The Role Of μ Opioid Receptors In Acute Stress-induced Memory Impairment

In daily life people go through various experience of stress, a situation that potentially imposes a physical or psychological threat. Stress causes physiological changes in the body and brain that enable organisms adapt to the threatening situations. However, strong stress exposure has negative effects on a number of physiological systems. It Ample reports have indicated that acute stress impaired learning and memory of animals, but the underlie mechanisms is still not clear. The influences of acute stress in different phases of memory such as acquisition, consolidation or retrieval were not alike. A large number of human and animal experiments show that endogenous opioid system plays a role in stress, as endogenous opioids release is increased and opioid receptors are activated during stress experience. On the other hand, endogenous opioid system mediates many functions of organism, as well as learning and memory. Our previous work has demonstrated that acute stress by 50 min elevated platform (EP) impairs the retrieval of spatial reference memory in mice. Both naloxone (i.p.), a no-selected opioid receptor antagonist, and CTAP (i.c.v.), a selected μ opioid receptor antagonist, prior stress could block the spatial reference memory retrieval impairment induced by EP stress. These all indicated that μ opioid receptor may be activated during acute stress and the activation of μ receptors might mediate stress-induced memory impairment.In present work, we used behavioral and molecular methods to explore the effect of μ opioid receptors on acute stress-induced learning and memory impairment. Our research consists of the following two parts.In the first part, a three-day pattern of new object recognition task was used to study the effect of acute forced swimming stress on recognition memory of c57 mice and the role of opioid receptor during that. We found that 15 min acute forced swimming damage the retrieval of recognition memory but have no detective effect on acquisition and consolidation of recognition memory. Mice were given μ opioid receptor antagonist naloxone by intraperitoneal injection alone has no significant effect on object recognition memory in mice. While intraperitoneal injection of naloxone before forced swimming stress could inhibit the impairment of recognition memory retrieval which was coursed by forced swimming stress. This suggests that acute stress damage recognition memory retrieval is implemented by activating the μ opioid receptor. Next, we used the fluorescence quantitative PCR technique to test the μ opioid receptors mRNA expression in different brain regions, including whole brain, hippocampus and prefrontal cortex. The results showed that acute forced swimming decrease the μ opioid receptor mRNA level in whole brain and hippocampus while injection of naloxone before stress could reverse this change. Those prompted that μ opioid receptor plays a critical role in the impairment of recognition memory which induced by acute forced swimming stress.In the second part, we used the two days (12 training trials during the 1st day, then test in the 2nd day) Morris water maze model which has been built successfully before. The effect of p. opioid receptor activation through hippocampal microinjection of DAMGO (selected μ opioid agonist) on memory retrieval was investigated. In addition, the specific μ opioid receptor on GABAergic neuron conditional knockout mice and 50 min EP stress were used to explore whetherμ opioid receptor mediate the elevated platform stress-induced impairment of memory retrieval. The experimental results showed that the hippocampal DAMGO microinjection would damage the retrieval of spatial reference memory of C57 mice.50min EP stress before test impaired retrieval of spatial reference memory of wild type mice but not GABAergic μ opioid receptor knock out mice. These results indicate that the activation of μ opioid receptor either by agonist or stress will damage the retrieval of spatial reference memory. The μ opioid receptor on GABAergic neurons participate the stress-induced impairment of the spatial reference memory retrieval. Here we also used the fluorescence quantitative PCR to test the μ opioid receptors mRNA expression in different brain regions after mice accept the 50 min EP stress. Similar to the effects of acute forced swimming stress, acute 50min EP stress decreases the μ opioid receptor mRNA level in whole brain and hippocampus while injection of naloxone before stress could reverse this change.. Those all indicates the μ opioid receptor plays a critical role in the acute stress-induced impairment of memory.In conclusion, endogenous opioid system takes part in the impairments of recognition and spatial reference memory retrieval coursed by acute stress via activation of μ opioid receptors expressed on hippocampal GABAergic interneurons.