, 2002; Le Novere, Zoli, & Changeux, 1996; Quik et al., 2000), which plays a major role in supporting the positive reinforcing actions of nicotine. In the NAc and other domains of the striatum, dopaminergic terminals express ��6��2��3* and selleck chem inhibitor ��6��4��2��3* nAChR subtypes (Champtiaux et al., 2003; Salminen et al., 2004; Zoli et al., 2002), with considerable evidence suggesting that ��6��3* nAChRs regulate the stimulatory effects of nicotine on dopamine release in this region (Champtiaux et al., 2003). The ��6��4��2��3* nAChR subtype enriched in the NAc and striatum has the highest sensitivity to nicotine of any native nAChR so far identified (Grady et al., 2007). Gotti et al.

(2010) reported that infusion of ��-conotoxin MII (CntxMII), a ��3/��6��2* selective antagonist, or ��-conotoxin PIA (CntxPIA), a ��6��2* nAChR selective antagonist, directly into the VTA decreased nicotine-evoked increases in midbrain dopamine levels. Intra-VTA infusion of CntxMII also decreased responding for intravenous nicotine self-administration in rats (Gotti et al., 2010). Similarly, Brunzell and colleagues reported that intra-NAc infusion of CntxMII decreased the motivation of rats to self-administer nicotine, as measured using a progressive ratio schedule of reinforcement (Brunzell, Boschen, Hendrick, Beardsley, & McIntosh, 2010). More recently, it was shown that KO mice lacking protein kinase C epsilon (PKC�� KO mice) self-administered less nicotine and had attenuated place conditioning for nicotine than their wildtype counterparts (Lee & Messing, 2011).

The PKC�� KO mice also demonstrated decreased levels of ��6 and ��3 nAChR subunit mRNA transcripts in the midbrain and striatum, and deficits in cholinergic modulation of dopamine release in the NAc (Lee & Messing, 2011). Hence, it was hypothesized that PKC�� may regulate ��6 (and also ��3) nAChR signaling and thereby influence nicotine reinforcement (Lee & Messing, 2011). Using an ��acute�� nicotine self-administration procedure in which mice are restrained but can nose-poke for intravenous nicotine infusions via a catheter in the tail vein during a single session, it was shown that ��6 subunit KO mice had attenuated levels of nicotine intake compared with wildtype mice (Pons et al., 2008). Taken together, these findings suggest that ��6* nAChRs may be promising targets for medications development for tobacco dependence. However, it is important to note that ��6 KO mice were recently shown to respond for AV-951 nicotine infusions in a manner similar to wildtype mice, as measured using a self-administration procedure in which nicotine infusions were delivered directly into the VTA (Exley et al., 2011). Using this same procedure, ��4 KO mice had a marked deficit in responding for the drug (Exley et al., 2011).