Effects Of Metabolic Glutamate Receptor 2/3 Agonists On Conditioned Avoidance Response And Maternal Behavior In Rats

Background:Metabolic glutamate 2/3（mGlu2/3）receptor agonists are a class of potential drugs for the treatment of psychiatric disorders.As a new and highly selective mGlu2/3 receptor agonist,LY404039 has shown significant antipsychotic effects in pre-clinical animal studies,although it has not been used in clinical practice.The conditioned avoidance response paradigm is an important method to evaluate the effect of antipsychotics.Antipsychotics can inhibit the conditioned avoidance response.Studies have shown that the sensitivity of most antipsychotics will change after long-term medication,which is manifested in the increase（sensitization）or decrease（tolerance）of the inhibition of the conditioned avoidance response.In view of the long-term purpose of clinical medication,it is very necessary to study the antipsychotic effects of LY404039 long-term medication in pre-clinical animal models.Compared with traditional antipsychotics,LY404039 has fewer side effects and high bioavailability.It is of great significance to find out whether LY404039 combined with traditional antipsychotics can enhance the antipsychotic effect（without increasing side effects）.Maternal behavior is an instinctive social behavior,which is more complicated than conditioned avoidance response,without artificial deliberate training,and no specific conditioned and unconditional stimuli.Conditional avoidance response belongs to conditional learning.It is the ability acquired after overtraining and the process of learning and memory.Studying the behavior of LY404039 in two different models can also understand the complex effects of LY404039 on different behaviors in more detail,providing enlightenment and reference for future clinical research and use.Objective:The study will use the conditional avoidance response paradigm to investigate the effects of long-term use of LY404039 on the sensitivity to antipsychotic effects and its antipsychotic effects in combination with olanzapine,and use the maternal behavior related paradigm to investigate the effects of LY404039 on maternal behavior and its psychological mechanism.Method:Study 1 investigates the effect of LY404039 on the conditioned avoidance response of rats and the antipsychotic effect of combination with olanzapine.In the experiment,the conditional avoidance response model was selected for research.This model is divided into three stages:training,drug-test and challenge test,in order to achieve the purpose of studying the change of drug sensitivity.After 10 days of conditioned avoidance training,in experiment 1,rats were treated with LY404039 at different doses for 5 consecutive days and tested for conditioned avoidance response.After 2 days of retraining,rats were tested for olanzapine and LY404039,respectively.In Experiment 2,the rats underwent 5 consecutive days of olanzapine and LY404039treatment and conditional avoidance response test,and 2 days of retraining were followed by drug stimulation test of olanzapine and LY404039,respectively.In Experiment 3,the rats underwent 5 consecutive days of olanzapine pretreatment and conditioned avoidance response test,2 days of retraining were followed by 5consecutive days of LY404039 treatment and conditioned avoidance response test,and2 days of retraining were followed by drug stimulation test of olanzapine.Study 2:The influence of LY404039 on maternal behavior and its psychological mechanism.Experiment 1 selected the maternal behavior paradigm in the rat home-cage after 30minutes of administration on the four days of 3,5,7,and 9 postpartum,and experiment2 selected the maternal behavior paradigm in the home-cage to conduct a systematic study of maternal behavior,further verify the results of experiment 1,and use the elevated plus maze（EPM）pup retrieval test,Pup preference test,Marble burying test,Open field test,Sucrose preference test and Forced swimming test reflect the effects of LY404039 on different mental functions of rats.Results:Study 1 showed that:（1）LY404039 can dose-dependent inhibition of conditional avoidance response,but with the time of administration,this inhibition effect weakened,showing the antipsychotic effect of LY404039 tolerance.（2）LY404039 combined with olanzapine can enhance the inhibition of conditioned avoidance response.（3）Five consecutive days of olanzapine administration did not affect the subsequent inhibitory effect of LY404039 on conditioned avoidance response,and there was no interaction between the two.Study 2 showed that:（1）LY404039 can disrupt the maternal behavior of rats.Include:the number of pups retrieved,nest building time,and also prolong the latency of pup retrieval.（2）In the EPM pup retrieval test,LY404039 treatment significantly reduced the rats at arm opening time and the number of pups retrieved,but did not affect the total distance of movement.（3）In the pup preference test,LY404039 did not affect the duration of pup exploration,nor did it affect the pup preference rate.（4）In the marble buried test,LY404039 treatment significantly reduced the number of marble buried in rats.（5）In the open field test,LY404039 treatment significantly reduced the total distance of movement,but did not affect the residence time in the central region of rats.（6）In the sucrose preference test,LY404039 treatment had no effect on the sucrose preference rate of rats.（7）In the forced swimming test,LY404039 treatment significantly increased the duration of active swimming in rats.Conclusion:（1）The mGlu2/3 receptor agonist LY404039 inhibited the conditioned avoidance response（antipsychotic effect）in rats,and long-term administration resulted in tolerance to this inhibitory effect.（2）The combination of LY404039 and olanzapine can enhance the antipsychotic effect,while the previous medication experience of LY404039 does not affect the subsequent antipsychotic effect of olanzapine,and the previous medication experience of olanzapine does not affect the subsequent antipsychotic effect of LY404039.（3）LY404039 can disrupt maternal behavior in rats,which may be achieved by inhibiting maternal motivation in rats.This study investigated the sensitivity changes of LY404039 in antipsychotic effects,which not only provided data and theoretical support for the sensitization or tolerance of mGlu2/3receptor agonist,but also provided evidence and enlightenment for the need for dynamic changes in clinical dosage.The antipsychotic effect of olanzapine combined with LY494039 was discussed,which provided new evidence for the study of the interaction between mGlu2/3 receptor and 5-HT/D₂ receptor in the treatment of schizophrenia,and also provided important inspiration for the consideration of clinical medication history and combination medication.Studying the effect of LY404039 on postpartum maternal behavior can also better evaluate the effect of antipsychotics on parent-child care behavior and related psychological functions of mothers with schizophrenia.To provide more abundant evidence for the treatment and possible side effects of perinatal medication,and to provide guiding reference for the medication treatment of postpartum mothers.