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The 5-hydroxytryptamine 7 receptor (5-HT 7 R) is one of the most recently cloned serotonin receptors which have been implicated in many physiological and pathological processes including drug addiction. Behavioral sensitization is the progressive process during which re-exposure to drugs intensified the behavioral and neurochemical responses to drugs. Our previous study has demonstrated that the ventrolateral orbital cortex (VLO) is critical for morphine-induced reinforcing effect. The aim of the present study was to investigate the effect of 5-HT 7 Rs in the VLO on morphine-induced behavioral sensitization and their underlying molecular mechanisms. Our results showed that a single injection of morphine, followed by a low challenge dose could induce behavioral sensitization. Microinjection of the selective 5-HT 7 R agonist AS-19 into the VLO during the development phase significantly increased morphine-induced hyperactivity. Microinjection of the 5-HT 7 R antagonist SB-269970 suppressed acute morphine-induced hyperactivity and the induction of behavioral sensitization, but had no effect on the expression of behavioral sensitization. In addition, the phosphorylation of AKT (Ser 473) was increased during the expression phase of morphine-induced behavioral sensitization. Suppression of the induction phase could also block the increase of p-AKT (Ser 473). In conclusion, we demonstrated that 5-HT 7 Rs and p-AKT in the VLO at least partially contribute to morphine-induced behavioral sensitization., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

Neurofilament light chain (NF-L) plays critical roles in synapses that are relevant to neuropsychiatric diseases. Despite postmortem evidence that NF-L is decreased in opiate abusers, its role and underlying mechanisms remain largely unknown. We found that the microinjection of the histone deacetylase (HDAC) inhibitor Trichostatin A (TSA) into the ventrolateral orbital cortex (VLO) attenuated chronic morphine-induced behavioral sensitization. The microinjection of TSA blocked the chronic morphine-induced decrease of NF-L. However, our chromatin immunoprecipitation (ChIP)-qPCR results indicated that this effect was not due to the acetylation of histone H3-Lysine 9 and 14 binding to the NF-L promotor. In line with the behavioral phenotype, the microinjection of TSA also blocked the chronic morphine-induced increase of p-ERK/p-CREB/p-NF-L. Finally, we compared chronic and acute morphine-induced behavioral sensitization. We found that although both chronic and acute morphine-induced behavioral sensitization were accompanied by an increase of p-CREB/p-NF-L, TSA exhibited opposing effects on behavioral phenotype and molecular changes at different addiction contexts. Thus, our findings revealed a novel role of NF-L in morphine-induced behavioral sensitization, and therefore provided some correlational evidence of the involvement of NF-L in opiate addiction.