The addictive properties of psychostimulants such as cocaine are rooted in their ability to activate the mesocorticolimbic dopamine (DA) system. This system consists primarily of dopaminergic projections arising from the ventral tegmental area (VTA) and projecting to the limbic and cortical brain regions, such as the nucleus accumbens (NAc) and prefrontal cortex (PFC). While the basic anatomy and functional relevance of the mesocorticolimbic DA system is relatively well-established, a key challenge remaining in addiction research is to understand where and how molecular adaptations and corresponding changes in function of this system facilitate a pathological desire to seek and take drugs. Several lines of evidence indicate that inhibitory signaling, particularly signaling mediated by the Gi/o class of heterotrimeric GTP-binding proteins (G proteins), plays a key role in the acute and persistent effects of drugs of abuse. Moreover, recent evidence argues that these signaling pathways are targets of drug-induced adaptations. In this review we discuss inhibitory signaling pathways involving DA and the inhibitory neurotransmitter GABA in two brain regions - the VTA and PFC - that are central to the effects of acute and repeated cocaine exposure and represent sites of adaptations linked to addiction-related behaviors including sensitization, craving, and relapse.