The Role Of Cholinergic Neurons In Medial Septum In The Heroin Self-administration And Heroin Seeking Behavior

ObjectiveThe aims of present studies were not only to investigate the effect of selective lesion ofcholinergic neurons in medial septum(MS) on the heroin self-administration, extinction, heroinseeking induced by cues or heroin priming and learning and memory, but also to observe the effectof lesion of cholinergic neurons projecting from medial septum to ventral subiculum(vSUB) onthe heroin seeking behavior and septial learning and memory.MethodsExperiment1Cholinergic neurons in MS of lesion group (n=8) were selectively lesioned by microinjectionof192IgG-saporin(0.25μg) in male SD rats, while control group (n=7) were infused with thesame amount of sterile saline water. After one week, the rats were tested with heroin self-administration for14days under a FR1schedule. Then after two weeks of extinction, cue-inducedheroin seeking test was taken. Following a short extinction, heroin-induced drug seeking behaviorwas detceted in2hours. In order to observe the difference in spital memory, rats of the thesegroups plus drug naive group were perfomanced in Morris water maze. Chat-positive cells in MSwere observed cholinergic damage using ABC immunohistochemical staining.Experiment2Thirteen male SD rats were traning in heroin self-administration with14days under a PR1schedule. In the periods of withdraw, lesion group (n=7) were selectively lesion cholinergicneurons projecting from MS to vSUB by bilateral microinjections192IgG-saporin(0.5μg) into thevSUB, and control group (n=6) were infused with the same amount of sterile saline water.Following a short extinction, heroin-induced drug seeking behavior was detceted in2hours.Observe the difference perfomance between two groups in Morris water maze. Chat-positive cellsin MS were observed using ABC immunohistochemical staining.ResultsExperiment1After the recovery of lesions in the medial septum, the rats were self-administered heroin.There was no difference in active or inactive nose-pokes between lesion and control groups in theacquisition. While maintenance of heroin self-administration, the numbers of heroin infusionslesion group were significantly higher than the control group(P <0.05). The active or inactive responses during the extinction and cue-induced heroin reinstatement were not different from thoseof the control group In the heroin-induced reinstatement of heroin-seeking, the responses of thelesion group were significantly higher than those of the control group(P <0.05). In the Morris watermaze, there is no significant difference in latency, the total distance and the number of crossingplatform between the two groups. The average speed of lesion group on the third day is less thanthe control group (P<0.05). But the two groups in the place navigation test and spatial probe testperformance were worse than drug naive group rats (P<0.05).Immunohistochemical stainingshows approximate70%cholinergic neurons are irreversiblly lesioned.Experiment2After self-administration for14days, microinjection of192IgG-Saporin into the ventralsubiculum. There was no difference in cue or drug induced heroin-seeking and Morris water mazetest between the lesion group and control group.ConclusionsAfter cholinergic neurons of MS lesion, the numbers of infusions were increased and drug-seeking induced by heroin priming also were increased, indicating the MS cholinergic transmissionmay play an important role in the heroin reward and drug seeking behavior. The significantlyincreasing of drug-seeking in lesioned group reflects the ability of inhibition control is weakened.There is no difference between group of lesion cholinergic neurons in MS before heroin self-administration and control group, which may normal learning and memory function is damaged byheroin addiction. The study also suggests that lesion the cholinergic neurons projecting frommedial septum to ventral subiculum may be not involved in the heroin seeking and the spatiallearning.