TY - JOUR
T1 - The endogenous cannabinoid anandamide has effects on motivation and anxiety that are revealed by fatty acid amide hydrolase (FAAH) inhibition
AU - Scherma, Maria
AU - Medalie, Julie
AU - Fratta, Walter
AU - Vadivel, Subramanian K.
AU - Makriyannis, Alexandros
AU - Piomelli, Daniele
AU - Mikics, Eva
AU - Haller, Jozsef
AU - Yasar, Sevil
AU - Tanda, Gianluigi
AU - Goldberg, Steven R.
N1 - Funding Information:
This research was supported by the Intramural Research Program of the NIH, National Institute on Drug Abuse, Department of Health and Human Services, by NIH Grants DA09158, DA7215, DA12413, and DA12447, by the Institute of Experimental Medicine, Hungarian Academy of Sciences, and by the Italian Ministry of University and Scientific Research (MIUR) and the Centre of Excellence on ‘Neurobiology of Dependence’.
PY - 2008/1
Y1 - 2008/1
N2 - 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 μg/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 CB1-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.
AB - 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 μg/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 CB1-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.
KW - Anandamide
KW - Anxiety
KW - Conditioned place preferences
KW - Endogenous cannabinoids
KW - FAAH
KW - Locomotor activity
KW - Rats
KW - URB597
KW - WIN 55,212-2
UR - http://www.scopus.com/inward/record.url?scp=37449017773&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=37449017773&partnerID=8YFLogxK
U2 - 10.1016/j.neuropharm.2007.08.011
DO - 10.1016/j.neuropharm.2007.08.011
M3 - Article
C2 - 17904589
AN - SCOPUS:37449017773
SN - 0028-3908
VL - 54
SP - 129
EP - 140
JO - Neuropharmacology
JF - Neuropharmacology
IS - 1
ER -