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Title page for ETD etd-03072007-170823


Type of Document Dissertation
Author Garcia, Efrain Eduardo
Author's Email Address efrain.garcia@vanderbilt.edu
URN etd-03072007-170823
Title Unraveling the Role of G-proteins in Hallucinogenic Drug Action
Degree PhD
Department Pharmacology
Advisory Committee
Advisor Name Title
Randy Blakely Committee Chair
Craig Kennedy Committee Member
Elaine Sanders-Bush Committee Member
Heidi Hamm Committee Member
Ron emeson Committee Member
Keywords
  • Head-twitch respnse
  • Elevated plus maze
  • Gq
  • 5-HT2A receptors
  • Hallucinogens
  • c-fos
  • Serotonin--Receptors--Effect of drugs on
  • G proteins--Mechanism of action
Date of Defense 2006-12-06
Availability unrestricted
Abstract
Extensive evidence suggests that 5-HT2 receptors may play a role in mental disorders including schizophrenia, depression and psychosis. In addition, several studies indicate that Gq-coupled 5-HT2A family of receptors are likely targets for the initiation of events leading to the hallucinogenic behavior elicited by lysergic acid diethylamide (LSD), (+/-)1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), and related drugs. However, 5-HT2A receptors couple to other G proteins in addition to Gq protein. To evaluate the role of the Gq signaling pathway in DOI-induced behaviors, we utilized two behavioral models of 5-HT2A receptor activation: induction of head-twitches by DOI, a common response to hallucinogenic drugs in rodents, and DOI elicited anxiolytic-like effects in the elevated plus maze. Experimental subjects were genetically modified mice [Gq(-/-)] in which the gene is eliminated by heterologous recombination. Gq(-/-) mice exhibited a decrease in DOI-induced head-twitches, when compared to wild-type littermates. In addition, the DOI-induced increase in anxiolytic-like behavior was abolished in Gq(-/-) mice. These results, combined with our finding that DOI-induced FOS expression in the medial prefrontal cortex was also eliminated in Gq(-/-) mice, suggests a key role for Gq protein in hallucinogenic drug effects.
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