Modulation Of Hippocampal Neuronal Plasticity By Chronic Opiates Treatment

Long-term usage of opiates eventually leads to drug addiction, which is believed as a brain disease involved maladaptive changes in brain function. Provided the knowledge on the influence of hippocampal function by opiates like morphine and heroin, we further investigated the modulation of long-term potentiation (LTP, a leading experimental model for studying synaptic plasticity) at CA1 synapses in rat hippocampus following chronic opiate treatment. Our results revealed that chronic exposure of rats to morphine or heroin, which induced severe drug tolerance and dependence, markedly reduced the capacity of hippocampal CA1 LTP during the period of drug withdrawal (from ~190% in control to ~120%). And the capacity of LTP could be restored to the normal level by re-exposure of the animals to corresponding opiates, indicating that the synaptic function was already adapted to opiates. More interestingly, under the cross-usage of morphine or heroin, such adaptation exhibited a differential response to a distinct opiate (distinct from the drug for chronic treatment), and a differential blockage effect by naloxone. Morris water maze test, which measures behavioral consequences of synaptic plasticity, showed parallel learning deficits after chronic exposure to opiates. Furthermore, the opiate-reduced LTP could also be restored by inhibitors of cAMP-dependent protein kinase A (PKA), suggesting that up-regulation of cAMP pathway was likely one of the underlying mechanisms of the observed phenomena. Meanwhile, the differential effect under the cross-usage of morphine and heroin could also be a result of this cAMP-PKA signal pathway alteration. These findings demonstrated that chronic opiate treatment could significantly modulate synaptic function in the hippocampus, leading to an opiate dependent plasticity.