| Objective1.To explore the effect of melatonin on acute methamphetamine-induced aggressive behavior of ICR mice,and provide evidence for improving the negative mood of patients with methamphetamine dependence.2.To evaluate the effects of intervention model"motivation-desensitization-neurotransmitter regulation"on motivation level,addiction memory intense,negative mood,and/or attentional bias,general response inhibition,and self-esteem.Methods1.This experiment adopted isolation-induced aggression in a resident-intruder model with 100 male ICR mice(18-22 g)(50 as residents and 50 as intruders).Then the 50 resident mice were randomly divided into 5 groups(n = 10 per group).The vehicle group was intragastrically(i.g.)administered 0.5%CMC-Na(an aqueous solution of sodium carboxymethyl cellulose)and then intraperitoneally(i.p.)injected with 0.9%normal saline.The MA group was treated with 0.5%CMC-Na(i.g.)and then injected with MA(3 mg/kg,i.p.).The MA+MT2.5mg,MA+MT5mg,and MA+MT10mg groups were pretreated with melatonin(2.5,5,10 mg/kg,i.g.,respectively)15 min before the MA injection(3 mg/kg,i.p.).The single intruder mouse was lightly placed into the resident mouse’s box 15 min after drug administration.Latency to initial attack(LIA),number of attacks(NA),and the total duration of attacks(TDA)were recorded were video recorded with a computer-controlled path-tracking system.The test for aggressive behaviors initiated by introducing an intruder mouse lasted for 15 min.High performance liquid chromatography with electrochemical detection(HPLC-ECD)was used to measure the concentrations of 5-HT,5-HIAA,DA,DOPAC,and HVAin the hippocampus of vehicle group,MA group and MA+MT 5mg group.2.135 methamphetamine-dependent patients from 3 voluntary drug rehabilitation hospitals in Wuhan,Hubei Province were randomly assigned to the control group(27 cases),the motivation group(26 cases),and the desensitization group(27 cases),melatonin group(27 cases),comprehensive group(28 cases)in the parallel controlled trial.The control group patients did not accept any other interventions except for the routine psychotropic medication and rehabilitation training.All other intervention groups received interventions based on routine psychotropic medication and rehabilitation training.In addition,the motivation group received motivational intensive treatment(precontemplation period,contemplation period,readiness period)for 90 minutes every day for 5 consecutive days;desensitization group received desensitization treatment for 90 minutes every day for 5 consecutive days(recalling plus rapid eye movement desensitization,NaiKan plus rapid eye movement desensitization,hypnosis desensitization,NLP changes memory element desensitization);melatonin group received melatonin(National Food Jianzi approval symbol)oral replenishment for 15 days,the supplemental dose is 6mg per day orally;The comprehensive group first received 5 days of motivational intensive treatment,followed by 5 days of desensitization treatment,and received melatonin for 15 days just like the melatonin intervention group while receiving the motivation and desensitization treatment.Before and after the intervention,the University of Rhode Island Change Assessment(URICA),The Addiction Memory Intensity Scale(AMIS),Self-rating Anxiety Scale(SAS),and Self-rating Depression Scale(SDS)were used to evaluate the motivation level,addiction memory intensity,negative emotion of the subjects and the attention bias and general response inhibition ability were evaluated before and after intervention by visual Dot-Probe and GO/NOGO of Event-Related Potentials(ERP)paradigm.The effects of intervention were evaluated by covariance analysis,logistic regression,generalized estimating equation and linear mixed effect model.3.318 methamphetamine-dependent patients from 5 coercionary isolation drug rehabilitation center in Wuhan,Hubei Province were randomly assigned to the control group(63 cases),the motivation group(64 cases),and the desensitization group(65 cases),melatonin group(63 cases),comprehensive group(63 cases)in the parallel controlled trial.Interventions were similar to those in voluntary drug rehabilitation hospitals,but the motivational interviews were improved combined with the motivation-based synthetic addiction theory developed by West and Brow.With more image information in order to help addicts to dig deeper things they care about the most,form a strong conflict with their addictive behaviors,and put the maximum tolerable pressure on the individual to make the change.And let them understand the gap between their desired goals and the consequences of continue drugs use,thereby,patients could seek important resources for continued drug addiction motivation.Before and after the intervention,Stage of change readiness and the treatment-eagerness scale(SOCRATES),AMIS,Irritability,Depression and Anxiety Scale(IDA)and Rosenberg Self-esteem Scale(RSES)were used to evaluate the motivation level,addiction memory intensity,negative emotion and self-esteem of the subjects.After the scores of pre-intervention in all the scales were adjusted by covariance analysis,the subgroup comparison was made by using Bonferroni method,which were statistically significant in group effects.Results1.Acute administration of MA(3 mg/kg,ip)resulted in increased aggression in male ICR mice with a decrease 5-HIAA and HVA concentrations in the hippocampus of mice;medium dose of melatonin(5 mg/kg,ig)pretreatment could significantly reduce LIA(P = 0.04)and decrease NA(P = 0.004)and TDA(P<0.001)in mice,and also increase 5-HIAA(P<0.001),DA(P = 0.015)and HVA(P<0.001)in mouse hippocampus.In addition,the melatonin(5 mg/kg,ig)pretreatment could increase the turnover of DA(HVA/DA,(DOPAC+HVA)/DA)and 5-HT(5-HIAA/5-HT)(P<0.001),especially reversed the 5-HIAA/5-HT ratio.2.Although the motivation scores of the patients in the voluntary drug rehabilitation hospitals were improved,there were no significant differences in the subscale(precontemplation period,contemplation period,readiness period)scores and total scores of the URICA after adjusting the pre-intervention scale score((P>0.05);After intervention,there were statistically significant differences of AMIS scores between the desensitization group((P=0.032)and the comprehensive group((P=0.032)compared to the control group;however,there were no significant differences among other three groups compared with the control group(P>0.05).There were no significant differences in SAS,SDS scores among the five groups after intervention((P=0.681;P=0.417).Desensitization group and comprehensive group had advantages in shortening patient response time under both in the consistent and inconsistent conditions(P<0.001),but it could not be considered that the visual Dot-Probe paradigm used in this study could test the difference in response time of patients between drug pictures and neutrality pictures.There was a statistically significant difference in the amplitude of P3 caused by neutral images before and after intervention(P=0.011).At the same time,there was a statistically significant difference in P3 amplitude between drug images and neutral images after intervention(P=0.035);The P3 latency of the desensitization group and the comprehensive group after intervention were shorter than those before the intervention,and the difference was statistically significant(P<0.001);The NOGO false rate after intervention in desensitization group was lower than that before intervention(P=0.01),however,the false rate of melatonin group was higher than that before intervention(P=0.04).There were no statistical differences in NOGO false rate before and after intervention in other groups((P>0.05);There were no significant differences in the NOGO-N2 amplitude and the incubation period among groups before and after intervention((P>0.05),but the NOGO-P3 amplitude of the comprehensive group was statistically different before and after intervention(P = 0.001).The incubation period of NOGO-P3 was significantly different between the control group and the desensitization group(P = 0.009;P = 0.002)before and after convention.The incubation period of NOGO-P3 was shorter than that before intervention in the desensitization group,however,the incubation period of NOGO-P3 was longer than before intervention in the control group.3.Patients who were in the compulsory isolation drug rehabilitation center also received intervention.The scores of the“taking steps”motivation stage after intervention were higher than those of the control group,desensitization group and melatonin group((P=0.012;P=0.008;/P=0.001);The scores of AMIS in the desensitization group and the comprehensive group were lower than those in the control group,and the differences were statistically significant(P<0.001).There was no significant difference in scores of depression,anxiety,extro-irritation and intro-irritation before and after intervention in each group((P=0.208;P=0.221;P=0.107;P=0.328);The RSES scores of the desensitization group and the comprehensive group after intervention were higher than those of the control group,the difference was statistically significant((P=0.029;/P=0.006).Conclusions1.Melatonin(5mg/kg,i.g.)pretreatment can reverse acute methamphetamine-induced aggressive behavior,and DA and 5-HT systems were involved in the processing of aggressive behavior.2.The comprehensive motivation model of"motivation-desensitization-neurotransmitter regulation"could effectively reduce the memory intensity of addiction in patients with methamphetamine dependence and improve the general response inhibition ability of patients in voluntary drug rehabilitation hospitals.At the same time,this intervention model could also improve motivation and self-esteem level of patients in the coercionary isolation drug rehabilitation centers. |
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