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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
Journal article   Open access   Peer reviewed

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 and Vincent J Aloyo
Brain research, v 1491(23), pp 98-108
23 Jan 2013
DOI: https://doi.org/10.1016/j.brainres.2012.10.057
PMID: 23123701
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://europepmc.org/articles/pmc3559188View
Accepted (AM) Open Open Access (License Unspecified)

Abstract

Amphetamines - administration & dosage Amphetamines - pharmacology Animals Behavior, Animal - drug effects Behavior, Animal - physiology Cerebral Cortex Enzyme Activation - drug effects Enzyme Inhibitors - pharmacology Estrenes - pharmacology Hallucinogens - administration & dosage Hallucinogens - pharmacology Head Movements - drug effects Head Movements - physiology Hydrolysis Lysergic Acid Diethylamide - administration & dosage Lysergic Acid Diethylamide - pharmacology Male Microinjections Phosphatidylinositols - metabolism Prefrontal Cortex - physiology Pyrrolidinones - pharmacology Rabbits Receptor, Serotonin, 5-HT2A - drug effects Serotonin Antagonists - pharmacology Serotonin Receptor Agonists - administration & dosage Serotonin Receptor Agonists - pharmacology Signal Transduction - drug effects Type C Phospholipases - antagonists & inhibitors Type C Phospholipases - physiology
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.

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