Megens Anton A H P, Hendrickx Herman M R, Hens Koen A, Talloen Willem J-P E, Lavreysen Hilde
Janssen Research and Development, Turnhoutseweg 30, 2340 Beerse, Belgium.
Eur J Pharmacol. 2014 Mar 15;727:130-9. doi: 10.1016/j.ejphar.2014.01.044. Epub 2014 Jan 30.
Inhibition of conditioned avoidance behavior in rats is generally considered predictive for antipsychotic activity in man. The present study investigated the mGlu2-mediated modulation of conditioned avoidance and compared mGlu2 agonists with available antipsychotics for their relative effects on conditioned avoidance behavior and locomotion. The mGlu2/3 orthosteric agonist 4-amino-2-thiabicyclo[3.1.0]hexane-4,6-dicarboxylic acid 2,2-dioxide (LY-404039) and mGlu2 positive allosteric modulator (PAM) 3-(cyclopropylmethyl)-7-(4-phenylpiperidin-1-yl)-8-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridine (JNJ-42153605) inhibited avoidance and blocked escape behavior. The mGlu2/3 negative allosteric modulators (NAMs) 7-(dimethylamino)-4-(3-pyridin-3-ylphenyl)-8-(trifluoromethyl)-1,3-dihydro-2 H-1,5-benzodiazepin-2-one (JNJ-42112265) and 4-[3-(2,6-dimethylpyridin-4-yl)phenyl]-7-methyl-8-(trifluoromethyl)-1,3-dihydro-2H-1,5-benzodiazepin-2-one (RO-4491533) reversed the LY-404039-induced impairment of avoidance and escape. JNJ-42112265 also reversed the impairment of avoidance and escape induced by the mGlu2-specific PAM JNJ-42153605, suggesting that the effects on conditioned avoidance are specifically mGlu2-mediated. The mGlu2/3 antagonist (2-(2-carboxycyclopropyl)-3-(9H-xanthen-9-yl)-d-alanine (LY-341495; s.c.) reversed the LY-404039-induced escape impairment but failed to restore avoidance, suggesting interfering side effects. Like the tested antipsychotics, mGlu2/3 orthosteric and allosteric agonists inhibited avoidance behavior and locomotion at similar doses. Hence no clear-cut differences between mGlu2 modulators and currently available antipsychotics in the way they interfere with avoidance behavior in relation to inhibition of locomotion could be established.
大鼠条件性回避行为的抑制通常被认为可预测人类的抗精神病活性。本研究调查了代谢型谷氨酸受体2（mGlu2）介导的对条件性回避的调节作用，并比较了mGlu2激动剂与现有抗精神病药物对条件性回避行为和运动的相对影响。mGlu2/3的正构激动剂4-氨基-2-硫杂双环[3.1.0]己烷-4,6-二甲酸2,2-二氧化物（LY-404039）和mGlu2的正变构调节剂（PAM）3-(环丙基甲基)-7-(4-苯基哌啶-1-基)-8-(三氟甲基)[1,2,4]三唑并[4,3-a]吡啶（JNJ-42153605）抑制回避并阻断逃避行为。mGlu2/3的负变构调节剂（NAMs）7-(二甲基氨基)-4-(3-吡啶-3-基苯基)-8-(三氟甲基)-1,3-二氢-2H-1,5-苯并二氮杂卓-2-酮（JNJ-42112265）和4-[3-(2,6-二甲基吡啶-4-基)苯基]-7-甲基-8-(三氟甲基)-1,3-二氢-2H-1,5-苯并二氮杂卓-2-酮（RO-4491533）逆转了LY-404039诱导的回避和逃避障碍。JNJ-42112265也逆转了mGlu2特异性PAM JNJ-42153605诱导的回避和逃避障碍，表明对条件性回避的影响是由mGlu2特异性介导的。mGlu2/3拮抗剂（2-(2-羧基环丙基)-3-(9H-呫吨-9-基)-D-丙氨酸（LY-341495；皮下注射）逆转了LY-404039诱导的逃避障碍，但未能恢复回避，提示存在干扰性副作用。与测试的抗精神病药物一样，mGlu2/3的正构和变构激动剂在相似剂量下抑制回避行为和运动。因此，在干扰回避行为与抑制运动方面，无法确定mGlu2调节剂与现有抗精神病药物之间存在明显差异。
