human
***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: AIMS Animal studies have shown that nicotine releases dopamine , a neurotransmitter implicated in drug reinforcement . We hypothesized that bromocriptine would decrease smoking behavior in humans . DESIGN The study was conducted double blind and subjects ' order of dose exposure was r and omized . PARTICIPANTS The smoking behavior of 20 heavy smokers was recorded for 5 hours after ingesting placebo or one of two doses of bromocriptine ( 2.50 mg , 3.75 mg ) over three sessions ( one dose per session ) . FINDINGS There was a significant negative linear trend by dosage indicating shorter total puffing time with increasing bromocriptine dosages ( p < 0.02 ) . Other significant negative linear trends by increasing dosage include fewer number of puffs , fewer number of cigarettes smoked and mean latency to smoke after 3 hours ( expected CMAX on the drug ( all ps < 0.05 ) . There was a negative significant linear trend showing decreased plasma nicotine ( p < 0.02 ) and cotinine ( p < 0.005 ) with increasing dosages of bromocriptine . Shiffman/Jarvik Withdrawal Scale ( SJWS ) cigarette craving subscale scores decreased significantly across increasing dosages ( linear trend p < 0.02 ) . There was a significant negative linear trend ( p < 0.05 ) on the Profile of Mood States ( POMS ) Vigor and Depression subscales , with subjects reporting decreased vigor and depression with increasing bromocriptine doses . No other mood effects were observed . CONCLUSION These results support the hypothesis that dopaminergic mechanisms mediate cigarette smoking reinforcement Recent studies have suggested that heterogeneity in the level of dopamine activity and function might be useful for identifying a subgroup of cocaine-dependent patients responding better to dopamine-enhancement pharmacotherapy . Here we hypothesized that response to levodopa/carbidopa treatment would be greater in patients with genetically determined low levels of the dopamine metabolizing enzyme dopamine & bgr;-hydroxylase ( D&bgr;H ) . Seventy-one cocaine-dependent patients who participated in a 12-week r and omized double-blind placebo-controlled trial of levodopa/carbidopa  were genotyped for the D&bgr;H gene ( DBH ) polymorphism rs1611115 . Our results showed that for patients with the low D&bgr;H activity genotypes ( CT/TT ) who received levodopa , the odds of having cocaine-positive urine decreased significantly over treatment compared with placebo-treated patients with the CT/TT genotypes ( P=0.004 ) . Individuals with the normal D&bgr;H activity genotype ( CC ) showed no differential response to levodopa . These preliminary results need to be confirmed in a larger sample focusing on the DBH polymorphism Separate investigations have suggested that olanzapine , a D4 antagonist , decreases craving after a priming dose of alcohol and that the DRD4 variable number of t and em repeats ( VNTR ) polymorphism influences the expression of craving after a priming dose of alcohol . The present study tested the hypothesis that olanzapine may be differentially effective at reducing cue-elicited craving based on individual differences in DRD4 VNTR in a sample of heavy social drinkers . Participants were r and omly assigned to receive olanzapine ( 5 mg ) or a control medication ( cyproheptadine , 4 mg ) prior to consuming three alcoholic drinks . Participants completed subjective measures of craving and euphoria after each drink . Participants who were homozygous or heterozygous for the 7 ( or longer ) repeat allele of the DRD4 VNTR were classified as DRD4 L , while the other participants were classified as DRD4 S. The findings indicated that olanzapine reduces craving for alcohol at baseline for both DRD4 S and DRD4 L individuals , but only reduces craving after exposure to alcohol cues and after a priming dose of alcohol for DRD4 L individuals Disulfiram ( Antabuse ) is being used in outpatient clinical trials to determine its efficacy as a treatment for cocaine dependence . This inpatient r and omized , double-blind , placebo-controlled , within-subjects study was conducted to determine whether disulfiram ( placebo , 250 or 500 mg/day ) alters responses to acute intranasal cocaine ( placebo , 1 or 2 mg/kg ) administration . Effects of disulfiram on cocaine pharmacokinetics , physiological , and behavioral responses were determined . Disulfiram treatment increased plasma cocaine concentrations three to six times and significantly increased cocaine-associated cardiovascular responses , but did not significantly alter behavioral responses to cocaine . These interactions should be considered in the decision regarding disulfiram treatment in cocaine dependent patients Objectives To examine survival and long term cessation of injecting in a cohort of drug users and to assess the influence of opiate substitution treatment on these outcomes . Design Prospect i ve open cohort study . Setting A single primary care facility in Edinburgh . Participants 794 patients with a history of injecting drug use presenting between 1980 and 2007 ; 655 ( 82 % ) were followed up by interview or linkage to primary care records and mortality register  , or both , and contributed 10 390 person years at risk ; 557 ( 85 % ) had received opiate substitution treatment .  Main outcome measures Duration of injecting : years from first injection to long term cessation , defined as last injection before period of five years of non-injecting ; mortality before cessation ; overall survival . Results In the entire cohort 277 participants achieved long term cessation of injecting , and 228 died . Half of the survivors had poor health related quality of life . Median duration from first injection to death was 24 years for participants with HIV and 41 years for those without HIV . For each additional year of opiate substitution treatment the hazard of death before long term cessation fell 13 % ( 95 % confidence interval 17 % to 9 % ) after adjustment for HIV , sex , calendar period , age at first injection , and history of prison and overdose . Conversely exposure to opiate substitution treatment was inversely related to the chances of achieving long term cessation . Conclusions Opiate substitution treatment in injecting drug users in primary care reduces this risk of mortality , with survival benefits increasing with cumulative exposure to treatment . Treatment does not reduce the overall duration of injecting Objective To investigate the effect of opiate substitution treatment at the beginning and end of treatment and according to duration of treatment . Design Prospect i ve cohort study . Setting UK General Practice Research Data base Participants Primary care patients with a diagnosis of substance misuse prescribed methadone or buprenorphine during 1990 - 2005 . 5577 patients with 267 003 prescriptions for opiate substitution treatment followed-up ( 17 732 years ) until one year after the expiry of their last prescription , the date of death before this time had elapsed , or the date of transfer away from the practice . Main outcome measures Mortality rates and rate ratios comparing periods in and out of treatment adjusted for sex , age , calendar year , and comorbidity ; st and ardised mortality ratios comparing opiate users ’ mortality with general population mortality rates . Results Crude mortality rates were 0.7 per 100 person years on opiate substitution treatment and 1.3 per 100 person years off treatment ; st and ardised mortality ratios were 5.3 ( 95 % confidence interval 4.0 to 6.8 ) on treatment and 10.9 ( 9.0 to 13.1 ) off treatment . Men using opiates had approximately twice the risk of death of women ( morality rate ratio 2.0 , 1.4 to 2.9 ) . In the first two weeks of opiate substitution treatment the crude mortality rate was 1.7 per 100 person years : 3.1 ( 1.5 to 6.6 ) times higher ( after adjustment for sex , age group , calendar period , and comorbidity ) than the rate during the rest of time on treatment . The crude mortality rate was 4.8 per 100 person years in weeks 1 - 2 after treatment stopped , 4.3 in weeks 3 - 4 , and 0.95 during the rest of time off treatment : 9 ( 5.4 to 14.9 ) , 8 ( 4.7 to 13.7 ) , and 1.9 ( 1.3 to 2.8 ) times higher than the baseline risk of mortality during treatment . Opiate substitution treatment has a greater than 85 % chance of reducing overall mortality among opiate users if the average duration approaches or exceeds 12 months . Conclusions Clinicians and patients should be aware of the increased mortality risk at the start of opiate substitution treatment and immediately after stopping treatment . Further research is needed to investigate the effect of average duration of opiate substitution treatment on drug related mortality G*Power is a free power analysis program for a variety of statistical tests . We present extensions and improvements of the version introduced by Faul , Erdfelder , Lang , and Buchner ( 2007 ) in the domain of correlation and regression analyses . In the new version , we have added procedures to analyze the power of tests based on ( 1 ) single- sample tetrachoric correlations , ( 2 ) comparisons of dependent correlations , ( 3 ) bivariate linear regression , ( 4 ) multiple linear regression based on the r and om predictor model , ( 5 ) logistic regression  , and ( 6 ) Poisson regression . We describe these new features and provide a brief introduction to their scope and h and ling An A118 G nucleotide exchange in exon 1 of the mu-opioid receptor causes an Asn40Asp substitution polymorphism in the receptor 's extracellular domain . In vitro studies show that the Asp40 variant of the mu-opioid receptor binds β-endorphin three times more avidly than the more common Asn40 variant . Paraventricular corticotropin releasing hormone neurons , which activate the HPA axis , express mu-opioid receptors and are modulated by β-endorphin neurons . This preliminary study was design ed to test the hypothesis that the Asn40Asp substitution polymorphism in the mu-opioid receptor influences HPA axis activation induced by opioid receptor blockade . Thirty-nine healthy men were genotyped ( A vs. G ) and then underwent opioid receptor blockade with Naloxone . Subjects expressing the A118 G receptor variant had greater cortisol responses to opioid receptor blockade . Also , a significant difference in the rate of increase of ACTH ( slope ) between A/A and A/G was observed between 30–90 minutes as well as a significant difference in the rate of decrease after 90 minutes . Moreover , subjects expressing the variant polymorphism had lower scores on the Conscientiousness Factor and associated subscales of NEO Personality Inventory compared to subjects expressing the common receptor . Because serotonin also modulates the CRF neuron , subjects were genotyped for a functional polymorphism within the serotonin transporter gene . We did not see differences in hormone responses result ing from expression of this functional polymorphism . It is plausible that persons expressing the mu-opioid receptor variant have altered HPA axis dynamics and altered responses to other physiological processes regulated through activation of the mu-opioid receptor Aim Addictive behavior is importantly mediated by mesolimbic dopaminergic signaling . Here , we comprehensively analyzed the DRD2 gene locus , and in addition , the ANKK1 rs1800497C > T single nucleotide polymorphism ( SNP ) , formerly known as ‘ dopamine D2 receptor Taq1A C > T polymorphism ' , for associations with the risk of opiate addiction and the methadone dosage requirements . Methods Allelic frequencies of  DRD2/ANKK1  polymorphisms were compared between 85 methadone-substituted Caucasian patients and a r and om sample of 99 healthy Caucasian controls . Within patients , the average and maximum daily methadone dose during the first year of treatment and the time when that maximum dose was reached were analyzed for an association with DRD2/ANKK1 genetics . Results Compared with the control group , drug users carried more frequently the minor allele of DRD2 SNP rs1076560G > T SNP ( P=0.022 , odds ratio 2.343 ) or the ATCT haplotype of DRD2 rs1799978A > G , rs1076560G > T , rs6277C > T , ANKK1 rs1800497C > T ( P=0.048 , odds ratio 2.23 ) , with similar tendencies for ANKK1 rs1800497C > T ( P=0.056 , odds ratio 2.12 ) and the TCCTCTT haplotype of DRD2 rs12364283T > C , rs1799732C del , rs4648317C > T , rs1076560G > T , rs6275C > T , rs6277C > T , and ANKK1 rs1800497C > T ( P=0.059 , odds ratio 2.31 ) . The average and maximum daily methadone doses were significantly associated with the DRD2 rs6275C > T SNP ( P=0.016 and 0.005 for average and maximum dose , respectively ) . Carriers of the variant rs6275 T allele needed higher methadone doses than noncarriers . In addition , this variant was associated with a longer time to reach the maximum methadone dose 
    Output:
    
agent
Polymorphisms of the DRD2 , ANKK1 , DAT1 , DBH , and DRD4 genes have been found to moderate the effects of pharmacotherapy  of alcohol , opioid , and cocaine use disorders .
The integration of genetic information with clinical data will inform health professionals of the most efficacious pharmacotherapeutic intervention for substance use disorders .
***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: AIMS Animal studies have shown that nicotine releases dopamine , a neurotransmitter implicated in drug reinforcement . We hypothesized that bromocriptine would decrease smoking behavior in humans . DESIGN The study was conducted double blind and subjects ' order of dose exposure was r and omized . PARTICIPANTS The smoking behavior of 20 heavy smokers was recorded for 5 hours after ingesting placebo or one of two doses of bromocriptine ( 2.50 mg , 3.75 mg ) over three sessions ( one dose per session ) . FINDINGS There was a significant negative linear trend by dosage indicating shorter total puffing time with increasing bromocriptine dosages ( p < 0.02 ) . Other significant negative linear trends by increasing dosage include fewer number of puffs , fewer number of cigarettes smoked and mean latency to smoke after 3 hours ( expected CMAX on the drug ( all ps < 0.05 ) . There was a negative significant linear trend showing decreased plasma nicotine ( p < 0.02 ) and cotinine ( p < 0.005 ) with increasing dosages of bromocriptine . Shiffman/Jarvik Withdrawal Scale ( SJWS ) cigarette craving subscale scores decreased significantly across increasing dosages ( linear trend p < 0.02 ) . There was a significant negative linear trend ( p < 0.05 ) on the Profile of Mood States ( POMS ) Vigor and Depression subscales , with subjects reporting decreased vigor and depression with increasing bromocriptine doses . No other mood effects were observed . CONCLUSION These results support the hypothesis that dopaminergic mechanisms mediate cigarette smoking reinforcement Recent studies have suggested that heterogeneity in the level of dopamine activity and function might be useful for identifying a subgroup of cocaine-dependent patients responding better to dopamine-enhancement pharmacotherapy . Here we hypothesized that response to levodopa/carbidopa treatment would be greater in patients with genetically determined low levels of the dopamine metabolizing enzyme dopamine & bgr;-hydroxylase ( D&bgr;H ) . Seventy-one cocaine-dependent patients who participated in a 12-week r and omized double-blind placebo-controlled trial of levodopa/carbidopa  were genotyped for the D&bgr;H gene ( DBH ) polymorphism rs1611115 . Our results showed that for patients with the low D&bgr;H activity genotypes ( CT/TT ) who received levodopa , the odds of having cocaine-positive urine decreased significantly over treatment compared with placebo-treated patients with the CT/TT genotypes ( P=0.004 ) . Individuals with the normal D&bgr;H activity genotype ( CC ) showed no differential response to levodopa . These preliminary results need to be confirmed in a larger sample focusing on the DBH polymorphism Separate investigations have suggested that olanzapine , a D4 antagonist , decreases craving after a priming dose of alcohol and that the DRD4 variable number of t and em repeats ( VNTR ) polymorphism influences the expression of craving after a priming dose of alcohol . The present study tested the hypothesis that olanzapine may be differentially effective at reducing cue-elicited craving based on individual differences in DRD4 VNTR in a sample of heavy social drinkers . Participants were r and omly assigned to receive olanzapine ( 5 mg ) or a control medication ( cyproheptadine , 4 mg ) prior to consuming three alcoholic drinks . Participants completed subjective measures of craving and euphoria after each drink . Participants who were homozygous or heterozygous for the 7 ( or longer ) repeat allele of the DRD4 VNTR were classified as DRD4 L , while the other participants were classified as DRD4 S. The findings indicated that olanzapine reduces craving for alcohol at baseline for both DRD4 S and DRD4 L individuals , but only reduces craving after exposure to alcohol cues and after a priming dose of alcohol for DRD4 L individuals Disulfiram ( Antabuse ) is being used in outpatient clinical trials to determine its efficacy as a treatment for cocaine dependence . This inpatient r and omized , double-blind , placebo-controlled , within-subjects study was conducted to determine whether disulfiram ( placebo , 250 or 500 mg/day ) alters responses to acute intranasal cocaine ( placebo , 1 or 2 mg/kg ) administration . Effects of disulfiram on cocaine pharmacokinetics , physiological , and behavioral responses were determined . Disulfiram treatment increased plasma cocaine concentrations three to six times and significantly increased cocaine-associated cardiovascular responses , but did not significantly alter behavioral responses to cocaine . These interactions should be considered in the decision regarding disulfiram treatment in cocaine dependent patients Objectives To examine survival and long term cessation of injecting in a cohort of drug users and to assess the influence of opiate substitution treatment on these outcomes . Design Prospect i ve open cohort study . Setting A single primary care facility in Edinburgh . Participants 794 patients with a history of injecting drug use presenting between 1980 and 2007 ; 655 ( 82 % ) were followed up by interview or linkage to primary care records and mortality register  , or both , and contributed 10 390 person years at risk ; 557 ( 85 % ) had received opiate substitution treatment .  Main outcome measures Duration of injecting : years from first injection to long term cessation , defined as last injection before period of five years of non-injecting ; mortality before cessation ; overall survival . Results In the entire cohort 277 participants achieved long term cessation of injecting , and 228 died . Half of the survivors had poor health related quality of life . Median duration from first injection to death was 24 years for participants with HIV and 41 years for those without HIV . For each additional year of opiate substitution treatment the hazard of death before long term cessation fell 13 % ( 95 % confidence interval 17 % to 9 % ) after adjustment for HIV , sex , calendar period , age at first injection , and history of prison and overdose . Conversely exposure to opiate substitution treatment was inversely related to the chances of achieving long term cessation . Conclusions Opiate substitution treatment in injecting drug users in primary care reduces this risk of mortality , with survival benefits increasing with cumulative exposure to treatment . Treatment does not reduce the overall duration of injecting Objective To investigate the effect of opiate substitution treatment at the beginning and end of treatment and according to duration of treatment . Design Prospect i ve cohort study . Setting UK General Practice Research Data base Participants Primary care patients with a diagnosis of substance misuse prescribed methadone or buprenorphine during 1990 - 2005 . 5577 patients with 267 003 prescriptions for opiate substitution treatment followed-up ( 17 732 years ) until one year after the expiry of their last prescription , the date of death before this time had elapsed , or the date of transfer away from the practice . Main outcome measures Mortality rates and rate ratios comparing periods in and out of treatment adjusted for sex , age , calendar year , and comorbidity ; st and ardised mortality ratios comparing opiate users ’ mortality with general population mortality rates . Results Crude mortality rates were 0.7 per 100 person years on opiate substitution treatment and 1.3 per 100 person years off treatment ; st and ardised mortality ratios were 5.3 ( 95 % confidence interval 4.0 to 6.8 ) on treatment and 10.9 ( 9.0 to 13.1 ) off treatment . Men using opiates had approximately twice the risk of death of women ( morality rate ratio 2.0 , 1.4 to 2.9 ) . In the first two weeks of opiate substitution treatment the crude mortality rate was 1.7 per 100 person years : 3.1 ( 1.5 to 6.6 ) times higher ( after adjustment for sex , age group , calendar period , and comorbidity ) than the rate during the rest of time on treatment . The crude mortality rate was 4.8 per 100 person years in weeks 1 - 2 after treatment stopped , 4.3 in weeks 3 - 4 , and 0.95 during the rest of time off treatment : 9 ( 5.4 to 14.9 ) , 8 ( 4.7 to 13.7 ) , and 1.9 ( 1.3 to 2.8 ) times higher than the baseline risk of mortality during treatment . Opiate substitution treatment has a greater than 85 % chance of reducing overall mortality among opiate users if the average duration approaches or exceeds 12 months . Conclusions Clinicians and patients should be aware of the increased mortality risk at the start of opiate substitution treatment and immediately after stopping treatment . Further research is needed to investigate the effect of average duration of opiate substitution treatment on drug related mortality G*Power is a free power analysis program for a variety of statistical tests . We present extensions and improvements of the version introduced by Faul , Erdfelder , Lang , and Buchner ( 2007 ) in the domain of correlation and regression analyses . In the new version , we have added procedures to analyze the power of tests based on ( 1 ) single- sample tetrachoric correlations , ( 2 ) comparisons of dependent correlations , ( 3 ) bivariate linear regression , ( 4 ) multiple linear regression based on the r and om predictor model , ( 5 ) logistic regression  , and ( 6 ) Poisson regression . We describe these new features and provide a brief introduction to their scope and h and ling An A118 G nucleotide exchange in exon 1 of the mu-opioid receptor causes an Asn40Asp substitution polymorphism in the receptor 's extracellular domain . In vitro studies show that the Asp40 variant of the mu-opioid receptor binds β-endorphin three times more avidly than the more common Asn40 variant . Paraventricular corticotropin releasing hormone neurons , which activate the HPA axis , express mu-opioid receptors and are modulated by β-endorphin neurons . This preliminary study was design ed to test the hypothesis that the Asn40Asp substitution polymorphism in the mu-opioid receptor influences HPA axis activation induced by opioid receptor blockade . Thirty-nine healthy men were genotyped ( A vs. G ) and then underwent opioid receptor blockade with Naloxone . Subjects expressing the A118 G receptor variant had greater cortisol responses to opioid receptor blockade . Also , a significant difference in the rate of increase of ACTH ( slope ) between A/A and A/G was observed between 30–90 minutes as well as a significant difference in the rate of decrease after 90 minutes . Moreover , subjects expressing the variant polymorphism had lower scores on the Conscientiousness Factor and associated subscales of NEO Personality Inventory compared to subjects expressing the common receptor . Because serotonin also modulates the CRF neuron , subjects were genotyped for a functional polymorphism within the serotonin transporter gene . We did not see differences in hormone responses result ing from expression of this functional polymorphism . It is plausible that persons expressing the mu-opioid receptor variant have altered HPA axis dynamics and altered responses to other physiological processes regulated through activation of the mu-opioid receptor Aim Addictive behavior is importantly mediated by mesolimbic dopaminergic signaling . Here , we comprehensively analyzed the DRD2 gene locus , and in addition , the ANKK1 rs1800497C > T single nucleotide polymorphism ( SNP ) , formerly known as ‘ dopamine D2 receptor Taq1A C > T polymorphism ' , for associations with the risk of opiate addiction and the methadone dosage requirements . Methods Allelic frequencies of  DRD2/ANKK1  polymorphisms were compared between 85 methadone-substituted Caucasian patients and a r and om sample of 99 healthy Caucasian controls . Within patients , the average and maximum daily methadone dose during the first year of treatment and the time when that maximum dose was reached were analyzed for an association with DRD2/ANKK1 genetics . Results Compared with the control group , drug users carried more frequently the minor allele of DRD2 SNP rs1076560G > T SNP ( P=0.022 , odds ratio 2.343 ) or the ATCT haplotype of DRD2 rs1799978A > G , rs1076560G > T , rs6277C > T , ANKK1 rs1800497C > T ( P=0.048 , odds ratio 2.23 ) , with similar tendencies for ANKK1 rs1800497C > T ( P=0.056 , odds ratio 2.12 ) and the TCCTCTT haplotype of DRD2 rs12364283T > C , rs1799732C del , rs4648317C > T , rs1076560G > T , rs6275C > T , rs6277C > T , and ANKK1 rs1800497C > T ( P=0.059 , odds ratio 2.31 ) . The average and maximum daily methadone doses were significantly associated with the DRD2 rs6275C > T SNP ( P=0.016 and 0.005 for average and maximum dose , respectively ) . Carriers of the variant rs6275 T allele needed higher methadone doses than noncarriers . In addition , this variant was associated with a longer time to reach the maximum methadone dose 
    Output:
    