Losing RGS2 and a Taste for GHB

Science's STKE  04 Dec 2007:
Vol. 2007, Issue 415, pp. tw438
DOI: 10.1126/stke.4152007tw438

Depending on concentration, agonists of the γ-aminobutyric acid type B (GABAB) receptor can either potentiate or inhibit the activity of dopaminergic neurons arising in the ventral tegmentum (a pathway involved in addiction). Labouèbe et al.--researchers who provided a plausible mechanism for these opposing effects by showing that the coupling efficiency of GABAB receptors to G protein-activated inwardly rectifying potassium (GIRK) channels was greater in inhibitory GABAergic neurons than in dopaminergic neurons--explored regulation of GABAB-GIRK coupling. Immunoelectron microscopy of transgenic mice lacking different GIRK subunits showed that GIRK2 and GIRK3 were present in both ventral tegmental neurons in which they could detect tyrosine hydroxylase (TH, the rate-limiting enzyme for dopamine synthesis) and in neurons lacking TH, whereas GIRK1 was not found in TH-containing neurons. Both GIRK2 and GIRK3 contributed to currents evoked in dopaminergic neurons by the high-affinity GABAB agonist baclofen. Pharmacological analysis indicated that inhibition of regulator of G protein signaling proteins (RGS proteins, which act as GTPase-activating proteins) increased coupling efficiency (lowered EC50) of GABAB to GIRK. Furthermore, RGS2 was preferentially expressed in dopaminergic neurons and coupling efficiency was increased in mice lacking RGS2. Fluorescence resonance energy transfer (FRET) analysis, as well as electrophysiological analysis of knockout mice, indicated that RGS2 interacted directly with GIRK3 but not GIRK2. Repeated exposure of mice to γ-hydroxybutyrate (GHB, an addictive, low-affinity GABAB receptor agonist) or morphine over several days led to an increase in coupling efficiency between GABAB receptors and GIRK in dopaminergic neurons, as well as a decrease in RGS2 mRNA in the ventral tegmentum. Intriguingly, chronic exposure to GHB caused mice to lose their preference for solutions containing it and instead to avoid them. The authors suggest that these data may provide insight into new approaches to targeting dopaminergic activity in the ventral tegmentum to treat addiction.

G. Labouèbe, M. Lomazzi, H. G. Cruz, C. Creton, R. Luján, M. Li, Y. Yanagawa, K. Obata, M. Watanabe, K. Wickman, S. B. Boyer, P. A. Slesinger, C. Lüscher, RGS2 modulates coupling between GABAB receptors and GIRK channels in dopamine neurons of the ventral tegmental area. Nat. Neurosci. 10, 1559-1568 (2007). [PubMed]