Project Summary/Abstract Nicotine addiction is associated with elevated release of dopamine in brain reward centers of the striatum and the basal forebrain including the nucleus accumbens (NAc) synapsed by dopaminergic neurons of the ventral tegmental area (VTA) and the substantia nigra (SN) of the midbrain.1-3 Nicotine is a potent psychostimulant whose addictive potential originates from modulation of activity of dopaminergic VTA and SN neurons resulted from activation of nicotinic acetylcholine receptors (nAChRs) expressed in these neurons in high densities.1,2,4 Because nAChRs are non-selective cation channels5, stimulation of nAChRs6,7 by nicotine excites midbrain dopaminergic neurons, stimulates the mesostriatal projections and elevates release of dopamine in the basal forebrain and the striatum commencing nicotine reinforcement.2,4,8 Studies utilizing rodent models of nicotine rewarding efficacy indicated that the addictive potential of nicotine is primarily linked to activation of β2-containing (i.e., β2*) nAChRs (e.g., α4β2, α6β2)8, because β2 subunits are required for the maintenance of nicotine self-administration9, while re-expression of β2 subunits in the VTA of β2 knock-out mice reinstates nicotine self-administration behavior in mice10. The other key player in nicotine reinforcement and a promising target in nicotine cessation therapies is the α7 subtype of nAChRs. Activation of α7 nAChRs inhibits nicotine rewarding effects in conditioned place preference (CPP) and self-administration models of nicotine dependence in mice.11,12 Thus, α7 selective agonists and positive allosteric modulators (PAMs) may prove to be valuable as potential treatments in smoking cessation therapies.13 Accordingly, the only two FDA-approved drugs, varenicline and bupropion, directly interact with central nAChRs:14 varenicline is a full α7 agonist and partial β2 agonist15,16, while less effective, bupropion, is a non-selective nAChR antagonist and an inhibitor of dopamine uptake14,17. A major problem in the treatment of nicotine addiction is relapse.20 Despite being clinically safe and effective for smoking cessation14,18, both varenicline and bupropion allow for high relapse rates at 1 year of treatment.17,19-21 Both drugs also cause a number of side effects including nausea22, constipation23 and insomnia17 that may reduce treatment adherence14. Bupropion is also contraindicated for people with seizures.14 Thus, the rationale for this proposal arises from the critical need for safe novel α7 ligands that inhibit nicotine rewarding effects and produce superior treatment adherence and relapse rates. We hypothesize that these superior therapeutic properties may be offered by PAMs, a class of selective α7 ligands24. Importantly, a recent study in mice demonstrated significant inhibition of nicotine reinforcement in the nicotine CPP test12 suggesting that endogenous cholinergic tone is sufficient to engage PAM-dependent therapeutic mechanisms with significant in...