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[Display omitted] • Prazosin potentiates morphine-induced conditioned place preference (CPP). • Prazosin decreases the expression of α 1 adrenoceptor, phospho-CaMKII, CRTC1, BDNF, PSD95 & norepinephrine in VLO of morphine-induced CPP rats. • Prazosin reduces the levels of norepinephrine in VLO of morphine-induced CPP rats. • Prazosin increases the levels of TNF-α, IL-1β & IL-6 in serum of morphine-induced CPP rats. The norepinephrine (NE) system is involved in pathways that regulate morphine addiction. Here, we investigated the role of α 1 adrenoceptor in the ventrolateral orbital cortex (VLO) of rats with repeated morphine treatment and underlying molecular mechanisms. The rewarding properties of morphine were assessed by the conditioned place preference (CPP) paradigm. Prazosin, an α 1 adrenoceptor antagonist, was microinjected into the VLO. The expression of α 1 adrenoceptor, p-CaMKII/CaMKII, CRTC1, BDNF and PSD95 in the VLO were determined by immunohistochemistry or western blotting. Neurotransmitter NE in the VLO and inflammatory factors in serum were detected separately through high-performance liquid chromatography and enzyme-linked immunosorbent assay. Our experimental results showed that repeated morphine administration induced stable CPP and prazosin promoted the morphine-induced CPP. Microinjection of prazosin in the VLO not only blocked the activity of α 1 adrenoceptor, decreased CaMKII phosphorylation and CRTC1, which eventually resulted in a regression of synaptic plasticity-related proteins, but also was accompanied by significantly decreasing of NE in the VLO and increasing of inflammatory cytokines in peripheral blood. These findings suggested that prazosin potentiates the addictive effects of morphine. The effect of increased CPP through reducing α 1 adrenoceptor and NE was associated with the CaMKII-CRTC1 pathway and synaptic plasticity-related proteins in the VLO and inflammatory cytokines in the peripheral blood. The NE system may therefore be an underlying therapeutic target in morphine addiction. Additionally, we believe that the clinical use of prazosin in hypertensive patients with morphine abuse may be a potential risk because of its reinforcing effect on addiction. [ABSTRACT FROM AUTHOR]