Effects of Δ9-Tetrahydrocannabinol, Synthetic Cannabinoids, and Fatty Acid Amide Hydrolase Inhibitors on Mood and Serotonin Neurotransmission

Abstract The psychological feelings produced by cannabis have been described as fatuous euphoria, elation, and talkativeness. However, heavy cannabis consumption can induce mood disturbances and lead to depression, especially after chronic use. Despite these clinical findings, little was known about the capacity of cannabis to modulate the transmission of serotonin (5-HT), the primary neurotransmitter implicated in the regulation of mood and depression. Since 2005 our laboratory has attempted to clarify how CB1 receptor (CB1R) agonists, CB1R antagonists, and fatty acid amide hydrolase (FAAH) inhibitors modulate the firing activity of 5-HT neurons located in the dorsal raphe nuclei. While the CB1R agonist WIN 55,212-2 produces a bell-shaped curve, increasing 5-HT firing at low doses and decreasing firing at higher doses, the FAAH inhibitor URB 597 produces a σ-shaped curve, with a plateau at the highest doses tested. Acute injection of Δ 9 -tetrahydrocannabinol (Δ 9 -THC) produces a mixed response on 5-HT firing activity; however, after 4 days of intraperitoneal injections, Δ 9 -THC produces a significant elevation in 5-HT firing. Finally, both WIN 55,212 and Δ 9 -THC evoke a robust decrease in 5-HT firing rate after long-term administration during adolescence, with associated deficits in emotional reactivity. These data indicate that both natural and synthetic CB1R agonists and FAAH inhibitors modulate the 5-HT system, which may have implications for emotional behavior and mood disturbances.