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A role for cannabinoid CB1 receptors in mood and anxiety disorders

Witkin, J. M.a; Tzavara, E. T.b; Nomikos, G. G.a

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Mood and anxiety disorders, the most prevalent of the psychiatric disorders, cause immeasurable suffering worldwide. Despite impressive advances in pharmacological therapies, improvements in efficacy and side-effect profiles are needed. The present literature review examines the role that the endocannabinoid system may play in these disorders and the potential value of targeting this system in the search for novel and improved medications. Cannabis and its major psychoactive component (−)-trans9-tetrahydrocannabinol, have profound effects on mood and can modulate anxiety and mood states. Cannabinoid receptors and other protein targets in the central nervous system (CNS) that modulate endocannabinoid function have been described. The discovery of selective modulators of some of these sites that increase or decrease endocannabinoid neurotransmission, primarily through the most prominent of the cannabinoid receptors in the CNS, the CB1 receptors, combined with transgenic mouse technology, has enabled detailed investigations into the role of these CNS sites in the regulation of mood and anxiety states. Although data point to the involvement of the endocannabinoid system in anxiety states, the pharmacological evidence seems contradictory: both anxiolytic- and anxiogenic-like effects have been reported with both endocannabinoid neurotransmission enhancers and blockers. Due to advances in the development of selective compounds directed at the CB1 receptors, significant progress has been made on this target. Recent biochemical and behavioural findings have demonstrated that blockade of CB1 receptors engenders antidepressant-like neurochemical changes (increases in extracellular levels of monoamines in cortical but not subcortical brain regions) and behavioural effects consistent with antidepressant/antistress activity in rodents.

aPsychiatric Drug Discovery, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA

bINSERM U-513, Neurobiology and Psychiatry, Faculty of Medicine, Creteil, France

Correspondence and requests for reprints to Jeff Witkin, Psychiatric Drug Discovery, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285-0510, USA

E-mail: jwitkin@lilly.com

Received 13 May 2005 Accepted as revised 30 June 2005

Abbreviations: AM404: 5,8,11,14-eicosatetraenamide, N-(4-hydroxyphenyl)- (5Z,8Z,11Z,14Z)-(9CI)

AM251: 1H-pyrazole-3-carboxamide, 1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-1-piperidinyl-(9CI)

Anandamide; N-arachidonoylethanolamide: 5,8,11,14-eicosatetraenamide, N-(2-hydroxyethyl)-(5Z,8Z,11Z,14Z)-(9CI)

SR141716A; rimonabant: 1H-pyrazole-3-carboxamide, 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-1-piperidinyl-(9CI)

URB597: carbamic acid, cyclohexyl-3′-(aminocarbonyl)[1,1′-biphenyl]-3-yl ester

(9CI)VDM11: 5,8,11,14-eicosatetraenamide, N-(4-hydroxy-2-methylphenyl)- (5Z,8Z,11Z,14Z)-(9CI)

2-AG: 2-arachidonylglycerol, FAAH: fatty acid amino hydrolase

© 2005 Lippincott Williams & Wilkins, Inc.