Computational modeling of opioid-induced synaptic plasticity in hippocampus.

According to a broad range of research, opioids consumption can lead to pathological memory formation. Experimental observations suggested that hippocampal glutamatergic synapses play an indispensable role in forming such a pathological memory. It has been suggested that memory formation at the synaptic level is developed through LTP induction. Here, we attempt to computationally indicate how morphine induces pathological LTP at hippocampal CA3-CA1 synapses. Then, based on simulations, we will suggest how one can prevent this type of pathological LTP. To this purpose, a detailed computational model is presented, which consists of one pyramidal neuron and one interneuron both from CA3, one CA1 pyramidal neuron, and one astrocyte. Based on experimental findings morphine affects the hippocampal neurons in three primary ways: 1) disinhibitory mechanism of interneurons in CA3, 2) enhancement of NMDARs current by μ Opioid Receptor (μOR) activation and 3) by attenuation of astrocytic glutamate reuptake ability. By utilizing these effects, simulations were implemented. Our results indicate that morphine can induce LTP by all aforementioned possible mechanisms. Based on our simulation results, attenuation of pathologic LTP achieved mainly by stimulation of astrocytic glutamate transporters, down-regulation of the astrocytic metabotropic glutamate receptors (mGlurs) or by applying NMDAR's antagonist. Based on our observations, we suggest that astrocyte has a dominant role in forming addiction-related memories. This finding may help researchers in exploring drug actions for preventing relapse.