Intracellular Signal Pathways Of Modulation Of Dopamine Receptor Subtype 4 On Gamma Network Oscillations

Backgroundγ oscillation is a rhythmic activity with frequency between 30-80 Hz in neuronal networks,generated by the mutual coordination effect of inhibition and excitatory neurons,and is associated with the cognitive function,e.g.learning and memory.γ oscillation exists in multiple brain regions such as hippocampus,thalamus and neocortex.In a previous study,we found that the dopamine D4 receptor(D4R)agonists increased the amplitude ofγ oscillation.However,intracellular mechanisms of modulation of dopamine receptor subtype 4 on γ oscillations have not been reported.Objectives We aim to study the impact and the cellular mechanisms of D4 R agonists on CA3 γoscillations of rat hippocampal slices.Methods1 field potential recording3~4 weeks male SD rats were anesthesiaed by chloral hydrate and myocardial perfusion was made with precooling(0℃)of ACSF-cutting solution satured with carbogen(5% CO2 +95% O2).When the all limbs of the rats become white,the brain was quickly removed and sliced horizontally(400μm).The brain slices were moved into interface chamber by using a stainless steel spoon and incubated 60 min before an extracellular recording.Kainate was used to induce the gamma oscillation.All the data were analyzed by Spike 2 software.All statistical tests were performed using Sigma Stat software.Results are expressed as mean ± standard error.Measures were considered statistically significant if P<0.05.Results1)D4R agonists increased the γ oscillation power.2)Protein kinase A(PKA)inhibitor H89 did not affect the effect of D4 R agonist on γoscillation.3)Extracellular signal kinase(ERK)inhibitor U0126 blocked the effect of D4 R agonist onγ oscillations.4)NMDA receptor antagonist D-AP5 blocked the effect of D4 R agonists on γ oscillations.5)Phosphatidylinositol 3-kinase(Phosphatidylinositol 3-kinase,PI3K)inhibitor wortmannin reversed the effect of D4 R agonists on γ oscillations.Conclusions These results indicate that,D4 R agonists increase the amplitude of γ oscillation,which may be related to the activation of ERK,PI3 K and the NMDA receptor.