mGlu₂ receptor-mediated modulation of conditioned avoidance behavior in rats

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• 作者：Anton A.H.P. Megens ; ^{amegens@its.jnj.com" class="auth_mail} ; Herman M.R. Hendrickx ^{hhendric@its.jnj.com" class="auth_mail} ; Koen A. Hens ^{khens@its.jnj.com" class="auth_mail} ; Willem J.-P.E. Talloen ^{wtalloen@its.jnj.com" class="auth_mail} ; Hilde Lavreysen ^{hlavrey1@its.jnj.com" class="auth_mail}
• 关键词：BINA ; 3壮-{[(2-cyclopentyl-6 ; 7-dimethyl-1-oxo-2 ; 3-dihydro-1H-inden-5-yl)oxy]methyl}biphenyl-4-carboxylic acid ; JNJ-42112265 ; 7-(dimethylamino)- 4-(3-pyridin-3-ylphenyl)-8-(trifluoromethyl)-1 ; 3-dihydro-2H-1 ; 5-benzodiazepin-2-one ; JNJ-42153605 ; 3-(cyclopropylmethyl)-7-(4-phenylpiperidin-1-yl)-8-(trifluoromethyl) [1 ; 2 ; 4]triazolo[4 ; 3-a]pyridine ; LY-341495 ; 2-(2-carboxycyclopropyl)-3-(9H-xanthen-9-yl)-d-alanine ; LY-354740 ; 2-aminobicyclo[3.1.0]hexane-2 ; 6-dicarboxylic acid ; LY-404039 ; 4-amino-2-thiabi
• 刊名：European Journal of Pharmacology
• 出版年：15 March, 2014
• 年：2014
• 卷：727
• 期：Complete
• 页码：130-139
• 全文大小：665 K

文摘

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 mGlu_2/3 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 mGlu_2/3 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 mGlu_2/3 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, mGlu_2/3 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.