Serotonin 2C Receptor Agonists Inhibit Key Brain Areas Of Conditioned Avoidance Response

Background:Conditional avoidance response is based on the classic conditioned reflection theory of Baplov.It is an operational conditioned reflection developed by Skinner.It can be tested by two-way signaled active avoidance apparatus.In the conditional avoidance response,avoidance is a ne gatively enhanced operational behavior.If the animals do not shuttle to the other side,it will be punished（shock）.In this paradigm,avoidance is parallel with active avoidance,where harm is prevented by taking action after warning signals（signaled active avoidance）.Avoidance is a natural and adaptive response to danger,and without this ability to avoid danger,animals cannot survive.Nevertheless,maladjustment of avoidance is the core of various mental disorders.For example,in preclinical studies,conditional avoidance responses are often used as a measure of screening antipsychotic drugs;avoidance behaviors are associated with generalized anxiety disorder（GAD）,and anxiolytic drugs（e.g.,diazepam）causes the animal to avoidance deficiencies.Previous studies have shown that multiple brain regions are related to conditional avoidance response,such as ventral tegmental area and nucleus accumbens.Serotonin is a kind of anxiety neurotransmitter related to defense response.It seems to play different roles in avoidance and escape behavior.The administration of serotonin can enhance avoidance and inhibit escape,that is,it may leads to different types of defensive behaviors depending on the proximity of the threat（imminent or ongoing）.5-HT_2C receptors（5-hydroxytryptamine 2C receptor）are highly expressed in multiple brain regions including nucleus accumbens,medial prefrontal cortex,Amygdala,ventral tegmental area and other brain regions.At present,it has been experimentally proven that the 5-HT_2C receptor agonist MK212alone can damage the conditional avoidance behavior.In addition,MK212 can also play a important role in conditional avoidance without endogenous dopamine.However,there is no experimental evidence that the 5-HT_2C receptor agonist MK212 exerts a mechanism for regulating the conditional avoidance response,and there is no evidence to indicate which brain region or regions of 5-HT_2C receptors play a key role in regulating conditional avoidance.Research hypothesis:We hypothesized that there are key brain regions when 5-HT_2CC receptors agonist MK212 regulates condition avoidance,and when it is independent of endogenous dopamine,MK212 also plays a role in regulating condition avoidance through this brain region.Research aim:To clarify the regulation mechanism of MK212 to conditional avoidance behavior and explore the key brain regions when 5-HT_2C receptor regulates conditional avoidance behavior.Research method:In experiment one to experiment five,By using conditional avoidance behavior paradigm,we choose the successfully trained animals and injected a small amount of5-HT_2C receptor agonist MK212 into the brain areas of rats in each experimental group（nucleus accumbens,medial prefrontal cortex,amygdala,ventral tegmental area）through stereotactic brain surgery.After inj ection,the rats were placed in a two-way shuttle box to test the conditional avoidance response.According to the purpose of the experiment,we observe the change in conditional avoidance and selectively recorded and analyzed the data.In experiment six,through conditional avoidance behavior paradigm and stereotactic brain surgery,and combined with the results of research four,rats were treated with reserpine+quinpirole.Then the rats in the experimental group were micro injected with MK212 into ventral tegmental area.Changes in rat avoidance behavior were observed.If the number of avoidances in the experimental group decreased significantly,it indicates that 5-HT_2C receptors in the ventral tegmental area play an important role in the regulation of conditional avoidance without endogenous dopamine.If there is no change,it indicates that 5-HT_2C receptor in ventral tegmental area plays a role in regulating conditional avoidance behavior by inhibiting the release of dopamine.Results:The results of experiment one showed that he injection of MK212 into nucleus accumbens did not reduce avoidance（p=0.464,n=8）.The results of experiment two showed that MK212 was injected into medial prefrontal cortex do not reduce avoidance（p=0.242,n=8）.The results of experiment three showed that MK212 was injected into amygdala do not reduce avoidance（p=0.237,n=8）.The results of experiment five showed that MK212 was injected into vCA1（p=0.211,n=6）did not reduce the number of avoidance,but MK212was injected into vCA1 can significantly shortened average avoid latency（p=0.023,n=6）.The results of experiment five showed that MK212 was injected into ventral tegmental area can significantly reduce the number of avoidance in rats（p=0.000,n=8）.The results of experiment six showed that in the new conditional avoidance behavior paradigm,MK212 was injected into ventral tegmental area can significantly reduce avoidance compared with the control group（p=0.000,n=8）.The results indicate that the key brain region where MK212regulates avoidance behavior without endogenous dopamine is ventral tegmental area.Conclusion:The key brain region for 5-HT_2C receptor agonist MK212 to inhibite conditional avoidance is ventral tegmental area.And when animals exhaust endogenous dopamine,ventral tegmental area is also the key brain region for MK212 to regulate conditional avoidance.The activation of 5-HT_2C receptor in vCA1 may reduce response time through increasing attention in conditione d avoidance.