| Background Ketamine is a derivative of phencyclidine(PCP).The main pharmacological mechanism of ketamine is a non-competitive antagonist of N-methyl-D-aspartate(NMDA)receptors.Ketamine was introduced into China in 1990 s and has become one of the most commonly abused drugs among young people.Numerous studies have shown that ketamine can impair cognitive function.Healthy volunteers showed impairments in the domain of memory recall,recognition,attention,verbal memory,episodic memory,semantic memory and working memory after receiving rapid intravenous injection of ketamine,as well as identification memory,procedural learning,response inhibition,sensorimotor information processing and language processing,while perceptual priming and executive function were not affected.Studies also demonstrated cognitive dysfunction among ketamine abusers.Brain-derived neurotrophic factor(BDNF)plays an important role in synaptic plasticity,learning and memory.Neural growth factor(NGF)can promote the development of the nervous system and enhance synaptic plasticity,neuronal nutrition and neurite outgrowth.Ketamine induced alterations of BDNF and NGF levels in various rat brain areas.Ricci et al found elevated serum BDNF levels among ketamine abusers,while NGF level did not change.BDNF Val66 Met polymorphism does not affect the mature protein function,but it can alter the intracellular pro-BDNF processing and mature BDNF adhesion to secretory granules,which influences the secretion of mature BDNF,as well as the human hippocampus and prefrontal cortex anatomy structure and cognitive function,such as memory.Studies revealed that this polymorphism was associated with heroin dependence and methamphetamine abuse,but no association with alcohol and tobacco dependence was found.There are no researches about relationship between ketamine dependence and BDNF Val66 Met polymorphism.The studies of ketamine effect on BDNF and NGF are confined to animals.Although Ricci’s team has investigated the alteration of serum BDNF and NGF levels among ketamine users,the participants are poly-substance abusers,which is the same as cognition studies.These are confounding factors that can’t be ignored.The relationship between cognitive dysfunction and altered serum neurotrophic factor levels has not been reported yet among ketamine dependent users,despite the current studies on these two respective issues.The BDNF Val66 Met polymorphism may affect BDNF levels and cognitive functions.It is unknown whether the variation of this polymorphism in ketamine abusers could affect the serum BDNF level and cognitive function.Part One Study on cognitive function in ketamine-dependent patientsAims To explore cognitive alteration in ketamine-dependent patients,and clarify the influencing factors on cognitive function.Methods Sixty-three chronic ketamine users and 65 healthy subjects were recruited.Cognitive function was assessed by using immediate/delayed visual reproduction tasks,immediate/delayed logical memory tasks,the Stroop test,the Wisconsin card sorting test(WCST),and the continuous performance test(CPT).Psychological symptoms were assessed with the Positive and Negative Syndrome Scale(PANSS),Beck Depression Inventory(BDI)and Beck Anxiety Inventory(BAI).BDNF Val66 Met polymorphism was measured with immunofluorescence polymerase chain reaction(PCR).Factorial ANOVA was implemented to compare the cognitive function between the two groups with alcohol and tobacco consumption as stratification factors.One-way ANOVA or Kruskal-Wallis rank-sum test was employed to analyse differences on demographics,psychological rating,serum neurotrophin levels and cognition between ketamine-dependent users with three different genotypes.Correlations were analyzed between cognition and age,education level,characteristics of ketamine users and psychopathological scores.Multiple linear regression models were developed using a stepwise method to analyze the linear association between cognitive function and a set of exploratory variables that emerged as significant in the correlation analyses described above,including age,education level,ketamine usage characteristics and psychopathological variables.Results The two groups differed significantly on the scores of immediate visual reproduction test,delayed visual reproduction test,immediate logical memory test,delayed logical memory test,word reading,color interference reading,auditory missed hits and average auditory response time.No significant differences were found in the main effects of alcohol and tobacco consumption.No statistically significant interaction between the three factors was found.Significant differences on color interference reading score were found between group with AA genotype and GG genotype(p=0.006).The multiple linear regression results showed that the immediate visual reproduction score was affected by the education level(F=5.074,p=0.028).The higher the education level,the higher the immediate visual reproduction score(β=0.277,p=0.028).The delayed visual reproduction score was affected by the education level(F=5.637,p=0.021).The higher the education level,the higher the delayed visual reproduction score(β=0.291,p=0.021).The immediate logical memory score was affected by the PANSS negative symptom score(F=7.099,p=0.010).The more severe the negative symptom,the lower the immediate logical memory score(β=-0.323,p=0.010).The delayed logical memory score was affected by the PANSS negative symptom score(F=6.003,p=0.017).The more severe the negative symptom,the lower the delayed logical memory score(β=-0.299,p=0.017).Stroop color naming score was affected by the education level(F=4.358,p=0.041).The higher the education level,the higher the color naming score(β=0.260,p=0.041).Stroop word reading score was affected by the education level and duration of ketamine use(F=5.310,p=0.008).The higher the education level,the higher the word reading score(β=0.255,p=0.038).The shorter the duration of ketamine use,the higher the word reading score(β=-0.277,p=0.025).The duration of ketamine use affected the word reading score most according to the standard partial regression coefficient.Stroop color interference reading score was affected by the education level(F=4.613,p=0.036).The higher the education level,the higher the color interference reading score(β=0.267,p=0.036).Auditory CPT false hits score was affected by the duration of ketamine use(F=5.260,p=0.026).The longer the duration of ketamine use,the higher the auditory CPT false hits score(β=0.293,p=0.026).Conclusions(1)Ketamine addicts had cognitive impairments in the domains of episodic memory(including visual and verbal memory),selective attention(response inhibition)and auditory sustained attention.(2)The higher the education level,the better the visual memory,selective attention,response inhibition and the auditory sustained attention in ketaminedependent patients.The longer the ketamine use,the worse the selective attention and auditory sustained attention.The more severe the negative symptom,the worse the verbal memory.(3)AA genotype of BDNF Val66 Met polymorphism may be the risk factor for ketamine-dependent uses with respect to the response inhibiton function.Part Two Study on serum BDNF and NGF levels in ketamine-dependent patientsAims To explore serum BDNF and NGF levels in ketamine-dependent patients,and clarify the relationship between cognitive dysfunction and altered serum neurotrophic factor levels,and influencing factors on serum concentration of neurotrophic factors.Methods Ninety-three chronic ketamine users and 41 healthy subjects were recruited.Serum BDNF and NGF levels were assayed by enzyme-linked immunosorbent assay(ELISA).Psychological symptoms were assessed with the Positive and Negative Syndrome Scale(PANSS),Beck Depression Inventory(BDI)and Beck Anxiety Inventory(BAI).Some ketamine users received cognition tests.Factorial ANOVA was implemented to compare the neurotrophic factor levels between the two groups with alcohol and tobacco consumption as stratification factors.Correlations were analyzed between the neurotrophic factor level and cognition,education level,characteristics of ketamine users and psychopathological scores.Multiple linear regression models were developed using a stepwise method to analyze the linear association between the neurotrophic factor level and a set of exploratory variables that emerged as significant in the correlation analyses described above,including education level,ketamine usage characteristics and psychopathological variables.Results The two groups differed significantly on the BDNF and NGF concentration.No significant differences were found in the main effects of alcohol and tobacco consumption.No statistically significant interaction between the three factors was found.Correlation analyses displayed no significant correlation coefficients between the cognitive function and neurotrophic factor levels.The multiple linear regression results showed that the BDNF level was affected by the frequency of ketamine use and PANSS positive symptom(F=13.517,p<0.001).The lower the frequency of ketamine use,the higher the BDNF level(β=-0.192,p=0.042).The more severe the PANSS positive symptom,the higher the BDNF level(β=0.446,p<0.001).The PANSS positive symptom affected the BDNF level most according to the standard partial regression coefficient.Conclusions(1)Serum BDNF and NGF levels decreased in ketamine-dependent patients.(2)Impaired cognitive function in patients with ketamine dependence may not be related to the altered serum levels of neurotrophic factors.(3)Decrement of BDNF level correlates with the high frequency of ketamine use.The lower BDNF level is associated with the milder positive symptom.Part Three Association of brain-derived neurotrophic factor Val66 Met single nucleotide polymorphism with ketamine dependenceAims To explore association of BDNF Val66 Met polymorphism with ketamine dependence.Methods Seventy-six ketamine addicts were recruited and their BDNF Val66 Met polymorphism was measured and compared with 90 healthy subjects by employing immunofluorescence polymerase chain reaction.Serum BDNF and NGF levels were assayed by enzyme-linked immunosorbent assay(ELISA).Results The distribution of the BDNF Val66 Met genotypes in ketamine-dependent patients(χ2=1.839,p>0.05)and healthy controls(χ2=3.795,p>0.05)was in Hardy–Weinberg equilibrium.No significant difference in Val66 Met allele distribution was found between two groups(χ2=1.173,p=0.279),while difference in the genotype distribution is significant(χ2=6.595,p=0.037).Ketamine consumption characteristics(including age at first ketamine use,total months of ketamine use,frequency and daily dose of current ketamine use),depressive symptoms and serum NGF concentration did not differ significantly(p>0.05)between genotypic grouping among ketamine-dependent patients,while serum BDNF level differed significantly(χ2=18.586,p<0.001).Differences on BDNF level between AA and GG genotype carriers(Z=-3.399,p=0.001),GA and GG genotype carriers(Z=-3.974,p<0.001)were significant.Conclusions The BDNF Val66 Met genotype distribution differs between ketamine-dependent patients and healthy subjects,while the allele distribution does not.The serum BDNF level of carriers with GG genotype is higher than that with GA and AA genotypes among ketamine-dependent users.The ketamine use characteristics,depressive symptoms and serum NGF level does not differ between various genotypic grouping among ketamine-dependent patients. |
