Effects Of Dopamine D1 Receptor Activity In Medial Prefrontal Cortex And Nucleus Accumbens On Sensory Gating In Mice

Background: Schizophrenia is a heterogeneous mental illness.Deficits in sensory gating,which refers to the brain’s ability to filter sensory information by reducing its response to repeated exposure to the same sensory stimulus,are thought to be a biological hallmark of schizophrenia.Pre-pulse suppression refers to the normal reduction in startle amplitude when a strong startle stimulus(or pulse)is preceded by a weaker pre-stimulus(or pre-pulse).The prepulse inhibition paradigm is commonly used to evaluate sensorimotor gating and has been found in many species,including humans and rodents.Loss of prepulse inhibition has been observed in subjects with schizophrenia and other neuropsychiatric disorders and in established animal models of these disorders.Structural and functional impairment of dopamine D1 and D2 receptors has been implicated in many psychiatric disorders.It has been shown that either dopamine D1 or dopamine D2 agonists can mimic the deficits of prepulse inhibition in different rodent species,but the key brain regions in which dopamine agonists disrupt prepulse inhibition are unknown.Identifying key brain regions will play an important role in the further study of neural circuits in schizophrenia.Hypothesis: Intraperitoneal injection of D1 agonist SKF82958 caused prepulse inhibition deficits in mice.Intraperitoneal injection of D2 agonist quinpirole had no effect on prepulse inhibition,and intraperitoneal injection of D1 receptor antagonist SCH23390 reversed prepulse inhibition deficits caused by intraperitoneal injection of D1 agonist SKF82958.The medial prefrontal cortex,ventral hippocampus,or nucleus accumbens may be involved in the regulation of dopamine D1 receptor inhibition of prepulse.Methods: Experiment 1: To investigate the effects of dopamine D1 receptor agonists and dopamine D2 receptor agonists on the prepulse inhibition of C57 mice,using the prepulse inhibition test of auditory starker reflex,Mice were intraperitoneally administered D1 agonist SKF82958(0.3 mg/kg)and D2 agonist quinpirole(0.5 mg/kg),followed by behavioral tests 10 or 15 minutes later.The inhibitory rate and the startled response of mice were recorded when the pre-pulse stimuli were 73 d B(d B),76 d B and 82 d B respectively.Experiment 2 investigated whether the D1 receptor antagonist SCH23390 could reverse the deficits of prepulse inhibition caused by D1 receptor agonist SKF82958.D1 receptor agonist SKF82958(0.3 mg/kg)and D2 receptor antagonist SCH23390(1.0 mg/kg)were intraperitoneallyinjected 10 minutes before the test.Inhibition rates and the amplitude of the starker response were recorded when the pre-pulse stimuli were 73 d B,76 d B and 82 d B,respectively.In experiments 3 to 5,the D1 receptor antagonist SCH23390 was used to restore the key brain regions of the absence of prepulse inhibition in mice.Microinjection cannulas were implanted in animal brain during stereostereolocation surgery,followed by microinjection of dopamine D1 receptor agonist SKF82958(1.0 μg/ 0.25 μl/ side)and D1 receptor antagonist SCH23390(0.5 μg/ 0.25 μl/ side)into brain regions.The inhibition rate and the amplitude of startled response were recorded when the pre-pulse stimuli were 73 d B,76 d B and 82 d B respectively.Experiments 6 to 9 investigated whether intraperitoneal injection of SKF82958,a dopamine D1 receptor agonist,and brain microinjection of SCH23390,a dopamine D1 receptor antagonist,had any effect on motor activity 7 days after the prepulse inhibition test in experiments 2 to 5.fter injecting SKF82958,a dopamine D1 receptor agonist,and SCH23390,a dopamine D1 receptor antagonist,into the medial prefrontal cortex,nucleus accumbens and ventral hippocampus,the animals were placed in the spontaneous activity test box and allowed to move freely for 90 minutes.The distance and speed of movement in the spontaneous activity test box were analyzed.Results: In experiment 1,prepulse inhibition deficits was induced by intraperitoneal injection of SKF82958(p = 0.004),while prepulse inhibition was not affected by intraperitoneal injection of quinpirole(p = 0.138).In experiment 2,intraperitoneal injection of SCH23390 reversed prepulse inhibition deficits caused by SKF82958,a dopamine D1 receptor agonist(p < 0.001).In experiment 3,prepulse inhibition deficits was reversed by local injection of SCH23390 in medial prefrontal lobe(p = 0.015),and in experiment 4,prepulse inhibition deficits was reversed by local injection of SCH23390 in nucleus accumbens(p = 0.001).In experiment 5,local administration of SKF82958 in the ventral hippocampus had no significant effect on prepulse inhibition(p = 0.280).The results of experiment 6 showed that intraperitoneal administration of SKF82958 increased the total kinetic distance of animals(p = 0.011),and intraperitoneal administration of SCH23390 significantly reduced the total kinetic distance of animals(p < 0.001).In experiment 7,SKF82958 administered by medial prefrontal cortex increased the total moving distance of animals(p = 0.010),and SCH23390 administered by medial prefrontal cortex significantly decreased the total moving distance of animals(p = 0.001).In experiment 8,total motor capacity was significantly reduced by SCH23390 administration in the nucleus accumbens region(p < 0.001).In experiment 9,SCH23390 administration to the ventral hippocampus significantly reduced the total distance of movement(p = 0.023).Conclusions:(1)Selective stimulation of dopamine D1 receptor activity in mice can destroypreimpulse inhibition in animals,and inhibition of dopamine D1 receptor activity can restore the loss of preimpulse inhibition caused by dopamine D1 receptor agonists;(2)Excitation of dopamine D1 receptors in the medial prefrontal lobe and nucleus accumbens disrupts prepulse inhibition;(3)Selectively stimulating the activity of dopamine D1 receptor in mice can enhance the exercise ability of the animals,and inhibiting the activity of dopamine D1 receptor can restore the increase in exercise ability caused by dopamine D1 receptor agonists;(4)Activation of dopamine D1 receptors in medial prefrontal cortex and nucleus accumbens can improve motor performance,while inhibition of dopamine D1 receptor activity in medial prefrontal cortex,nucleus accumbens and ventral hippocampus significantly reduces motor performance in mice.