Role of G(q) protein in behavioral effects of the hallucinogenic drug 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane

Extensive evidence suggests that 5-HT2 receptors may play a role in mental disorders including schizophrenia. In addition, several studies indicate that G_q-coupled 5-HT_2A 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-HT_2A receptors couple to other G proteins in addition to G_q protein. To evaluate the role of the G_q signaling pathway in DOI-induced behaviors, we utilized two behavioral models of 5-HT_2A 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 [G_q(−/−)] in which the G_q alpha gene was eliminated. G_q(−/−) 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 G_q(−/−) mice. These results, combined with our finding that DOI-induced FOS expression in the medial prefrontal cortex was also eliminated in G_q(−/−) mice, suggests a key role for G_q protein in hallucinogenic drug effects.