The broad goal of this proposal is to evaluate the role of the Gq signaling pathway in hallucinogenic drug activity by manipulating cell signaling in specific brain regions. As a tool to manipulate cell signaling, we have prepared an HIV-1-based vector containing a minigene encoding for the last 11 amino acids of the carboxy terminus of the Galpha subunit of Gq (GqCT), which has been shown to specifically disrupt protein-protein interactions between the 5HT2A receptor and the heterotrimeric Gq protein. We have performed microinjections of HIV-1-GqCT into the anterior cingulate cortex (ACC) of rats, and shown that our lentiviral construct is effective at infecting brain cells in vivo. Future experiments will evaluate the efficacy of Gq blockade utilizing biochemical approaches followed by expression of our construct in the brain of adult mice heterozygous for Gq. By combining heterozygous Gq (+/-) mice and lentiviral-mediated delivery of GqCT in adults, we will be able to evaluate the effects of an acute blockade of Gq signaling pathways, due to a synergistic effect between Gq blocking peptides and the knockdown of Gq protein, after developmental events have taken place.
| Garcia, Efrain E; Smith, Randy L; Sanders-Bush, Elaine (2007) Role of G(q) protein in behavioral effects of the hallucinogenic drug 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane. Neuropharmacology 52:1671-7 |
