ORIGINAL ARTICLES
Behavioural Pharmacology. 18(5-6):431-438, September 2007.
McLaughlin, Ryan J.; Hill, Matthew N.; Morrish, Anna C.; Gorzalka, Boris B.Abstract:
Systemic administration of direct cannabinoid CB1 receptor agonists and inhibitors of the hydrolytic enzyme fatty acid amide hydrolase have been shown to elicit antidepressant effects. Moreover, the endocannabinoid system in the hippocampus is sensitive to both chronic stress and antidepressant administration, suggesting a potential role of this system in emotional changes associated with these regimens. The aim of this study was to determine if cannabinoid CB1 receptors in the hippocampus modulate emotionality in rats as assessed via the forced swim test. Male Sprague-Dawley rats were bilaterally implanted with cannulae directed at the dentate gyrus of the dorsal hippocampus and subsequently received three infusions of either the cannabinoid CB1 receptor agonist HU-210 (1 and 2.5 [mu]g), the fatty acid amide hydrolase inhibitor URB597 (0.5 and 1 [mu]g), the cannabinoid CB1 receptor antagonist AM251 (1 and 2.5 [mu]g), or vehicle (dimethyl sulfoxide) and were assessed in the forced swim test. Infusion of both doses of HU-210 resulted in a dramatic reduction in immobility and increase in swimming behaviour, indicative of an antidepressant response, which was partially reversed by coadministration of AM251. No effect of URB597 administration or any effect following the administration of AM251 alone was, however, observed. These data indicate that activation of CB1 receptors in the dentate gyrus of the hippocampus results in an antidepressant-like response. Collectively, these data highlight the potential importance of changes in the hippocampal endocannabinoid system following stress or antidepressant treatment with respect to the manifestation and/or treatment of depression.
(C) 2007 Lippincott Williams & Wilkins, Inc.
Volume 103 Issue 1 Page 47-56, October 2007
To cite this article: Matthew N. Hill, Alasdair M. Barr, W.-S. Vanessa Ho, Erica J. Carrier, Boris B. Gorzalka, Cecilia J. Hillard (2007)
Electroconvulsive shock treatment differentially modulates cortical and subcortical endocannabinoid activity
Journal of Neurochemistry 103 (1), 47–56.
doi:10.1111/j.1471-4159.2007.04688.x
Abstract
Electroconvulsive shock treatment differentially modulates cortical and subcortical endocannabinoid activity
- Matthew N. Hill*,
- Alasdair M. Barr†,
- W.-S. Vanessa Ho‡,
- Erica J. Carrier‡,
- Boris B. Gorzalka* and
- Cecilia J. Hillard‡
- *Department of Psychology, University of British Columbia, Vancouver, British Columbia, Canada
†Department of Psychiatry, University of British Columbia, Vancouver, British Columbia, Canada
‡Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
Address correspondence and reprint requests to Cecilia J. Hillard, PhD, Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, USA 53226. E-mail: chillard@mcw.edu: 2-AG, 2-arachidonylglycerol; AEA, anandamide; ECS, electroconvulsive shock; FAAH, fatty acid amide hydrolase, PFC, prefrontal cortex.
Previous studies indicate that the endocannabinoid system is a potential target for the treatment of depression. To further examine this question we assessed the effects of electroconvulsive shock (ECS) treatment, both a single session and 10 daily sessions, on endocannabinoid content, CB1 receptor binding parameters and CB1 receptor-mediated [35S]GTPγS binding in the prefrontal cortex, hippocampus, hypothalamus and amygdala. A single ECS session resulted in a general reduction in the binding affinity of the CB1 receptor in all brain regions examined, as well as reductions in N-arachidonylethanolamine (anandamide) content in the prefrontal cortex and the hippocampus, reduced hydrolysis of anandamide by fatty acid amide hydrolase (FAAH) in the prefrontal cortex and an increase in the binding site density of the CB1 receptor in the amygdala. Following 10 ECS sessions, all these effects subsided except for the reductions in anandamide content in the prefrontal cortex, which increased in magnitude, as well as the reductions in FAAH activity in the prefrontal cortex. Additionally, repeated ECS treatment resulted in a significant reduction in the binding site density of the CB1 receptor in the prefrontal cortex, but did not alter CB1 receptor-mediated [35S]GTPγS binding. Repeated ECS treatment also significantly enhanced the sensitivity of CB1receptor-mediated [35S]GTPγS binding in the amygdala. Collectively, these data demonstrate that ECS treatment results in a down-regulation of cortical and an up-regulation of subcortical endocannabinoid activity, illustrating the possibility that the role of the endocannabinoid system in affective illness may be both complex and regionally specific.
doi:10.1016/j.biopsych.2006.12.001 
Copyright © 2007 Society of Biological Psychiatry Published by Elsevier Inc.
Original Article
Antidepressant-like Activity of the Fatty Acid Amide Hydrolase Inhibitor URB597 in a Rat Model of Chronic Mild Stress
Marco Bortolatoa, b, Regina A. Mangieria, b, Jin Fua, b, Janet H. Kima, b, Oliver Arguelloa, b, Andrea Durantic, Andrea Tontinic, Marco Mord, Giorgio Tarziac and Daniele Piomellia, b,  , 
aDepartment of Pharmacology, University of California, Irvine, California
bCenter of Drug Discovery, University of California, Irvine, California
cInstitute of Medicinal Chemistry, University of Urbino “Carlo Bo,” Urbino, Italy
dPharmaceutical Department, University of Parma, Parma, Italy.
Received 2 August 2006; revised 18 November 2006; accepted 2 December 2006. Available online 23 May 2007.
Background
The endocannabinoid anandamide may be involved in the regulation of emotional reactivity. In particular, it has been shown that pharmacological inhibition of the enzyme fatty acid amide hydrolase (FAAH), which catalyzes the intracellular hydrolysis of anandamide, elicits anxiolytic-like and antidepressant-like effects in rodents.
Methods
We investigated the impact of chronic treatment with the selective FAAH inhibitor, URB597 (also termed KDS-4103), on the outcomes of the chronic mild stress (CMS) in rats, a behavioral model with high isomorphism to human depression.
Results
Daily administration of URB597 (.3 mg·kg−1, intraperitoneal [IP]) for 5 weeks corrected the reduction in body weight gain and sucrose intake induced by CMS. The antidepressant imipramine (20 mg·kg−1, once daily, IP) produced a similar response, whereas lower doses of URB597 were either marginally effective (.1 mg·kg−1) or ineffective (.03 mg·kg−1). Treatment with URB597 (.3 mg·kg−1) resulted in a profound inhibition of brain FAAH activity in both CMS-exposed and control rats. Furthermore, the drug regimen increased anandamide levels in midbrain, striatum, and thalamus.
Conclusions
URB597 exerts antidepressant-like effects in a highly specific and predictive animal model of depression. These effects may depend on the ability of URB597 to enhance anandamide signaling in select regions of the brain.
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