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 GIRK currents in GABA neurons (containing GIRK1 subunits), leading to disinhibition of DA neurons. In addition, DA neurons in the VTA also selectively express RGS2, which contributes to the lower GABABR-GIRK sensitivity26. Interestingly, chronic exposure to morphine or GHB enhances the coupling efficiency (EC50) for GABAB receptors and GIRK channels by lowering levels of RGS2 in DA neurons26. Under these circumstances the concentration window for disinhibition is much narrower and now low concentrations of drug are sufficient to inhibit DA neurons and become behaviorally aversive26. Thus, the combination of GIRK subunits expressed in a neuron can determine the signaling properties of neuronal circuits. In the case of cannabinoids, the disinhibition of DA neurons seems to occur primarily through presynaptic, GIRK-independent mechanisms154 (but see 124,125).
