| Objective：Deep brain stimulation (DBS) has been used as a method to treat depressionepilepsy, obsessive-compulsive and other psychiatric disorders in clinic. DBS has thecharacteristics of being minimally invasive, reversible and adjustable. DBS was administeredby implanting a micro-electrodes in a specific areas of the brain, and the stimulating currentwas delivered with adjusting parameters such as current, pulse, frequency etc. In recent years,experimental and clinical studies suggest that DBS has the potential for the treatment of drugaddiction. But research about effect of DBS on heroin addiction has been just started, it is notentirely clear which part of the brain and what kind of paradigm should be applied, and alsowith the mechanisms underlying unkown. Therefore, in this basic study, a heroin self-administration model and microdialysis was used to investigate the role and possiblemechanisms of DBS stimulation for LHb in the self-administration and reinstatement ofheroin seeking behavior.Experiment1: effect of DBS in LHb on heroin self-administration behaviorMethods: Adult male SD rats were catheterized in the left jugular vein and implanted aself-designed electrode in the left LHb. After recovery for7days,all rats were placed in theoperant chambers for self-administration under FR1schedule,4h daily sessions. After8daysof self-administration,24rats reaching steady self-administration (ie, the variation of effectivenose pokes about self-administration in the last there days within15%) were randomlydivided into three groups: low frequency stimulation group (L-DBS, n=8), the high frequencystimulation group (H-DBS, n=8) and combined stimulation group (Combined-DBS, n=8).These three groups were given low frequency (10Hz,0.2mA, pulse width0.5ms)stimulation,high frequency (100Hz，0.2mA, pulse width0.5ms) and combined frequency stimulation for15min respectively, and then placed in the operant chambers for self-administration underFR1schedule. The data of effective nose pokes and infusions were recorded, and comparingwith the data before stimulation.Results: Compared with rats under stable of self-administration, high frequency DBScould increase the number of active nose pokes (P=0.008) and infusions (P=0.004)significantly. Combined DBS also can increase the number of active nose pokes (P=0.006) and infusions (P=0.001) significantly. But low frequency DBS had no effect on self-administration (p＞0.05).Experiment2: effect of BDS in LHb on cue-induced heroin seekingMethods:32rats were placed in the operant cambers for a daily4h heroin self-administration training under fixed ratio FR1schedule for consecutive14d. When the ratsachieved stable heroin self-administration (the change of active nose pokes in the last threedays is less than15%), all rats were divided into four groups randomly: the sham group, H-DBS (n=8), L-DBS (n=8), Combined DBS (n=8). Extinction training was conducted forsuccessive12d, and a15min before each extinction session, DBS(Sham, Low-frequency,High-frequency and Combined-bursts) was given in the LHb. Chronic effect of DBS on cue-induced heroin seeking was tested24h after the last extinction session under the same FR1schedule as which was used during the heroin self-administration session，no pre-treatmentDBS was given for the test.After the first test, the rats were again exposed to extinction session until the baselineresponse decreased to <5nosepokes per session. Then, acute effect of DBS on cue-inducedheroin seeking was conducted with a15min pretreatment with DBS. Again, followingextinction sessions, acute effect of DBS on drug-induced heroin seeking was conducted with a15min pretreatment with DBSResults: During the first test session of cue-induced heroin seeking, no pretreatment ofDBS was given. Compared with the Sham group, results showed that combined-burstsstimulation of the LHb preceded with each extinction session could significantly increase thetotal nose-poking during the later reinstatement test (P=0.008＜0.05). Low-frequency or high-frequency DBS had no effect (p＞0.05). One way ANOVA revealed a significant overalleffect of groups (F(3，23)=3.142, P <0.005). Pairwise comparisons showed that rats in thegroup of combined-bursts emitted significantly more responses during the reinstatement testscompared with sham control rats (P <0.05).Acute effect of DBS in LHb on cue-induced heroin seeking was observed in the secondreinstatement test. Results showed that15min pretreatment with combined-bursts stimulationin the LHb could significantly decrease the nose-poking responding during the reinstatementtest. One way ANOVA revealed a significant overall effect of groups (F（3，22）=5.432, P<0.005). Pairwise comparisons showed that rats in the group of combined-bursts emittedsignificantly lower responses during the reinstatement tests compared with sham control rats(P <0.05).Acute effect of DBS in LHb on drug-induced heroin seeking was observed in the third reinstatement test. Results showed that15min pretreatment with combined-bursts stimulationin the LHb has no effect no nose poking responding during the reinstatement test.Experiment3: effect of DBS in LHb on DA release in NAc.Methods: Fifteen na ve rats were used for DA microdialysis under pentobarbitalanesthesia. An micro-electrode was inserted into the left LHb, and a microdialysis probe wasinserted ipsilaterally into the left NAc. DA basal release was collected each15min for threesamples, then DBS (three groups: Low-frequency, High-frequency, Combined bursts, n=5foreach group) was delivered through the electrode and sample was collected for45min.Results: Low-frequency stimulation of LHb resulted in about50%decrease of baselinedopamine release in NAc (Fig.5A), while high-frequency or combined-bursts stimulation ofLHb increased DA release in about45%or100%, respectively.ConclusionsHigh frequency and combined DBS stimulation could enhance heroin self-administrationof rats, which may be related to the fact that high frequency and combined DBS stimulation ofLHb can increase the level of DA in NAc. Chronic stimulation of LHb may cause stress in therats, so as to promote the cue-induced heroin seeking; Acute DBS stimulatlion of LHb couldsignificantly inhibit cue-induced heroing seeking. DAralease might play a vital role. |
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