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The Journal of Neuroscience, October 24, 2007, 27(43):11700-11711; doi:10.1523/JNEUROSCI.1636-07.2007

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Neurobiology of Disease
Cannabinoids Elicit Antidepressant-Like Behavior and Activate Serotonergic Neurons through the Medial Prefrontal Cortex

Francis Rodriguez Bambico,¹ Noam Katz,^1,2 Guy Debonnel,¹  and Gabriella Gobbi^1,2

¹Neurobiological Psychiatry Unit, Department of Psychiatry, McGill University, Montréal, Quebec, Canada H3A 1A1, and ²Department of Psychiatry, Centre de Recherche Fernand Seguin, Hôpital L.H. Lafontaine, Université de Montréal, Quebec, Canada H1N 3V2

Correspondence should be addressed to Dr. Gabriella Gobbi, Neurobiological Psychiatry Unit, Department of Psychiatry, Research and Training Building, McGill University, 1033 Pine Avenue West, Montréal, Quebec, Canada H3A 1A1. Email: gabriella.gobbi{at}mcgill.ca

Preclinical and clinical studies show that cannabis modulates mood and possesses antidepressant-like properties, mediated by the agonistic activity of cannabinoids on central CB₁ receptors (CB₁Rs). The action of CB₁R agonists on the serotonin (5-HT) system, the major transmitter system involved in mood control and implicated in the mechanism of action of antidepressants, remains however poorly understood. In this study, we demonstrated that, at low doses, the CB₁R agonist WIN55,212-2 [R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)]pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl) methanone mesylate] exerts potent antidepressant-like properties in the rat forced-swim test (FST). This effect is CB₁R dependent because it was blocked by the CB₁R antagonist rimonabant and is 5-HT mediated because it was abolished by pretreatment with the 5-HT-depleting agent parachlorophenylalanine. Then, using in vivo electrophysiology, we showed that low doses of WIN55,212-2 dose dependently enhanced dorsal raphe nucleus 5-HT neuronal activity through a CB₁R-dependent mechanism. Conversely, high doses of WIN55,212-2 were ineffective in the FST and decreased 5-HT neuronal activity through a CB₁R-independent mechanism. The CB₁R agonist-induced enhancement of 5-HT neuronal activity was abolished by total or medial prefrontocortical, but not by lateral prefrontocortical, transection. Furthermore, 5-HT neuronal activity was enhanced by the local microinjection of WIN55,212-2 into the ventromedial prefrontal cortex (mPFCv) but not by the local microinjection of WIN55,212-2 into the lateral prefrontal cortex. Similarly, the microinjection of WIN55,212-2 into the mPFCv produced a CB₁R-dependent antidepressant-like effect in the FST. These results demonstrate that CB₁R agonists possess antidepressant-like properties and modulate 5-HT neuronal activity via the mPFCv.

Key words: cannabinoid; CB₁ receptor; serotonin; dorsal raphe nucleus; medial prefrontal cortex; depression; forced swim test

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Received April 11, 2007; revised Sept. 11, 2007; accepted Sept. 11, 2007.

Correspondence should be addressed to Dr. Gabriella Gobbi, Neurobiological Psychiatry Unit, Department of Psychiatry, Research and Training Building, McGill University, 1033 Pine Avenue West, Montréal, Quebec, Canada H3A 1A1. Email: gabriella.gobbi{at}mcgill.ca

Related articles in J. Neurosci.:

Serotonin, the Prefrontal Cortex, and the Antidepressant-Like Effect of Cannabinoids

Fabrício A. Moreira
J. Neurosci. 2007 27: 13369-13370. [Full Text]  

This article has been cited by other articles:

				S. Haj-Dahmane and R.-Y. Shen Endocannabinoids Suppress Excitatory Synaptic Transmission to Dorsal Raphe Serotonin Neurons through the Activation of Presynaptic CB1 Receptors J. Pharmacol. Exp. Ther., October 1, 2009; 331(1): 186 - 196. [Abstract] [Full Text] [PDF]

				F. A. Moreira Serotonin, the Prefrontal Cortex, and the Antidepressant-Like Effect of Cannabinoids J. Neurosci., December 5, 2007; 27(49): 13369 - 13370. [Full Text] [PDF]

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