Rewarding properties of nicotine were altered in pEnk, βend, mu and delta KO mice, as shown by decreased nicotine CPP in these mutant mice (Berrendero et al., 2002; Berrendero et al., 2005; Berrendero et al., 2012; Trigo et al., 2009; Walters et al., 2005). In agreement, enhanced extracellular dopamine induced by nicotine in the nucleus accumbens was attenuated in mice lacking pEnk (Berrendero et al., 2005) and delta receptors (Berrendero et al., 2012). Also, the acquisition of nicotine SA was decreased in delta KO mice (Berrendero et al., 2012), further substantiating the notion that delta/pEnk receptor signaling contributes to reinforcing properties of nicotine. In contrast, self-administration of a low nicotine dose was increased in pDyn KO mice (Galeote et al., 2009) suggesting that, as for THC, dynorphin may contribute to aversive effects of nicotine. It would be interesting to pursue similar experiments in kappa KO mice to confirm this hypothesis.
