GIRK channels are thought to have a role in the acute rewarding effects and/or the adaptation that occurs with chronic exposure to addictive drugs that work through GPCRs, such as opioids, the club-drug GHB, and cannabinoids. Addictive drugs are known to strongly increase dopamine levels in the mesocorticolimbic system. Based on in vivo and in vitro experiments, distinct cellular mechanisms have been proposed for different classes of drugs152. Opioids and the club drug γ-hydroxbutyrate (GHB) activate GIRK channels leading to disinhibition of DA neurons. Morphine stimulates μ-opioid receptors that are selectively expressed on interneurons of the VTA and activate GIRK channels, reducing the firing of these cells, eventually leading to disinhibition of DA neurons153. The effect of GHB is more complex, as GABAB receptors are expressed on both GABA and DA neurons. However, DA neurons in the VTA are an order magnitude less sensitive (higher EC50) to GABAB receptor agonists than GABA interneurons43 most likely due to the selective expression of GIRK2c and GIRK3 and the lack of GIRK1 subunit (see discussion above). Consequently, low concentrations of GHB only activate
