The endogenous cannabinoid anandamide has effects on motivation and anxiety that are revealed by fatty acid amide hydrolase (FAAH) inhibition

NEUROPHARMACOLOGY

卷:54

Article

Scherma, Maria^1,2  Medalie, Julie¹  Fratta, Walter²  Vadivel, Subramanian K.³  Makriyannis, Alexandros³  Piomelli, Daniele⁴  Mikics, Eva⁵  Haller, Jozsef⁵  Yasar, Sevil⁶  Tanda, Gianluigi⁷  Goldberg, Steven R.¹ 

[1] NIDA, Preclin Pharmacol Sect, Behav Neurosci Res Branch, Intramural Res Program,NIH,DHHS, Baltimore, MD USA

[2] Univ Cagliari, Bb Brodie Dept Neurosci, I-09124 Cagliari, Italy

[3] Northeastern Univ, Ctr Drug Discovery, Boston, MA 02115 USA

[4] Univ Calif Irvine, Dept Pharmacol, Irvine, CA 92717 USA

[5] Hungarian Acad Sci, Inst Expt Med, Budapest, Hungary

[6] Johns Hopkins Univ, Sch Med, Dept Med, Div Geriatr Med & Gerontol, Baltimore, MD 21224 USA

[7] Natl Inst Drug Abuse, Psychobiol Sect, Med Discovery Res Branch, Intramural Res Program,NIH,Dept Hlth & Human Serv, Baltimore, MD 21224 USA

关键词: endogenous cannabinoids;    anandamide;    FAAH;    URB597;    WIN 55,212-2;    conditioned place preferences;    anxiety;    locomotor activity;    rats;   

DOI  :  10.1016/j.neuropharm.2007.08.011

来源: Elsevier

【 摘 要 】

Converging evidence suggests that the endocannabinoid. system is an important constituent of neuronal substrates involved in brain reward processes and emotional responses to stress. Here, we evaluated motivational effects of intravenously administered anandamide, an endogenous ligand for cannabinoid CB1-receptors, in Sprague-Dawley rats, using a place-conditioning procedure in which drugs abused by humans generally produce conditioned place preferences (reward). Anandamide (0.03-3 mg/kg intravenous) produced neither conditioned place preferences nor aversions. However, when rats were pre-treated with the fatty acid amide hydrolase (FAAH) inhibitor URB597 (cyclohexyl carbamic acid 3'-carbamoyl-3-yl ester; 0.3 mg/kg intraperitoneal), which blocks anandamide's metabolic degradation, anandamide produced dose-related conditioned place aversions. In contrast, URB597 alone showed no motivational effects. Like URB597 plus anandamide, the synthetic CB1-receptor ligand WIN 55,212-2 (50-300 mu g/kg, intravenous) produced dose-related conditioned place aversions. When anxiety-related effects of anandamide and URB597 were evaluated in a light/dark box, both a low anandamide dose (0.3 mg/kg) and URB597 (0.1 and 0.3 mg/kg) produced anxiolytic effects when given alone, but produced anxiogenic effects when combined. A higher dose of anandamide (3 mg/kg) produced anxiogenic effects and depressed locomotor activity when given alone and these effects were potentiated after URB597 treatment. Finally, anxiogenic effects of anandamide plus URB597 and development of place aversions with URB597 plus anandamide were prevented by the CBI-receptor antagonist AM251 (3 mg/kg intraperitoneal). Thus, additive interactions between the effects of anandamide on brain reward processes and on anxiety may account for its aversive effects when intravenously administered during FAAH inhibition with URB597. (c) 2007 Elsevier Ltd. All rights reserved.

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