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J Psychopharmacol. 2012 Oct;26(10):1333-47. doi: 10.1177/0269881112450786. Epub 2012 Jul 11.

Cannabinoid-induced enhanced interaction and protein levels of serotonin 5-HT(2A) and dopamine D₂ receptors in rat prefrontal cortex.

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Department of Pharmacology and Toxicology, University of Kansas, Lawrence, KS, USA.


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.

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