Abstract
Recent evidence suggests that non-selective cannabinoid receptor agonists may regulate serotonin 2A (5-HT(2A)) receptor neurotransmission in brain. The molecular mechanisms of this regulation are unknown, but could involve cannabinoid-induced enhanced interaction between 5-HT(2A) and dopamine D2 (D₂) receptors. Here, we present experimental evidence that Sprague-Dawley rats treated with a non-selective cannabinoid receptor agonist (CP55,940, 50 µg/kg, 7 days, i.p.) showed enhanced co-immunoprecipitation of 5-HT(2A) and D₂ receptors and enhanced membrane-associated expression of D₂ and 5-HT(2A) receptors in prefrontal cortex (PFCx). Furthermore, 5-HT(2A) receptor mRNA levels were increased in PFCx, suggesting a cannabinoid-induced upregulation of 5-HT(2A) receptors. To date, two cannabinoids receptors have been found in brain, CB1 and CB2 receptors. We used selective cannabinoid agonists in a neuronal cell line to study mechanisms that could mediate this 5-HT(2A) receptor upregulation. We found that selective CB2 receptor agonists upregulate 5-HT(2A) receptors by a mechanism that seems to involve activation of Gα(i) G-proteins, ERK1/2, and AP-1 transcription factor. We hypothesize that the enhanced cannabinoid-induced interaction between 5-HT(2A) and D₂ receptors and in 5-HT(2A) and D₂ receptors protein levels in the PFCx might provide a molecular mechanism by which activation of cannabinoid receptors might be contribute to the pathophysiology of some cognitive and mood disorders.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cannabinoid Receptor Agonists / pharmacology*
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Cannabinoid Receptor Antagonists / pharmacology
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Cell Line
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Dopamine Agonists / pharmacology
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GTP-Binding Protein alpha Subunits, Gi-Go / metabolism
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MAP Kinase Signaling System / drug effects
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Male
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Nerve Tissue Proteins / agonists
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Nerve Tissue Proteins / antagonists & inhibitors
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism
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Neurons / drug effects*
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Neurons / metabolism
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Prefrontal Cortex / drug effects*
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Prefrontal Cortex / metabolism
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Protein Multimerization / drug effects
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RNA, Messenger / metabolism
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Random Allocation
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Rats
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Rats, Sprague-Dawley
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Receptor, Cannabinoid, CB1 / agonists
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Receptor, Cannabinoid, CB1 / antagonists & inhibitors
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Receptor, Cannabinoid, CB1 / metabolism
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Receptor, Cannabinoid, CB2 / agonists*
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Receptor, Cannabinoid, CB2 / antagonists & inhibitors
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Receptor, Cannabinoid, CB2 / metabolism
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Receptor, Serotonin, 5-HT2A / chemistry
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Receptor, Serotonin, 5-HT2A / genetics
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Receptor, Serotonin, 5-HT2A / metabolism*
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Receptors, Dopamine D2 / agonists
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Receptors, Dopamine D2 / genetics
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Receptors, Dopamine D2 / metabolism*
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Serotonin 5-HT2 Receptor Agonists / pharmacology
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Up-Regulation / drug effects*
Substances
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Cannabinoid Receptor Agonists
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Cannabinoid Receptor Antagonists
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Cnr1 protein, rat
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Cnr2 protein, rat
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Dopamine Agonists
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Nerve Tissue Proteins
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RNA, Messenger
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Receptor, Cannabinoid, CB1
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Receptor, Cannabinoid, CB2
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Receptor, Serotonin, 5-HT2A
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Receptors, Dopamine D2
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Serotonin 5-HT2 Receptor Agonists
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GTP-Binding Protein alpha Subunits, Gi-Go