Phospholipase C mediates (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI)-, but not lysergic acid diethylamide (LSD)-elicited head bobs in rabbit medial prefrontal cortex.
Emmanuelle A. D. Schindler, John A. Harvey, Vincent J. Aloyo
Brain Research November 1, 2012 DOI: 10.1016/j.brainres.2012.10.057 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical animal study Peer reviewed |
|---|---|
| Population | Rabbits (frontocortical tissue prisms and medial prefrontal cortex) |
| Interventions | DOI LSD U73122 ketanserin SB206553 |
| Topics | LSD |
| Keywords | Cerebral cortex Prefrontal cortex Animals Rabbits Amphetamines Pyrrolidinones Estrenes Phosphatidylinositols Receptor, serotonin, 5-ht2a Serotonin antagonists Hallucinogens Enzyme inhibitors Microinjections Behavior, animal Signal transduction Enzyme activation Hydrolysis Head movements Male Type c phospholipases Serotonin receptor agonists |
| Key points | DOI and LSD both stimulated phosphatidylinositol hydrolysis in rabbit frontocortical tissue but through different serotonergic receptors: ketanserin blocked DOI's signal, while SB206553 blocked LSD's. In rabbit medial prefrontal cortex, the phospholipase C inhibitor U73122 blocked DOI-elicited head bobs but not LSD-elicited head bobs, indicating that LSD's behavioral effects in this region are independent of phospholipase C activation. |
Abstract
The phenethylamine and indoleamine classes of hallucinogens demonstrate distinct pharmacological properties, although they share a serotonin(2A) (5-HT(2A)) receptor mechanism of action (MOA). The 5-HT(2A) receptor signals through phosphatidylinositol (PI) hydrolysis, which is initiated upon activation of phospholipase C (PLC). The role of PI hydrolysis in the effects of hallucinogens remains unclear. In order to better understand the role of PI hydrolysis in the MOA of hallucinogens, the PLC inhibitor, 1-[6-((17β-3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl]-1H-pyrrole-2,5-dione (U73122), was used to study the effects of two hallucinogens, the phenethylamine, (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), and the indoleamine, lysergic acid diethylamide (LSD). PI hydrolysis was quantified through release of [3H]inositol-4-phosphate from living rabbit frontocortical tissue prisms. Head bobs were counted after hallucinogens were infused into the medial prefrontal cortex (mPFC) of rabbits. Both DOI and LSD stimulated PI hydrolysis in frontocortical tissue through activation of PLC. DOI-stimulated PI hydrolysis was blocked by 5-HT(2A/2C) receptor antagonist, ketanserin, whereas the LSD signal was blocked by 5-HT(2B/2C) receptor antagonist, SB206553. When infused into the mPFC, both DOI- and LSD-elicited head bobs. Pretreatment with U73122 blocked DOI-, but not LSD-elicited head bobs. The two hallucinogens investigated were distinct in their activation of the PI hydrolysis signaling pathway. The serotonergic receptors involved with DOI and LSD signals in frontocortical tissue were different. Furthermore, PLC activation in mPFC was necessary for DOI-elicited head bobs, whereas LSD-elicited head bobs were independent of this pathway. These novel findings urge closer investigation into the intracellular mechanism of action of these unique compounds.
Comparable studies
Other preclinical and animal studies on LSD, most cited first.
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