Cannabinoids elicit antidepressant-like Behavior and activate Serotonergic neurons through the medial prefrontal cortex

Department of Psychiatry, McGill University, Montréal, Quebec, Canada
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.75). 11/2007; 27(43):11700-11. DOI: 10.1523/JNEUROSCI.1636-07.2007
Source: PubMed

ABSTRACT 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.


Available from: Gabriella Gobbi, Jun 03, 2015
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    ABSTRACT: Background The use of cannabis, or marijuana, for medicinal purposes is deeply rooted though history, dating back to ancient times. It once held a prominent position in the history of medicine, recommended by many eminent physicians for numerous diseases, particularly headache and migraine. Through the decades, this plant has taken a fascinating journey from a legal and frequently prescribed status to illegal, driven by political and social factors rather than by science. However, with an abundance of growing support for its multitude of medicinal uses, the misguided stigma of cannabis is fading, and there has been a dramatic push for legalizing medicinal cannabis and research. Almost half of the United States has now legalized medicinal cannabis, several states have legalized recreational use, and others have legalized cannabidiol-only use, which is one of many therapeutic cannabinoids extracted from cannabis. Physicians need to be educated on the history, pharmacology, clinical indications, and proper clinical use of cannabis, as patients will inevitably inquire about it for many diseases, including chronic pain and headache disorders for which there is some intriguing supportive evidence.Objective To review the history of medicinal cannabis use, discuss the pharmacology and physiology of the endocannabinoid system and cannabis-derived cannabinoids, perform a comprehensive literature review of the clinical uses of medicinal cannabis and cannabinoids with a focus on migraine and other headache disorders, and outline general clinical practice guidelines.Conclusion The literature suggests that the medicinal use of cannabis may have a therapeutic role for a multitude of diseases, particularly chronic pain disorders including headache. Supporting literature suggests a role for medicinal cannabis and cannabinoids in several types of headache disorders including migraine and cluster headache, although it is primarily limited to case based, anecdotal, or laboratory-based scientific research. Cannabis contains an extensive number of pharmacological and biochemical compounds, of which only a minority are understood, so many potential therapeutic uses likely remain undiscovered. Cannabinoids appear to modulate and interact at many pathways inherent to migraine, triptan mechanisms ofaction, and opiate pathways, suggesting potential synergistic or similar benefits. Modulation of the endocannabinoid system through agonism or antagonism of its receptors, targeting its metabolic pathways, or combining cannabinoids with other analgesics for synergistic effects, may provide the foundation for many new classes of medications. Despite the limited evidence and research suggesting a role for cannabis and cannabinoids in some headache disorders, randomized clinical trials are lacking and necessary for confirmation and further evaluation.
    Headache The Journal of Head and Face Pain 05/2015; Epub ahead of print. DOI:10.1111/head.12570 · 3.19 Impact Factor
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    01/2011, Degree: BACHELOR OF MEDICAL AND HEALTH SCIENCES (HONOURS), Supervisor: Francesca Fernandez, Teresa Du bois
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    ABSTRACT: ÖZET: Tıbbi esrar psikiyatrik bozuklukların tedavisinde kullanılabilir mi? Esrar en yaygın ve en çok tüketilen yasadışı uyuşturucu maddedir. Esrarın bilinen uyuşturucu etkileri yanısıra bazı tıbbi hastalık belirtilerini düzeltmek için de kullanıldığı iddia edilmektedir. Son yıllarda esrarın kanser ve Edinilmiş Bağışıklık Yetersizliği Sendromu (AIDS) gibi bazı hastalıkla-ra bağlı aşırı kusma ve kilo kaybı durumları için tıbbi otori-telerden onay alması, esrarın bazı diğer hastalıklarda da kul-lanılabileceğini düşündürmektedir. Bu derlemede, esrarın bilimsel literatürde bildirilmiş olan bazı tıbbi kullanım alan-ları tartışılacak ve esrarın bazı psikiyatrik bozuklukların (ya da belirtilerinin) tedavisinde yardımcı olabilceğini bildiren iddialar bilimsel olarak gözden geçirilecektir. Bu sunumun esrar kullanımını yasallaştırmayı destekleme amacı yoktur. Anahtar sözcükler: Kannabis, kannabinoid sistem, tıbbi esrar, psikiyatrik bozukluklar Kli nik Psikofarmakoloji Bülteni 2012;22(1):98-109 ABS TRACT: Can medical marijuana be used in the treatment of psychiatric disorders? Cannabis is known to be the most commonly and most widely consumed illicit drug. Despite the known risks of cannabis use, there are anecdotal reports advocating that cannabis can be used in the treatment of or to correct the symptoms of some diseases. Since the approval of use of cannabis in some diseases such as AIDS, cancer, and extreme weight loss, it is suggested that cannabis may safely be used in the treatment of some other medical disorders. In this review, the medical use of cannabis in some medical conditions that were reported in the scientific literature will be reviewed and possible benefits of cannabis use in some psychiatric disorders (or symptoms) will be discussed. This presentation does not aim to support the legalization of cannabis use.
    Bulletin of Clinical Psychopharmacology 08/2012; 22(1):98-109. DOI:10.5455/bcp.20120223123828 · 0.37 Impact Factor