title: Potential anxiogenic effects of cannabinoid CB1 receptor antagonists/inverse agonists in rats: comparisons between AM4113, AM251, and the benzodiazepine inverse agonist FG-7142.
abstract: Cannabinoid CB1 inverse agonists suppress food-motivated behaviors, but may also induce psychiatric effects such as depression and anxiety. To evaluate behaviors potentially related to anxiety, the present experiments assessed the CB1 inverse agonist AM251 (2.0-8.0mg/kg), the CB1 antagonist AM4113 (3.0-12.0mg/kg), and the benzodiazepine inverse agonist FG-7142 (10.0-20.0mg/kg), using the open field test and the elevated plus maze. Although all three drugs affected open field behavior, these effects were largely due to actions on locomotion. In the elevated plus maze, FG-7142 and AM251 both produced anxiogenic effects. FG-7142 and AM251 also significantly increased c-Fos activity in the amygdala and nucleus accumbens shell. In contrast, AM4113 failed to affect performance in the plus maze, and did not induce c-Fos immunoreactivity. The weak effects of AM4113 are consistent with biochemical data showing that AM4113 induces little or no intrinsic cellular activity. This research may lead to the development of novel appetite suppressants with reduced anxiogenic effects.
authors.affiliation: Dept. of Psychology, University of Connecticut, Storrs, CT 06269-1020, USA.
authors.forename: K S
authors.initials: KS
authors.lastname: Sink
authors.forename: K N
authors.initials: KN
authors.lastname: Segovia
authors.forename: J
authors.initials: J
authors.lastname: Sink
authors.forename: P A
authors.initials: PA
authors.lastname: Randall
authors.forename: L E
authors.initials: LE
authors.lastname: Collins
authors.forename: M
authors.initials: M
authors.lastname: Correa
authors.forename: E J
authors.initials: EJ
authors.lastname: Markus
authors.forename: V K
authors.initials: VK
authors.lastname: Vemuri
authors.forename: A
authors.initials: A
authors.lastname: Makriyannis
authors.forename: J D
authors.initials: JD
authors.lastname: Salamone
mesh_terms: D000818:Animals; D001007:Anxiety / Q000139:chemically induced*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002243:Carbolines / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D054314:Drug Inverse Agonism; D005106:Exploratory Behavior / Q000187:drug effects; D018756:GABA Antagonists / Q000494:pharmacology; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D010880:Piperidines / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D011720:Pyrazoles / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors*
chemical_list: C529765:AM4113; D002243:Carbolines; D018756:GABA Antagonists; D010880:Piperidines; D016760:Proto-Oncogene Proteins c-fos; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; C103505:AM 251; C035874:FG 7142