| The rewarding effects of abused drug and natural (food. sex. etc.) share the common neural basis, the mesolimibic dopamine system (MLDS). This system involves the amygdala, arcuate nucleus, locus coeruleus. midbrain periaqueductal gray, ventral tegmental area (VTA), nucleus accumbens (NAc) and other regions, and its extension includes the frontal cortex and hippocampus which are closely related to emotional, learning and memory. The current view is that rewarding stimuli acts on the brain reward system, leading the enhancement of dopamine release, thus induces rewarding effects.NAc plays a vital role in addiction. More and more attention is being paid to the adaptive changes in NAc neuron during morphine treatment and withdrawal. One of the functions of the prefrontal cortex (PFC) is assessing the importance of favorable stimuli, and inhibiting inappropriate behavior in the current environment. PFC plays important role in drug-seeking motivation assessment and inhibiting psychological dependence. It was reported that stimulation of PFC at physiologically relevant frequencies inhibited dopamine release in the NAc, suggesting PFC negatively regulates the release of dopamine in the NAc. Immunocytochemistry studies confirmed glutamatergic synaptic projection from PFC to NAc which provides structural basis for this regulation. However, it is unclear how morphine application modifies glutamatergic synaptic transmission of PFC-NAc.To explore this question, in vivo field excitatory postsynaptic potentials (fEPSPs) induced by electric stimulating PFC-NAc projection fibers were recorded to evaluate the change on glutamaergic synaptic transmission in NAc shell during morphine treatment. Here we will introduce two parts of works.(1) The effects of acute morphine (s.c.) and naloxone (i.p.) on the fEPSP amplitude and paired-pulse ratio (PPR) after chronic morphine/saline pretreatment (10mg/kg, twice-daily injection for5days).(2) The effects of acute and chronic morphine withdrawal on low frequency stimulation (LFS) induced synaptic long-term depression (LTD), as well as its underling mechanism. The main results are as follows:(1) Acute morphine exposure enhanced fEPSP amplitude and reduced PPR in saline group, which could be reversed by following naloxone injection, an opiate receptor antagonist. However, in chronic morphine pretreated group, acute morphine exposure induced both the enhancement of fEPSP amplitude and reduction of PPR were significantly inhibitedby. Those results indicate that the initial morphine exposure enhances PFC-NAc synaptic transmission by pre-synaptic mechanisms, whereas morphine pretreatment occludes this effect.(2) In saline group, LFS (5Hz,3min, three trains) application on glutamatergic input axons from PFC induced a robust LTD (LFS-LTD) at the NAc shell synapses. The PPR increased significantly during LTD expression. The effects of LFS on fEPSP amplitude and PPR could be abolished by LY341495(mGluR2/3antagonist) applied1hour before LTD induction. Compared with saline group, similar LFS protocal fail to induce LTD on rats of12hours (Mor-AW group) and10days (Mor-CW group) withdrawal from repeated morphine exposure.LFS-LTD could be restored by local infusion of LY379268(mGluR2/3agonist) in NAc30min before each morphine injection in Mor-CW group. These results indicate that morphine-induced functional downregulation of group Ⅱ mGluRs plays a role in the development of such neuronal plasticity and therefore might contribute to morphine-addictive behavior.In conclusion, the initial morphine exposure enhances PFC-NAc glutamate release by pre-synaptic mechanisms. After multiple morphine application, the NAc occurs adaptive changes that enable glutamate release increased. This change may cause by downregulation of number and/or function of mGluR2/3, therefore coming to remove the inhibition of neurotransmitter release. Those changes play an important role in drug addiction. |
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