Of Morphine Withdrawal Nucleus Accumbens Medium Spinous Process Of Neuronal Glutamate Synapses Incoming

Optias are among the most used analgesics and hypnotics in clinical. However, they are potentially extremely induced drug addictive and abuse, especially, the morphine and its derivatives heroin. It has long been recognized that adaptations in neural circuits of mesocorticolimbic dopamine systems, plays a key role in rewarding effects and drug addiction. Almost all of the experience-and drug-dependent neural plasticity are underling in the long-term changes at excitatory synaptic transmission, which concluded in long-term potentiation (LTP) or long-term depression (LTD) in associated synapses. The nucleus accumbens (NAc) is like a "relay station" in control motivational and emotional behaviors that are associated with rewarding and drug addiction. The90-95%cell type in NAc is GABAergic medium spiny neuron(MSN), and receives excitatory glutamatergic inputs from limbic structures, specifically the hippocampus and amygdala, prefrontal cortex (PFC), as well dopamine inputs from ventral tegmental area (VTA). Adaptations in the excitatory glutamatergic synaptic inputs onto NAc medium spiny neurons seem to be particularly important for mediating behaviors development, maintains and expression associated addiction. Thus the detailed cellular and molecular mechanisms by drugs of abuse related to modification excitatory synaptic function in the NAc have received increased attention. It seems that many dugs of abuse could modify synaptic plasticity in the NAc. However, direct electrophysiological evidence of the modulation of excitatory glutamatergic synaptic plasticity in the NAc after repeated morphine exposure withdrawal has not been provided. The properties and involved molecular mechanisms of synaptic plasticity underlying different times of morphine withdrawal are still unknown.Combinations of whole-cell patch clamp and field potential recording methods have been adopted in this research. Here we show that the excitatory glutamatergic synaptic adaptations in the NAc shell MSNs in rat during acute withdrawal (after12hours of the last morphine exposure) and chronic withdrawal (after10days of the last morphine exposure) period after repeated morphine exposure. The purposes of this study are to describe the changes of glutamatergic synaptic transmission in the NAc shell after morphine withdrawal, and provided candidate therapeutic strategies for treating morphine withdrawal. Firstly, we observed that the excitatory glutamatergic synaptic transmission in the NAc MSNs was increased during chronic morphine withdrawal, but not during acute morphine withdrawal. And, the electro-stimulation induced LTP/LTD in brain slice was also impaired after chronic morphine withdrawal. Then, we provide the first evidence suggest that functional down-regulation of presynaptic group Ⅱ metabotropic glutamate receptors (mGluR2/3) mediates the potentiation of synaptic transmission in the NAc shell MSNs after chronic morphine withdrawal. The detail results are as following:1. The effects of acute and chronic morphine withdrawal on excitatory glutamatergic synaptic strength in the NAc shell MSNsCompared with the saline group, the glutamatergic synaptic strength in the NAc shell MSNs was significantly increased in the group of chronic morphine withdrawal, however, no significant changes was observed in the group of acute morphine withdrawal. The potentiation of synaptic strength was demonstrated by a decreased the paired pulsed ratio (PPR), an increased frequency of miniature excitatory postsynaptic currents (mEPSCs) and an increased the ratio of α-amino-3-hydroxy-5-methyl-isoxazole propionic acid receptors-to N-methyl-d-aspartate receptors-(AMPAR/NMDAR) mediated currents. However, compared with the saline group, no significant changes were observed in the PPR, the AMPAR/NMDAR ratio, as well as the frequency and amplitude of mEPSCs during acute morphine withdrawal.2. LTP/LTD in the NAc shell brain slice is impaired by chronic morphine withdrawalIn saline groups, high frequency stimulation (HFS) and low frequency stimulation (LFS) could induce a robust LTP and LTD at excitatory glutamatergic synapses in the NAc slice, respectively. However, both HFS and LFS induced LTP/LTD were impaired during chronic morphine withdrawal.3. The potentiation of synaptic strength in the MSNs induced by chronic morphine withdrawal needs activation of NMD ARsBlockage of NMD ARs by their antagonist MK-801in vivo could prevent the potentiation of AMPAR/NMDAR ratio which induced by chronic morphine withdrawal. And, the function of NR2B contained NMD ARs were increased after chronic morphine withdrawal. It can be demonstrated by that the decay time constant was increased, as well as the ratio of NR2B/NR2A mediated currents were increased during chronic morphine withdrawal.4. Morphine down regulates the function of mGluR2/3to increase the synaptic strength in the N Ac shell MSNsActivation of mGluR2/3by bathing their agonist LY-379268could induce LTD on glutamatergic synaptic inputs in the NAc brain slice. However, this LTD was impaired in the group of chronic morphine withdrawal. Pretreatment with LY-379268in vivo could prevent not only the potentiation of synaptic strength, but also the increased frequency of mEPSCs and AMPAR/NMDAR ratio during chronic morphine withdrawal.Conclusions:The excitatory glutamatergic synaptic strength in the NAc MSNs was enhanced after chronic morphine withdrawal, but not in acute morphine withdrawal. Interestingly, both HFS and LFS induced LTP/LTD in the NAc brain slice were impaired during chronic morphine withdrawal. The possible signaling process of this potentiation of synaptic strength is that functional down regulation the function of presynaptic mGluR2/3induced by chronic morphine withdrawal makes the transmitter releasing increased, and enhanced in the capabilities of postsynaptic response. And this process needs to enhance the function of NR2B contained NMDARs.