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

Abstract

SUMMARYExtensive 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 [Gα q (−/−)] in which the G q alpha gene was eliminated. Gα 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 Gα q (−/−) mice. These results, combined with our finding that DOI-induced FOS expression in the medial prefrontal cortex was also eliminated in Gα q (−/−) mice, suggests a key role for G q protein in hallucinogenic drug effects.

Manganese-enhanced magnetic resonance imaging reveals increased DOI-induced brain activity in a mouse model of schizophrenia

“…Moreover, deletion of the G q gene results in the lack of DOI-induced head twitches (67). The complexity of 5-HT2AR signaling may help to explain the paradox of why structurally similar 5-HT2AR ligands differ in their hallucinogenic effects.…”

Characterization of serotonin-toxicity syndrome (toxidrome) elicited by 5-hydroxy-l-tryptophan in clorgyline-pretreated rats

“…To date the relationship between hallucination and DOI-induced shaking behavior is not fully understood. A recent molecular study revealed a possible link of head shakes to hallucination (Garcia et al, 2007). If this link is confirmed to be the case, it suggests that head shaking behavior may reflect not only physical but also mental changes.…”

Classic hallucinogens in the treatment of addictions

“…5HT2A receptor activation is coupled to several intracellular signaling pathways (reviewed in Halberstadt, 2015). G q -mediated signaling activates the inositol triphosphate-diacylglycerol pathway leading to activation of protein kinase C. Behavioral effects of DOI are attenuated in G q knockout mice (Garcia et al, 2007). Signaling through G i/o , leading to activation of Src and expression of the immediate early genes egr-1 and egr-2, may be necessary to produce hallucinogenic effects.…”