Proceedings of the National Academy of Sciences
December 13, 2005
Gabriella Gobbi, Francis Rodriguez Bambico, Regina A. Mangieri et al.
675 citations
Inhibiting the enzyme fatty-acid amide hydrolase (FAAH) with URB597, which prevents the breakdown of the endocannabinoid anandamide, produces antidepressant-like effects in mice and rats. URB597 reduced immobility in the tail-suspension and forced-swim tests, and increased firing of serotonin and norepinephrine neurons in brain regions linked to mood. These effects required CB1 receptor activation and were accompanied by higher brain anandamide levels. Unlike direct THC-like drugs, URB597 showed no rewarding or abuse-related effects. The findings suggest FAAH inhibition as a potential target for antidepressant drugs without the psychotropic side effects of cannabis.
Journal of Neuroscience
October 24, 2007
Francis Rodriguez Bambico, Noam Katz, Guy Debonnel et al.
325 citations
Low doses of the cannabinoid CB1 receptor agonist WIN55,212-2 produce antidepressant-like effects in rats, as measured by the forced-swim test. This effect depends on CB1 receptors and the serotonin system, as it is blocked by the CB1 antagonist rimonabant and by serotonin depletion. Electrophysiology shows that low doses of WIN55,212-2 increase serotonin neuron firing in the dorsal raphe nucleus via a CB1-dependent mechanism, while high doses decrease firing through a CB1-independent mechanism and lack antidepressant effects. The enhancement of serotonin activity requires the ventromedial prefrontal cortex, as local microinjection there mimics the antidepressant effect, whereas lateral prefrontal cortex involvement is not needed.
Expert Opinion on Therapeutic Targets
October 14, 2008
Francis Rodriguez Bambico, Gabriella Gobbi
80 citations
Major depression is the most common mental disorder, but current antidepressants have limited effectiveness. Recent research suggests that drugs activating cannabinoid CB(1) receptors or enhancing endocannabinoid levels have antidepressant-like effects, while the CB(1) antagonist rimonabant increases depression and suicide risk. CB(1) agonists and fatty acid amide hydrolase (FAAH) inhibitors work similarly to existing antidepressants by boosting serotonin and norepinephrine transmission and promoting new neuron growth in the hippocampus. FAAH inhibitors cause fewer adverse cannabinoid effects and have a wider therapeutic window than direct CB(1) agonists. However, because the endocannabinoid system also affects peripheral body functions, side effects require attention.
The International Journal of Neuropsychopharmacology
July 23, 2020
Danilo de Gregorio, Joshua Dean Conway, Martha-Lopez Canul et al.
39 citations
Chronic exposure to a low dose of THC (1 mg/kg) during adolescence in rats leads to depressive-like behaviors (increased immobility in the forced swim test and anhedonia in the sucrose preference test) and anxiety-like behavior (fewer open-arm entries in the elevated plus maze). Adult exposure also produces anxiety but not depressive-like behaviors. Both adolescent and adult THC exposure reduce the activity of serotonin neurons in the dorsal raphe, while noradrenergic neurons in the locus coeruleus remain unaffected. These findings suggest that the serotonin system is vulnerable to chronic low-dose THC, and that adolescents are particularly susceptible to THC-induced depressive effects.
Progress in Neuro-Psychopharmacology and Biological Psychiatry
October 1, 2025
Brandon Richardson, Antonio Inserra, Michael Pileggi et al.
2 citations
Psilocybin and lisuride both activate 5-HT2A receptors, but only psilocybin triggers the head twitch response (HTR) in mice, a proxy for hallucinogenic activity. In adult male C57BL/6N mice, psilocybin (0.3–3 mg/kg) inhibited serotonin neuron firing in the dorsal raphe nucleus via 5-HT2A receptors, while lisuride (0.1–0.5 mg/kg) did not. Both drugs reduced dopamine neuron firing in the substantia nigra, but lisuride's effect was more sensitive to 5-HT2A antagonism. Psilocybin elicited HTR; lisuride did not. Only high-dose lisuride reduced immobility in the forced swim test. Both drugs reduced locomotion in open field and elevated plus maze tests. Principal component analysis separated the drug effects, indicating distinct neurobiological pathways: psilocybin produces psychedelic-like, serotonin-dominant effects, while lisuride displays dopamine-linked improvements in coping behavior.
The International Journal of Neuropsychopharmacology
August 1, 2025
B. D. Richardson, Marco Pileggi, Thomas Prudhomme et al.
Psilocybin and lisuride both bind to 5-HT2A receptors, but only psilocybin produces hallucinogenic effects. In adult male mice, both drugs inhibited serotonin neuron activity in the dorsal raphe nucleus and dopamine neuron firing in the substantia nigra. A 5-HT2A antagonist blocked psilocybin's serotonin inhibition but not lisuride's, suggesting different mechanisms. Only lisuride showed an antidepressant-like effect at the highest doses. Psilocybin, but not lisuride, elicited head-twitch responses, and lisuride blocked those induced by psilocybin. Both drugs reduced locomotion. The findings indicate lisuride has antidepressant and sedative effects without hallucinogenic action, likely due to its distinct effects on serotonin and dopamine neurons.