Inhibitory pathways primarily involve GABA, which activates fast GABAA-type receptors and slower G protein-coupled GABAB receptors. Repeated exposure to cocaine reduces the amplitude of fast GABA-evoked IPSCs, promoting LTP induction (Liu et al., 2005), and genetic manipulation of GABAA receptors in DA neurons enhances reward learning and morphine response (Parker et al., 2011). Activation of GABAB receptors inhibits DA neuronal firing activity (Johnson and North, 1992; Seutin et al., 1994), reduces dopamine release (Klitenick et al., 1992), and provides a mechanism for opposing the reinforcing effects of drugs of abuse (Kalivas and Stewart, 1991). Previous studies have implicated GABAB receptors coupled to G protein-gated inwardly rectifying potassium (GIRK or Kir3) channels in the response to drugs of abuse (Cruz et al., 2004; Labouèbe et al., 2007; Luscher et al., 1997; Morgan et al., 2003; Padgett et al., 2012), with both GABAB receptors and GIRK channels emerging as an important therapeutic target for neurological disorders (Lujan et al., 2013; Lüscher and Slesinger, 2010; Tyacke et al., 2010).
