Key Brain Regions In The Regulation Of Prepulse Inhibition By Serotonin 2A Receptors

Background:5-hydroxytryptamine 2A receptor,5-HT_2A receptor is an important serotonin receptor widely expressed in the central nervous system.The abnormality of its structure and function is related to many mental diseases,plays an important role in a series of mental disorders,and is the therapeutic target of atypical antipsychotic drugs.Sensory gating refers to filtering irrelevant sensory information from significant sensory information and then performing attention-related cognitive processes in an environment full of stimuli,thus responding to significant stimuli.Pre-pulse suppression（Prepulse inhibition,PPI）is a classical paradigm for measuring sensory gating.Pre-pulse suppression means that 30-500 ms presents a weak stimulus（prepulse）before the appearance of a strong stimulus（pulse）,thus inhibiting the shock response to a stronger stimulus.The damage of pre-pulse inhibition is shown in a series of mental disorders such as schizophrenia,Alzheimer’s disease,obsessive-compulsive disorder and so on.Some studies have indirectly shown that 5-HT_2A receptor agonists can simulate the loss of pre-pulse inhibition,and 5-HT_2A receptor antagonists can restore pre-pulse inhibition in normal animals,but there is no direct evidence that 5-HT_2A receptor agonists can destroy pre-pulse inhibition in normal animals.There are some contradictions about the effect of the interaction between5-HT_2A receptor and dopamine D₂receptor on PPI.Therefore,the main purpose of this study is to investigate whether selective 5-HT_2A receptor agonist TCB-2 destroys PPI in rats and 5-HT_2A receptor agonist TCB-2 destroys key brain regions of PPI in rats,and whether injection of 5-HT_2A receptor antagonist M100907 into key brain regions can restore PPI loss induced by dopamine D₂ receptor.Hypothesis:Injection of 5-HT_2A receptor agonist TCB-2 into the right ventricle of rats could destroy the PPI of normal animals without affecting the shock response of animals,and there were key brain regions in which 5-HT_2A receptor affected PPI in rats.Microinjection of 5-HT_2A receptor agonist TCB-2 into this key brain region could destroy PPI of normal rats,and injection of 5-HT_2A receptor antagonist M100907 could restore PPI damage caused by intraperitoneal administration of dopamine D₂ receptor agonist quinpirole.Methods:in experiment 1,stereotaxic surgery was performed on animals whose baseline was less than two standard deviations using shock reflex anterior pulse suppression test.Microinjection of cannula into the right lateral ventricle of rats was performed,followed by microinjection of 5-HT_2Areceptor agonist TCB-2（10ug/1ul/side）and 5-HT_2A receptor antagonist M100907（5ug/1ul/side）into the right ventricle.The inhibition rate of rats when the pre-pulse stimulation was 73d B,76d B and82d B,the average of the inhibition rate of the three kinds of pre-pulse stimulation and the shock response of rats were recorded.In experiment 2～6,we explored the key brain regions in which 5-HT_2A receptor agonist TCB-2destroys PPI in normal animals.In experiment 2-6,the anterior pulse suppression test of shock reflex was used to perform stereotaxic surgery on animals whose baseline was less than two standard deviations.microinjected double cannulas were implanted in the medial prefrontal cortex,nucleus accumbens,ventral tegmental area,ventral hippocampus and ventral globus pallidus,respectively.After microinjection of 5-HT_2A receptor agonist TCB-2（10ug/1ul/side）and 5-HT_2A receptor antagonist M100907（5ug/1ul/side）into the brain area,the inhibition rates and the average inhibition rates of the three pre-pulse stimuli were recorded when the pre-pulse stimuli were 73d B,76d B and82d B,respectively,as well as the shock response of rats.In experiment 7,we investigated whether 5-HT_2A receptor antagonist M100907 could recover the loss of prepulse inhibition induced by dopamine D₂ receptor agonist Quinpirole in ventral globus pallidus.In experiment 7,the pre-pulse suppression test of shock reflex was used to perform brain stereotaxic surgery on animals whose baseline was less than two standard deviations.Double cannulas were microinjected into the ventral globus pallidus,followed by microinjection of 5-HT_2Areceptor antagonist M100907（5ug/1ul/side）into the brain area.5 minutes later,dopamine D₂ receptor agonist Quinpirole（0.6mg/kg）was intraperitoneally injected.The inhibition rate of rats when the pre-pulse stimulation was 73d B,76d B and 82d B,the average of the inhibition rate of the three kinds of pre-pulse stimulation and the shock response of rats were recorded.Results:1)The results of experiment 1 showed that administration of TCB-2 into the right ventricle of rats could destroy the preconditioning of PPI,M100907 in normal animals and reverse the deletion of PPI induced by TCB-2,and intracerebroventricular administration of M100907 did not affect the inhibition of prepulse in normal animals,while administration of TCB-2 and M100907 in the right ventricle did not affect the shock response of normal animals.2)The results from experiment 2 to experiment 6 showed that administration of TCB-2 only in the ventral globus pallidus could destroy the pre-pulse inhibition of normal rats,and M100907 could reverse the PPI deletion induced by TCB-2,but the administration of M100907 in the ventral globus pallidus did not affect the PPI of normal animals.However,injection of TCB-2 and M100907 into prefrontal lobe,nucleus accumbens,ventral hippocampus and ventral tegmental area did not affect the inhibition of anterior pulse in normal rats,and microinjection of TCB-2 and M100907 into prefrontal lobe,ventral globus pallidus,nucleus accumbens,ventral hippocampus and ventral tegmental area did not affect the shock response of normal animals.3)The results of experiment 7 showed that administration of M100907 to ventral globus pallidus could reverse the loss of PPI induced by intraperitoneal administration of dopamine D₂ receptor agonist Quinpirole,while intraperitoneal administration of Quinpirole and ventral globus pallidus administration did not affect the shock response of normal animals.Conclusion:1)Intracerebroventricular administration of 5-HT_2A receptor agonist TCB-2 can destroy the PPI;2 of normal animals)ventral globus pallidus is the key brain area in which 5-HT_2Areceptors participate in the regulation of prepulse inhibition;3)administration of TCB-2 in nucleus accumbens of rats can lead to a slight decrease of PPI in normal animals.