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mGlu(2) receptor-mediated modulation of conditioned avoidance behavior in rats
- Source :
- European journal of pharmacology. 727
- Publication Year :
- 2013
-
Abstract
- 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.
- Subjects :
- Agonist
Male
Reflex, Startle
Allosteric modulator
medicine.drug_class
medicine.medical_treatment
Allosteric regulation
Glutamic Acid
Pharmacology
Motor Activity
Receptors, Metabotropic Glutamate
chemistry.chemical_compound
Escape Reaction
Conditioning, Psychological
medicine
Avoidance Learning
Excitatory Amino Acid Agonists
Animals
Rats, Wistar
Antipsychotic
Trifluoromethyl
Behavior, Animal
Dose-Response Relationship, Drug
Antagonist
Brain
Receptor-mediated endocytosis
Dopamine D2 Receptor Antagonists
chemistry
Excitatory Amino Acid Antagonists
Antipsychotic Agents
Subjects
Details
- ISSN :
- 18790712
- Volume :
- 727
- Database :
- OpenAIRE
- Journal :
- European journal of pharmacology
- Accession number :
- edsair.doi.dedup.....da5312b022669a09b0fd50d2c0ef5843