DA And NMDA Receptor Dysfunction Induced The Spatial Memory In A Large-scale Maze And Sensory Gating Abnormalities In Monkeys

Section 1Objective(s):Dopamine(DA)has served a critical role in the study of neurobiological aspects of learning and memory in humans and animals.However,its functional roles in place learning and procedure memory in spatial memory tasks still remain unclear.Methods:Using an outdoor large-scale maze,we studied dopaminergic systems with respect to place learning and procedure memory in rhesus monkeys.DA antagonist(SKF-83566 or haloperidol)was(i.m.)administered to the monkeys 30 min prior to the testing.Results:We found that D2,not D1,antagonists induced learning and memory deficits in a dose-dependent pattern in the maze at different stages.The results indicated that:(1)haloperidol(0.01 mg/kg),not SKF-83566(0.02,0.2 mg/kg),impaired the spatial learning during the early(initial acquisition)phase which can be reflected as the place learning in the maze.(2)Haloperidol(0.05 mg/kg),but not SKF-83566,deteriorated spatial memory during late(extended training)phase which was a procedure memory in the maze task.Conclusion(s):Our data suggested that D2-like receptor antagonists,not D1-like,impaired place leaning at an early stage and procedure memory during late stage of memory.In conclusion,the memory at the early stage,while the spatial place memory was converting to the procedure memory,was more sensitive to D2 dopaminergic antagonists than the late stage.Section 2Objective(s):Aging-related cognitive changes often include specific impairments of learning and memory.Dopamine(DA)has served a critical role in the study of neurobiological aspects of learning and memory in humans and animals.Methods:Using an outdoor large-scale maze,we studied dopaminergic systems with respect to place learning and procedure memory in young and aging rhesus monkeys.D1 and D2 antagonists(SKF-83566 or haloperidol)were(i.m.)administered to the monkeys 30 min prior to the testing.Results:We found that:(1)aged monkeys were impaired on spatial memory contrasted to the young animals in the early stage.(2)haloperidol(0.01 mg/kg),impaired the spatial learning during the early phase which can be reflected as the place learning in young monkeys.(3)Haloperidol(0.05 mg/kg),deteriorated spatial memory during procedure memory in young monkeys.(4)SKF-83566(0.02 mg/kg),and haloperidol(0.001 mg/kg)improved place learning at the early stage in aged monkeys,as reflected by better performance in the Total-cup errors.(5)Haloperidol and SKF-83566 did not deteriorate procedure memory during late stage in the aged monkeys.Conclusion(s):Our studies are consistent with previous findings demonstrating that there is a limited extent of D1 and D2 receptor inhibition for optimal hippocampus spatial memory,and suggest that low dose of D1 and D2-like receptor antagonists may have cognitive-improving actions in the old ones.Section 3Objective(s):Sensory gating,often described as the ability to filter out irrelevant information that is repeated in close temporal proximity,is essential for the selection,processing,and storage of more salient information.This studyaimed to test the effect of sensory gating under anesthesia in the prefrontal cortex(PFC)of monkeys following injection of bromocriptine,haloperidol,and phencyclidine(PCP).Methods:We used an auditory evoked potential that can be elicited by sound to examine sensory gating during treatment with haloperidol,bromocriptine,and PCP in the PFC in the cynomolgus monkey.Scalp electrodes were located in the bilateral PFC and bilateral temporal,bilateral parietal,and occipital lobes.Administration of bromocriptine(0.313 mg/kg,0.625 mg/kg,and 1.25 mg/kg),haloperidol(0.001 mg/kg,0.01 mg/kg,and 0.05 mg/kg),and the N-methyl-D-aspartic acid receptor antagonist PCP(0.3 mg/kg)influenced sensory gating.Results:We demonstrated the following:(1)Administration of mid-dose bromocriptine disrupted sensory gating(N100)in the right temporal lobe,while neither low-dose nor high-dose bromocriptine impaired gating.(2)Low-dose haloperidol impaired gating in the right prefrontal cortex.Mid-dose haloperidol disrupted sensory gating in left occipital lobe.High-dose haloperidol had no obvious effect on sensory gating.(3)Gating was impaired by PCP in the left parietal lobe.Conclusion(s):Our studies showed that information processing was regulated by the dopaminergic system,which might play an important role in the PFC.The dopaminergic system influenced sensory gating in a dose-and region-dependent pattern,which might modulate the different stages that receive further processing due to novel information.Section 4Objective(s):It has been reported that perinatal administration with the noncompetitive N-methyl-D-aspartate(NMDA)receptor antagonist phencyclidine(PCP)disrupted the long-term spatial memory in the PFC,hippocampus and striatum structures of rat.As dysfunction of two structures is related with cognitive deficits in patients with schizophrenia,our goal was to find a neurodevelopmental model with predictive validity for the spatial impaired described in patients.Methods:Male rhesus monkey in half years old were treated with either saline or PCP(0.15 mg/kg,or 0.3 mg/kg)on 14days(twice per day).Using an outdoor large-scale maze,we studied the effect of the subchronic PCP with respect to place learning and procedure memory in adult monkeys.And then the sensory gating was tested in the PFC.Results:Low dose group,high dose group and control group differed on the whole training session days.Control monkeys performed more errors and percentage of correct choices during days 1-10 relative to the low dose group and high dose group reflecting as the Entry-cue errors,total-cue errors,entry-cup errors,total-cup errors,percentage of correct choices.Low dose monkeys showed less latencies performance as control or high group monkeys in entry-latency,exit-latency,and total-latency.However,there was no a significant difference between the control group and PCP group in the PFC.Conclusion(s):These findings provide that an increase in the spatial learning and memory and no changes in sensory gating may be associated with myelination and axonal changes in white matter tracts implying subacute PCP in infancy monkey accelerated the brain maturation.