Cannabinoid-induced enhanced interaction and protein levels of serotonin 5-HT(2A) and dopamine D₂ receptors in rat prefrontal cortex.
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.
Department of Pharmacology and Toxicology, University of Kansas, Lawrence, KS, USA.
Jade M
JM
Franklin
Gonzalo A
GA
Carrasco
D000818:Animals; D063386:Cannabinoid Receptor Agonists / Q000494:pharmacology*; D063387:Cannabinoid Receptor Antagonists / Q000494:pharmacology; D002460:Cell Line; D018491:Dopamine Agonists / Q000494:pharmacology; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D009419:Nerve Tissue Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D055503:Protein Multimerization / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism; D044402:Receptor, Serotonin, 5-HT2A / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D058826:Serotonin 5-HT2 Receptor Agonists / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects*
D063386:Cannabinoid Receptor Agonists; D063387:Cannabinoid Receptor Antagonists; C543264:Cnr1 protein, rat; C469526:Cnr2 protein, rat; D018491:Dopamine Agonists; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D044402:Receptor, Serotonin, 5-HT2A; D017448:Receptors, Dopamine D2; D058826:Serotonin 5-HT2 Receptor Agonists; D019206:GTP-Binding Protein alpha Subunits, Gi-Go