Effects Of Modulation Of Nitric Oxide Signaling Pathway On The Conditioned Activity Induced By Addictive Drugs

Background and Objective: Nitric Oxide (NO) signaling pathway plays animportant role in the learning and memory process, the conditioned respond inducedby addictive drugs is treated as a pathological paradigm of learning and memory,some researches have shown that NO associated closely with addictive memory, andthe occurrence location and mechanism remains to be determined. In order to furtherexplore the wide range of NO signaling pathways involved in learning and memoryprocess and the role of central NO in the conditioned activity induced by addictivedrugs, studies were performed to assess:1) the effect of cocaine on conditionedlocomotion (CL) in mice after an injection of the NO donors and inhibitors byperiphery;2) the effect of the central NO intervenors on conditioned place preference(CPP) induced by morphine.Methods: Male SD rats and male ICR mice were trainned respectively bymorphine CPP (incremental dose:5mg/kg,10mg/kg, and15mg/kg, bysubcutaneously,6days) and cocaine CL (morphine dose:20mg/kg, byintraperitoneally,5days). Animals were assigned randomly into the following groups:control group, L-NAME group,7-NI group, MOL group, SNP group, the group ofcombined administration of L-NAME and MOL. The NO intervenors weremicroinjected into insular lobe or injected intraperitoneally. In the experiment, weused two different administration paradigms: single injection or combined injection.We tested the change of the locomotion counts in mice and the CPP ratio scores inrats.Results:1) Compared with control groups, the conditioned locomotion activity in group training mice increased significantly (P <0.01), the conditioned locomotion activityin isolated training mice increased but there was no significant differences (P>0.05).The group training manner established the successful conditional locomotion easier.2) Compared with control groups, the conditioned locomotion activity in mice ofthe large dose of NO inhibitors L-NAME (30mg/kg) group and7-NI (10mg/kg)group (P <0.001, P <0.01) and spontaneous activity (P <0.05, P <0.01) weresignificantly decreased, the conditioned locomotion activity in mice of the small doseof NO inhibitors (L-NAME10mg/kg,7-NI2.5mg/kg) groups were significantlydecreased (P <0.05), but the spontaneous activity behavior had no significantly effect(P>0.05). NO inhibitors blocked the conditioned locomotion activity in mice.3) Compared with control groups, the NO donor MOL (20mg/kg) and the smalldose of SNP (1mg/kg) had no effect on conditioned locomotion activity and thespontaneous activity in mice (P>0.05). The NO donor had no effect on theconditioned locomotion activity in mice.4) L-NAME inhibited the conditioned locomotion activity induced by cocainein mice (P <0.01), while the conditioned locomotion activity in mice of combinedadministration of MOL had no significantly effect (P>0.05). Combinedadministration of MOL reversed the inhibiting effect induced by L-NAME onconditioned locomotion activity.5) Compared with control groups, the expression of morphine CPP in rats of theNO inhibitors L-NAME group and7-NI group were significantly decreased (P <0.01,P <0.05), and the expression of CPP of the7-NI group was still significantlydecreased in the CPP re-testing (P <0.05). Microinjection of NO inhibitors intoinsular inhibitted the CPP in rats, the time of7-NI inhibited CPP was relatively long(>24h).6) Microinjection of NO donor MOL had no significant effect on the CPPexpression induced by morphine (P>0.05). Microinjection of MOL into insular hadnot effect on CPP in rats. 7) L-NAME could inhibit the CPP induced by morphine in rats (P <0.01), andwhile the CPP expression induced by morphine of the combined microinjection ofMOL group had significantly change (P>0.05). Combined injecting MOL reversedthe inhibiting effect induced by L-NAME on expression of CPP.8) The operations of implanting the guide cannulae into insular, training CPPwith morphine, microinjectiong of drugs into insular, and the CPP recovery procedurein experiment could have no effect on crossing numbers in rats (P>0.05). Theexperimental operations of microinjecting had no effect on activity and capacity inrats.Conclusion:Administration of peripheral or central NO inhibitors would attenuate theconditioned activity induced by addictive drugs, and combined administration of NOdonor would reverse the inhibitory effect. NO signaling pathway would mediate theconditioned activity induced by addictive drugs, and the insula NO signaling pathwaywould be involved in learning and memory process.