Enhanced novelty/sensation seeking is a strong indicator of addiction-like behavior in both rodents and humans (Belin et al., 2010; Jupp and Dalley, 2013). Interestingly, SNX27DA KO mice were significantly more active in a novel environment than the two control lines of mice. Moreover, enhanced reaction to novelty in mutant mice often correlates with an augmentation of cocaine response (Bello et al., 2011; Dietrich et al., 2012), and mice lacking SNX27 in DA neurons exhibit a heightened sensitivity to cocaine. Restoration of GABABR-activated GIRK currents in DA neurons with ectopic expression of GIRK2a completely normalized the cocaine sensitivity, confirming the important role for GABABR-activated GIRK currents in VTA DA neurons. Fast GABA-evoked inhibitory currents also control VTA DA neuron firing. Genetic manipulations that reduce the amplitude of fast GABA-evoked IPSCs enhance dopamine release and learning of cue-reward associations (Parker et al., 2011), and repeated cocaine administration also reduces GABAAR signaling, facilitating LTP induction in VTA DA neurons (Liu et al., 2005). Taken together, these studies underscore the importance of inhibitory control of VTA DA neurons in regulating DA release in the brain reward circuit in response to drugs of abuse.
