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

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 α-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 α-subunit_{O 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 Gα_OA antisense depresses feeding by reducing meal frequency, while meal size and meal duration increased slightly, but not significantly. The effects of Gα_{O common} and Gα_OA antisense on feeding are specific since the chronic i.c.v. microinfusion of sense to Gα_{O common} or Gα_OA, antisense to the related subclass Gα_OB, and antisense to other G-protein α-subunits (Gα_S, Gα_Q, Gα₁₁ and Gα_{i common}) had no effect on food or water intake. The observed effects by Gα_{O common} and Gα_OA antisense imply a direct action in the central nervous system since the chronic subcutaneous microinfusion of Gα_{O common} and Gα_OA antisense in doses equivalent or two-fold higher relative to those administered centrally had no effect on food intake. The chronic microinfusion of Gα_{O common} antisense drastically decreased the levels of Gα_O protein detected in immunoblots of hypothalamic ventromedial nuclei. The results suggest that the G-protein α-subunit subclass Gα_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.