Järbe T U C, LeMay B J, Olszewska T, Vemuri V K, Wood J T, Makriyannis A
Northeastern University, Center for Drug Discovery, 116 Mugar, 360 Huntington Ave., Boston, MA 02115, USA.
Pharmacol Biochem Behav. 2008 Nov;91(1):84-90. doi: 10.1016/j.pbb.2008.06.014. Epub 2008 Jun 29.
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.]).
我们研究了大麻素1受体（CB1R）激动剂WIN55,212-2（WIN；3毫克/千克）对大鼠旷场行为的影响，以及它与CB1R假定的中性拮抗剂AM4113（0.3至3毫克/千克）的相互作用。单独的研究检测了AM4113（0.3至5.6毫克/千克）的作用。与CB1R拮抗剂利莫那班不同，在体外（例如，[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. 新型大麻素CB(1)受体中性拮抗剂AM4113抑制食物摄入和食物强化行为，但不会在大鼠中诱发恶心症状。神经精神药理学2008a；33：946-955。；Sink K.S., Vemuri V.K., Olszewska T., Makriyannis A., Salamone J.D. 大麻素CB1拮抗剂和多巴胺拮抗剂对涉及觅食行为中反应分配和努力相关选择的任务产生不同影响。精神药理学（柏林）2008b；196：565-574。]），AM4113不会使环磷酸腺苷（cAMP）积累发生变化（相对于反向激动作用而言为中性拮抗作用）。记录的行为包括：行走、站立、转圈、潜伏期、抓挠、梳理、排便、排尿以及发声/尖叫。WIN减少了行走和站立；AM4113完全（行走方面）或部分（站立方面）拮抗了这些行为。单独使用WIN会导致转圈以及离开起始区域的潜伏期增加；这些效应被AM4113阻断。AM4113增加了抓挠和梳理行为，WIN可减弱但不能消除这些效应。单独使用AM4113倾向于减少行走和站立，并且对潜伏期或转圈没有影响。单独使用AM4113会增加抓挠和梳理行为。对排便、排尿和发声的影响不显著。AM4113在旷场中的效应与在大鼠中报道的利莫那班的效应相似。然而，与反向激动剂利莫那班和AM251不同，假定的中性CB1R拮抗剂AM4113在雪貂和大鼠中不会产生恶心症状（[Chambers A.P., Vemuri V.K., Peng Y., Wood J.T., Olszewska T., Pittman Q.J., Makriyannis A., Sharkey K.A. 一种中性CB1受体拮抗剂可减轻大鼠体重。美国生理学杂志调节、整合与比较生理学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. 新型大麻素CB(1)受体中性拮抗剂AM4113抑制食物摄入和食物强化行为，但不会在大鼠中诱发恶心症状。神经精神药理学2008a；33：946-955。；Sink K.S., Vemuri V.K., Olszewska T., Makriyannis A., Salamone J.D. 大麻素CB1拮抗剂和多巴胺拮抗剂对涉及觅食行为中反应分配和努力相关选择的任务产生不同影响。精神药理学（柏林）2008b；196：565-574。]）。
