Antisense oligodeoxynucleotides to G-protein alpha-subunit subclasses identify a transductional requirement for the modulation of normal feeding dependent on G alpha OA subunit.

Abstract

A variety of G-protein-coupled receptors are proposed to participate in the modulation of ingestive behavior and in the mode of action of antiobesity drugs. In the present study, we investigated the involvement of G-protein alpha-subunit subclasses (molecular transducers of multiple chemical signals) in the control of ingestive behavior. We report here that the chronic intracerebroventricular (i.c.v.) microinfusion for 72 h (via osmotic minipumps) with antisense phosphothio-oligodeoxynucleotides corresponding to G-protein alpha-subunitO common (to OA and OB) and OA subclasses decrease the nighttime food intake without affecting water intake in rats. Computerized analyses of the microstructure of feeding indicate that the G alpha OA antisense depresses feeding by reducing meal frequency, while meal size and meal duration increased slightly, but not significantly. The effects of G alpha O common and G alpha OA antisense on feeding are specific since the chronic i.c.v. microinfusion of sense to G alpha O common or G alpha OA, antisense to the related subclass G alpha OB, and antisense to other G-protein alpha-subunits (G alpha S, G alpha Q, G alpha 11 and G alpha i common) had no effect on food or water intake. The observed effects by G alpha O common and G alpha OA antisense imply a direct action in the central nervous system since the chronic subcutaneous microinfusion of G alpha O common and G alpha OA antisense in doses equivalent to two-fold higher relative to those administered centrally had no effect on food intake. The chronic microinfusion of G alpha O common antisense drastically decreased the levels of G alpha O protein detected in immunoblots of hypothalamic ventromedial nuclei. The results suggest that the G-protein alpha-subunit subclass G alpha OA is critical for the integrative modulation of normal feeding behavior, and that changes in its activity may be associated with modifications of feeding. These studies also show a novel approach to study the molecular basis of specific behaviors by manipulating elements of the transductional systems.