Intrinsic effects of AM4113, a putative neutral CB1 receptor selective antagonist, on open-field behaviors in rats.
We examined open-field effects in rats of the cannabinoid 1 receptor (CB1R) agonist WIN55,212-2 (WIN; 3 mg/kg) and its interaction with the CB1R putative neutral antagonist AM4113 (0.3 to 3 mg/kg). Separate studies examined AM4113 alone (0.3 to 5.6 mg/kg). Unlike the CB1R antagonist rimonabant, in vitro (e.g., [Sink K.S., McLaughlin P.J., Wood J.A., Brown C., Fan P., Vemuri V.K., Pang Y., Olzewska T., Thakur G.A., Makriyannis A., Parker L.A., Salamone J.D. The novel cannabinoid CB(1) receptor neutral antagonist AM4113 suppresses food intake and food-reinforced behavior but does not induce signs of nausea in rats. Neuropsychopharmacology 2008a; 33: 946-955.; Sink K.S., Vemuri V.K., Olszewska T., Makriyannis A., Salamone J.D. Cannabinoid CB1 antagonists and dopamine antagonists produce different effects on a task involving response allocation and effort-related choice in food-seeking behavior. Psychopharmacology (Berl) 2008b; 196: 565-574.]) AM4113 produced no change in cAMP accumulation (neutral antagonism vis-a-vis inverse agonism). Recorded behaviors were: ambulation, rearing, circling, latency, scratching, grooming, defecation, urination and vocalization/squeaking. WIN reduced ambulation and rearing; AM4113 completely (ambulation) or partially (rearing) antagonized these behaviors. WIN alone resulted in circling and an increased latency to leave the start area; effects blocked by AM4113. AM4113 increased scratching and grooming, effects attenuated but not abolished by WIN. AM4113 alone tended to reduce ambulation and rearing and had no effect on latency or circling. AM4113 alone increased scratching and grooming. Effects on defecation, urination and vocalization were non-significant. The open-field effects of AM4113 are similar to those reported for rimonabant in rats. Yet, unlike the inverse agonists rimonabant and AM251, the putative neutral CB1R antagonist AM4113 did not produce signs of nausea in ferrets and rats ([Chambers A.P., Vemuri V.K., Peng Y., Wood J.T., Olszewska T., Pittman Q.J., Makriyannis A., Sharkey K.A. A neutral CB1 receptor antagonist reduces weight gain in rat. Am J Physiol Regul Integr Comp Physiol 2007; 293: R2185-2193.; Sink K.S., McLaughlin P.J., Wood J.A., Brown C., Fan P., Vemuri V.K., Pang Y., Olzewska T., Thakur G.A., Makriyannis A., Parker L.A., Salamone J.D. The novel cannabinoid CB(1) receptor neutral antagonist AM4113 suppresses food intake and food-reinforced behavior but does not induce signs of nausea in rats. Neuropsychopharmacology 2008a; 33: 946-955.; Sink K.S., Vemuri V.K., Olszewska T., Makriyannis A., Salamone J.D. Cannabinoid CB1 antagonists and dopamine antagonists produce different effects on a task involving response allocation and effort-related choice in food-seeking behavior. Psychopharmacology (Berl) 2008b; 196: 565-574.]).
Järbe
T U C
TU
Northeastern University, Center for Drug Discovery, 116 Mugar, 360 Huntington Ave., Boston, MA 02115, USA. t.jarbe@neu.edu
LeMay
B J
BJ
Olszewska
T
T
Vemuri
V K
VK
Wood
J T
JT
Makriyannis
A
A
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D048588:Benzoxazines / Q000494:pharmacology; D003672:Defecation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006120:Grooming / Q000187:drug effects; D007274:Injections, Intraperitoneal; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D009043:Motor Activity / Q000187:drug effects*; D009281:Naphthalenes / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors*; D000077285:Rimonabant; D014554:Urination / Q000187:drug effects; D014828:Vocalization, Animal / Q000187:drug effects
C529765:AM4113; D048588:Benzoxazines; D009025:Morpholines; D009281:Naphthalenes; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D000077285:Rimonabant