonstrate that ��4��2* nAChRs play a key role in regulating the stimulatory effects of nicotine on midbrain dopamine systems and thereby control the reinforcing properties of nicotine.

As such, ��4��2* nAChRs are key targets for medications development for smoking cessation and continued effects to develop molecules that modulate the activity of this nAChR subtype are likely to yield new effective smoking-cessation agents. Moreover, other subtypes of nAChRs are also involved in regulating the stimulatory effects of nicotine on midbrain dopamine systems, particularly ��6* and ��7 nAChRs, and as such may serve as novel targets for medications development. Nicotinic Acetylcholine Receptors and Smoking Cessation To date, varenicline is the only FDA-approved smoking-cessation agent that was rationally designed through traditional drug discovery processes based on its action as an ��4��2* nAChR partial agonist (Coe et al., 2005; Dwoskin et al., 2009; Lerman et al., 2007; Reus et al., 2007).

It is important to note, however, that varenicline is also a full agonist at ��7 nAChRs (Mihalak, Carroll, & Luetje, 2006). The rationale for developing a ��4��2* nAChR partial agonist for smoking cessation was twofold: First, it was hypothesized that a Entinostat partial agonist may competitively bind to ��4��2* nAChRs and thereby attenuate the stimulatory effects of nicotine obtained from tobacco smoke on mesoaccumbens dopamine transmission (Coe et al., 2005; Reperant et al., 2010). The stimulatory effect of nicotine on midbrain dopamine transmission is considered central to its reinforcing properties that contribute to the development and maintenance of the tobacco habit (Exley et al., 2011; Maskos et al., 2005; Pons et al., 2008). Hence, attenuation of this effect by varenicline may decrease the reinforcing effects of nicotine, thereby aiding smoking cessation efforts. Second, it was hypothesized that the intrinsic low levels of activation of ��4��2* nAChRs by a partial agonist may substitute for the stimulatory effects of nicotine on mesoaccumbens dopamine transmission during abstinence, eliciting a moderate and sustained increase in dopamine levels (Coe et al., 2005).

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