Cannabinoid-induced enhanced interaction and protein levels of serotonin 5-HT2A and dopamine D2 receptors in rat prefrontal cortex

Recent evidence suggests that non-selective cannabinoid receptor agonists may regulate serotonin 2A (5-HT2A) receptor neurotransmission in brain. The molecular mechanisms of this regulation are unknown, but could involve cannabinoid-induced enhanced interaction between 5-HT2A 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-HT2A and D2 receptors and enhanced membrane-associated expression of D2 and 5-HT2A receptors in prefrontal cortex (PFCx). Furthermore, 5-HT2A receptor mRNA levels were increased in PFCx, suggesting a cannabinoid-induced upregulation of 5-HT2A 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-HT2A receptor upregulation. We found that selective CB2 receptor agonists upregulate 5-HT2A receptors by a mechanism that seems to involve activation of Gai G-proteins, ERK1/2, and AP-1 transcription factor. We hypothesize that the enhanced cannabinoid-induced interaction between 5-HT2A and D2 receptors and in 5-HT2A 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.