中老年人体成分与骨密度的相关性研究

目的:研究中国天津地区中老年男性和女性骨密度(BMD)与年龄、BMI、脂肪量(FM)、非脂肪量(FFM)、腹部脂肪含量(ABDFM)的关系。方法:选择中老年男性82例,用双能X线吸收测量法(DXA)测量腰椎2￣4(L2￣4)BMD、全身BMD和体成分,并与中老年女性106例做对照比较。结果:(1)FM、FFM、ABDFM、BMI与中老年男性和女性BMD均呈显著正相关,年龄与BMD呈负相关;(2)多元线性回归分析显示,FFM是影响中老年男性BMD变化的主要决定因素;而FM是影响中老年女性BMD变化的主要决定因素;ABDFM可能影响中老年女性的L2￣4BMD。结论:中老年人的FM、FFM均与BMD呈正相关,并且具有性别差异;ABDFM与BMD有关,故腹型肥胖可能对L2￣4BMD有保护作用。     

桑叶黄酮对糖尿病小鼠降血糖作用的研究

目的研究桑叶黄酮的降血糖作用。方法采用腹腔注射四氧嘧啶复制小鼠糖尿病模型,造模成功后分为模型组、桑叶黄酮3个剂量组,并设正常对照组。每天分别灌胃给予蒸馏水、桑叶黄酮1.00、0.50、0.25g.kg-1体重,连续6周,每周称重1次;在实验2、4和6周末各测空腹血糖1次;实验末期进行糖耐量实验。结果桑叶黄酮能明显缓解糖尿病小鼠症状,具有明显控制糖尿病小鼠空腹血糖值升高、降低其血糖值和血糖曲线下面积的作用,糖尿病小鼠肝体比、肾脏重和肾体比均增高,而桑叶黄酮具有使其降低的作用。结论桑叶黄酮具有明显的降低血糖,改善糖尿病症状,降低肝体比的作用。     

Basal metabolic rate and body composition in elderly Indian males

Aging is associated with a decline in basal metabolic rate (BMR) and total energy expenditure. The extent to which changes in fat free mass (FFM) alone, explains the reduction in BMR is still unresolved. In this study, we documented changes in body composition and evaluated its contribution to measured BMR in young and elderly Indian subjects. We compared 16 healthy elderly male subjects in the age group of 60-75 years with 16 Body Mass Index (kg/m2) matched controls in the age group of 18-25 years. Body composition measurements were determined by using multiple skinfolds and bio-impedence method. BMR measured by indirect calorimetry. The % fat and fat free mass was significantly different between two groups. There were significant difference in BMR between elderly and control group (elderly, 5.91 +/- 0.54 vs control; 7.08 +/- 0.65 MJ/day, P < 0.001), which disappeared when corrected for FFM. This suggests that the age related decrease in the BMR is related to the absolute decrease in the FFM in the elderly without any change in the metabolic activity per kg FFM.     

多囊卵巢综合征患者静息能量消耗与非脂体质相关性

目的探讨多囊卵巢综合征（PCOS）患者的静息能量消耗与非脂体质（FFM）的关系。方法 20例P-COS患者为PCOS组,20例健康者为对照组,比较2组的静息能量消耗（REE）、体脂（FAT）、FFM、血脂谱、胰岛素抵抗指数（HOMA-IR）及C反应蛋白（CRP）。结果 PCOS组的FAT、血脂谱、HOMA-IR及CRP明显高于对照组,REE和FFM明显低于对照组,差异有统计学意义（P〈0.05）。2组间REE/FFM比较差异无统计学意义（P〉0.05）。结论 PCOS患者REE下降与患者的体脂增加有关。     

Relationships between body composition parameters and fluorouracil pharmacokinetics

AIMS: To verify whether fluorouracil (FU) clearance (CL) and volume of distribution (V(ss)) are better correlated with specific body compartments, such as body cell mass (BCM), total body water (TBW) or fat free mass (FFM), rather than with body surface area (BSA) or total body weight (BW). METHODS: Thirty-four patients (13 females and 21 males) affected by colorectal cancer and receiving FU as adjuvant therapy entered the study. CL and Vss were determined after a 2 min i.v. injection of FU (425 mg m(-2)) and leucovorin (20 mg m(-2)). Body composition, in terms of BCM, TBW and FFM, was evaluated non-invasively by bioelectrical impedance analysis (BIA). RESULTS: Significant but poor correlations were found between CL or V(ss) and most anthropometric parameters, including BIA-derived measures (r2 range=0.10-0.21). However, when multiple regression analysis was performed with sex, TBW and FFM as independent variables, the correlations improved greatly. The best correlation was obtained between CL and sex (r2=0.44) and between V(ss) and sex (r2=0.36). FFM-normalized CL was significantly higher in women than in men (0.030+/-0.008 vs 0.022+/-0.005 l min(-1) kg)(-1); 95% CI of difference 0.012, 0.003; P=0.003), suggesting that FU metabolism is more rapid in females. Surprisingly, V(ss) was highly correlated with CL (r2=0.67; CL=0.52+V(ss) x 0.040). This finding may either be explained by extensive drug metabolism in extra-hepatic organs or by variable inactivation on first-pass through the lung. Both these hypotheses need experimental validation. CONCLUSIONS: The pharmacokinetics of FU are better predicted by FFM and TBW than by standard anthropometric parameters and predictions are sex-dependent. The use of BIA may lead to improved dosing with FU.     

不同品系小鼠肥胖模型比较及C57BL/6J小鼠肥胖机制研究

目的建立和比较不同品系小鼠肥胖模型,并研究C57BL/6J小鼠肥胖形成的分子机制。方法选用C57BL/6J、ICR和KM 3个品系♂小鼠,各品系小鼠随机分为正常对照和高脂模型组,分别在饲养4周与8周后测定小鼠体重、脂肪重量、Lee’s指数;脂肪细胞形态学观察和横截面面积计量;酶法检测血脂和LPL活性,应用荧光实时定量PCR技术探讨模型形成分子机制。结果 C57BL/6J小鼠模型组体重、脂肪重量、Lee’s指数、脂肪细胞横截面面积与对照组比较均明显升高,形成良好肥胖模型,而ICR和KM小鼠肥胖指标不如C57BL/6J小鼠变化明显。机制研究表明,C57BL/6J小鼠造模后血清LPL活性升高,肝脏PPARα、脂肪组织PPARγ和DGAT表达上调,脂肪组织HSL、ATGL和TGH表达下调,这些酶、受体的表达变化是形成肥胖的重要机制。结论 C57BL/6J小鼠经高脂饲料诱导4周后可形成良好肥胖模型,PPARα、PPARγ、LPL、DGAT、HSL、ATGL和TGH既是肥胖形成的主要机制,也是减肥药物作用靶点判断的生物标志物。     

甘草甲醇提取物FM100对小鼠溃疡性结肠炎的药效学研究

目的观察甘草甲醇提取物FM100对小鼠溃疡性结肠炎的作用。方法用三硝基苯磺酸钠(TNBS)和乙醇制造小鼠溃疡性结肠炎模型,空白对照组和TNBS模型组灌胃等容量生理盐水,阳性对照组灌胃地塞米松0.2mg/kg,FM100大、中、小剂量组分别灌胃FM100300mg/kg、200mg/kg、100mg/kg,连续灌胃14d。观察小鼠体质量变化、腹泻、结肠黏膜组织形态学、脾脏指数及髓过氧化物酶(MPO)活力等指标。结果甘草甲醇提取物FM100可不同程度地改善TNBS/乙醇所致溃疡性结肠炎小鼠体质量下降和腹泻症状,明显降低结肠黏膜粘连及其溃疡分值和脾脏指数,但可增高MPO活力(P<0.05或P<0.01)。结论甘草甲醇提取物FM100对小鼠溃疡性结肠炎有较好的改善作用,能减轻结肠局部的病理性损伤。     

Fluospheres for cardiovascular phenotyping genetically modified mice

Assessment of systemic and regional hemodynamic phenotypes in genetically engineered mice by nonradioactive methods is yet an unsolved problem. We therefore investigated whether the reference sample method using fluorescent microspheres (FMs), already validated in rats, might be used for this purpose in C57BL/6 and in apolipoprotein E (ApoE)-deficient mice. FMs were injected into the left ventricle of instrumented anesthetized mice. In 10-week-old C57BL/6, cardiac output was 18-19 ml/min, and its regional distribution under basal conditions was approximately 1.5% (brain), 3.5% (heart), 9. 1% (left kidney), 9.8% (right kidney), 1% (spleen), and 0.8% (stomach) (i.e., values similar to those previously reported with radioactive microspheres). Proper mixing of FMs was achieved as both kidneys had identical flows; distribution of two differently labeled FMs injected simultaneously was shown to be identical by an agreement study, and FM trapping in the capillary bed was demonstrated both histologically and by the recovery in the lungs of 90% of intravenously injected FMs. In addition, identical values for cardiac output and its distribution were obtained in different age-matched groups of C57BL/6. The FM technique also proved to be able to evidence angiotensin II and isoprenaline classic systemic and regional hemodynamic effects. Finally, applied to 30-week-old ApoE-deficient mice and age-matched C57BL/6, the FM technique showed no major hemodynamic difference between the two groups, except for coronary blood flow, which was significantly decreased in ApoE-deficient mice. In conclusion, we demonstrated for the first time the feasibility, accuracy, and reliability of the FM technique at characterizing the cardiovascular phenotype of genetically engineered mice.     

Weight reduction decreases soluble cellular adhesion molecules in obese women

1. Obesity is known to increase the risk for atherosclerotic diseases. Serum levels of cellular adhesion molecules are reported to be indices of atherosclerosis. The aim of the present study was to assess the effect of weight reduction on soluble intercellular adhesion molecule-1 (sICAM-1) and soluble E-selectin (sE-selectin). 2. Eighteen non-diabetic normotensive obese women participated in a 3 month lifestyle-modification programme (intervention group). The programme consisted of lectures on diet, exercise sessions and behavioural modification by weight charting. Fourteen women who did not enter the programme served as controls. Body fat mass (FM) was measured by dual-energy X-ray absorptiometry. Soluble ICAM-1 and sE-selectin were measured by ELISA. 3. After 3 months, sICAM-1 and sE-selectin, as well as body FM, decreased in the intervention group (P < 0.001), while no changes were observed in the control group. The baseline sE-selectin was positively correlated with total body FM, trunk FM and percentage body fat (r = 0.50-0.57; P < 0.01), but not with leg FM. The change in sE-selectin was also correlated with changes in total body FM and trunk FM (both r = 0.46; P < 0.01). Baseline sICAM-1 was not significantly correlated with these variables. The associations between changes in sICAM-1 and changes in total body FM or trunk FM were of borderline significance (both r = 0.34; P = 0.06). Linear regression analysis indicated that the change in sE-selectin was explained by the change in trunk FM (R2 = 0.18; P < 0.01). 4. Soluble ICAM-1 and sE-selectin were positively correlated with obesity, especially with central obesity. Weight reduction resulted in decreases in soluble adhesion molecules, which may suggest a downregulation of endothelial activation.     

Environmental enrichment decreases the rewarding but not the activating effects of heroin

Rationale  Environmental conditions during adolescence, a critical period of brain maturation, can have important consequences on subsequent vulnerability to drugs of abuse. We have recently found that the behavioral effects of cocaine as well as its ability to increase expression of zif-268 are reduced in mice reared in enriched environments (EE). Objectives  The present experiments examined whether environmental enrichment has protective influences on the effects of heroin, a drug of addiction whose mechanism of action differs from that of cocaine. Materials and methods  Mice were housed either in standard environments (SE) or in EE from weaning to adulthood before any drug exposure. EE were constituted by big housing cages and contained constantly a running wheel and a small house and four to five toys that were changed once a week with new toys of different shapes and colors. We assessed the influence of EE on the ability of heroin to (1) induce conditioned place preferences, (2) induce behavioral sensitization, (3) increase dopamine levels in the nucleus accumbens (NAc), and (4) increase expression of the immediate early gene zif-268 in the striatum. Results  Conditioned place preference but not behavioral sensitization was reduced in EE mice compared to SE mice. Heroin induced similar increases in dopamine levels and in the expression of zif-268 in the NAc of EE and SE mice. Conclusions  The rewarding effects of heroin are blunted by EE and appear to be, at least in part, independent from activation of the mesolimbic system.     

p53+/-基因敲除小鼠尿烷致癌性初步验证试验

目的：观察自主建立的p53^+/-敲除小鼠（命名为B6-Trp53tm1/NIFDC）模型,在给予尿烷后的体重、脏器重量、血液学及血生化指标变化,为该模型将来用于临床前药物短期致癌性试验的替代试验提供背景数据。方法：共设计3个组：阴性对照组（野生型小鼠,给予生理盐水）、尿烷组1（B6-Trp53tm1/NIFDC小鼠,给予1000 mg·kg^-1尿烷）、尿烷组2（野生型小鼠,给予1000 mg·kg^-1尿烷）,各组动物数量均为20只,雌雄各半。试验期间及试验结束测定各组动物的体重、脏器重量和相对脏器重量、血液学及血生化指标,并进行统计分析。结果与结论：与阴性对照组相比,尿烷给药第2、3、11及21周尿烷组1和尿烷组2动物的体重显著下降;尿烷组1动物肺脏和脾脏绝对重量显著升高;尿烷组1和尿烷组2动物肺脏相对重量显著升高;尿烷组1动物NEU、RDW%、CHDW%以及尿烷组2动物LYM%、BASO%显著升高;尿烷组1及尿烷组2动物的血生化指标无明显改变。     

黄芩苷对FM1肺炎小鼠肺损伤的作用机制研究

目的研究黄芩苷对甲型流感病毒性肺炎小鼠肺组织炎性损伤的作用机制。方法将96只ICR鼠随机分为正常对照组、模型组、利巴韦林组(100 mg.kg-1),黄芩苷组(1 500、750、375 mg.kg-1)[5],每组16只。用流感病毒亚甲型鼠肺适应株A/FM/1/47(H1N1)感染小鼠,制备小鼠流感病毒性肺炎模型,用不同剂量黄芩苷溶液灌胃治疗后,观察肺组织H-E染色切片病理变化,采用RT-PCR测定肺组织c-jun、c-fos mRNA表达,采用Western blot测定肺组织c-jun、磷酸化c-jun蛋白表达,应用ELISA检测肺匀浆炎性细胞因子TNF-α、IL-1β的含量。结果黄芩苷750、375 mg.kg-1剂量均能明显减轻肺组织炎性损伤;明显降低c-jun、c-fosmRNA的表达(P<0.05,P<0.01),明显降低c-jun、磷酸化c-jun蛋白表达(P<0.01);明显抑制TNF-α、IL-1β的分泌(P<0.01)。结论黄芩苷能够缓解甲型流感病毒诱导的炎性病理损伤,其可能通过抑制流感病毒感染引起的转录因子AP-1高表达而降低炎性细胞因子的分泌水平,从而发挥抗流感病毒感染的作用。     

Differential Effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine on Motor Behavior and Dopamine Levels at Brain Regions in Three Different Mouse Strains

Developing an animal model for a specific disease is very important in the understanding of the underlying mechanism of the disease and allows testing of newly developed new drugs before human application. However, which of the plethora of experimental animal species to use in model development can be perplexing. Administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a very well known method to induce the symptoms of Parkinson''s disease in mice. But, there is very limited information about the different sensitivities to MPTP among mouse strains. Here, we tested three different mouse strains (C57BL/6, Balb-C, and ICR) as a Parkinsonian model by repeated MPTP injections. In addition to behavioral analysis, endogenous levels of dopamine and tetrahydrobiopterin in mice brain regions, such as striatum, substantia nigra, and hippocampus were directly quantified by liquid chromatography-tandem mass spectrometry. Repeated administrations of MPTP significantly affected the moving distances and rearing frequencies in all three mouse strains. The endogenous dopamine concentrations and expression levels of tyrosine hydroxylase were significantly decreased after the repeated injections, but tetrahydrobiopterin did not change in analyzed brain regions. However, susceptibilities of the mice to MPTP were differed based on the degree of behavioral change, dopamine concentration in brain regions, and expression levels of tyrosine hydroxylase, with C57BL/6 and Balb-C mice being more sensitive to the dopaminergic neuronal toxicity of MPTP than ICR mice.     

Antidepressant and Proneurogenic Influence of Environmental Enrichment in Mice: Protective Effects vs Recovery

Physical–cognitive activity has long-lasting beneficial effects on the brain and on behavior. Environmental enrichment (EE) induces brain activity known to influence the behavior of mice, as measured in learned helplessness paradigms (forced swim test), and neurogenic cell populations in the hippocampal dentate gyrus. However, it is not completely clear whether the antidepressant and proneurogenic effects of EE are different in animals that are naive or pre-exposed to the stress inducing helplessness, and if this depends on the type of stressor. It also remains unclear whether differential effects are exerted on distinct neurogenic subpopulations. We found that EE has a protective effect in adult female mice (C57BL/6J) when exposed twice to the same stressor (forced swim test) but it has no influence on recovery. The repeated exposure to this stressor was analyzed together with the effects of EE on different neurogenic populations distinguished by age and differentiation state. Younger cells are more sensitive and responsive to the conditions, both the positive and negative effects. These results are relevant to identify the cell populations that are the targets of stress, depression, and enrichment, and that form part of the mechanism responsible for mood dysfunctions.     

辣椒不同工艺提取物的镇痛作用比较

目的 比较丙酮温浸提取和免加热提取工艺得到的辣椒提取物的镇痛作用。方法 阿司匹林为阳性对照药，采用小鼠热板法疼痛模型，观察不同提取工艺得到的辣椒提取物灌胃给予小鼠后对小鼠痛阈的影响。结果 丙酮温浸组480mg／kg、960mg／kg、1280mg／kg组，免加热酯提取物960mg／kg、1920mg／kg组，免加热水提取物960mg／kg、1920mg／kg、3840mg／kg组均明显延长疼痛反应潜伏期。不同工艺提取物中960mg／kg剂量组显效的时间有差异。结论 免加热提取法得到的酯溶性、水溶性辣椒提取物以及丙酮温浸法得到的辣椒提取物均有镇痛作用。但相同剂量下三种提取物的镇痛效果明显不同。     

Total body water measurements by deuterium dilution in adult Indian males and females

Total Body Water (TBW) was measured in a group of 20 healthy adult Indian men and 10 women by the deuterated water dilution technique and their body composition was determined by applying a hydration factor of 0.7194 for fat free mass (FFM). The TBW in the male subjects whose mean body weight was 49.8 +/- 6.7 kg, was 60.6 +/- 3.2% of body weight (range 55.8%-65.4%), from which a FFM of 41.9 +/- 6.1 kg (range 31.8 kg-51.3 kg) was obtained. Total body water in the group of 10 female subjects whose mean body weight was 42.7 +/- 4.9 kg, was 57.0 +/- 4.5% of body weight (range 52.5%-64.2%) from which a FFM of 34.0 +/- 5.1 kg (range 28.4 kg-39.4 kg) was obtained.     

The population pharmacokinetics of allopurinol and oxypurinol in patients with gout

Purpose

The aims of this study were to develop a population pharmacokinetic model for allopurinol and oxypurinol and to explore the influence of patient characteristics on allopurinol and oxypurinol pharmacokinetics.

Methods

Data from 92 patients with gout and 12 healthy volunteers were available for analysis. A parent–metabolite model with a two-compartment model for allopurinol and a one-compartment model for oxypurinol was fitted to the data using non-linear mixed effects modelling.

Results

Renal function, fat-free mass (FFM) and diuretic use were found to predict differences in the pharmacokinetics of oxypurinol. The population estimates for allopurinol clearance, inter-compartmental clearance, central and peripheral volume were 50, 142 L/h/70 kg FFM, 11.4, 91 L/70 kg FFM, respectively, with a between-subject variability of 33 % (coefficient of variance, CV) for allopurinol clearance. Oxypurinol clearance and volume of distribution were estimated to be 0.78 L/h per 6 L/h creatinine clearance/70 kg FFM and 41 L/70 kg FFM in the final model, with a between-subject variability of 28 and 15 % (CV), respectively.

Conclusions

The pharmacokinetic model provides a means of predicting the allopurinol dose required to achieve target oxypurinol plasma concentrations for patients with different magnitudes of renal function, different body mass and with or without concomitant diuretic use. The model provides a basis for the rational dosing of allopurinol in clinical practice.     

Effects of age, gender and hyperparathyroidism on lean body mass in hemodialysis patients

Hyperparathyroidism of hemodialysis patients is associated with osteo-dystrophy, impairment of cardiac function, of peripheral nerve conduction, of response to r-HuEPO and with decrease of lean body mass. Primary hyperparathyroidism of post-menopausal women is associated with increased fat mass (FM). The study investigated if gender varies relationship between i-PTH, and body composition, assessed by multifrequency bio-electrical impedance analysis (BIA), cardiac function, assessed by echocardiography, and anemia, in long-term hemodialysis patients. Seventy patients on long-term bicarbonate dialysis, 34 male and 36 post-menopausal female, were studied. i-PTH RIA, multifrequency BIA and Kt/V were assessed at three months intervals. i-PTH (345.88 +/- 199.58 vs. 224.26 +/- 161.62 pg/ml, p < 0.01) and FM% (39.13 +/- 10.42 vs. 30.95 +/- 5.88, p < 0.001) were both significantly higher in women vs men; BMI was not significantly different. In the total group of patients (r = 0.572, p < 0.001) and in women (r = 0.68, p < 0.001) a positive correlation was found between i-PTH and FM%, and reciprocally an inverse negative correlation with free fat mass (FFM) was observed. No significant relationship was observed in men. Decrease of blood pressure measurements and increase of left ventricular Ejection Fraction, in the comparison of beginning and end of three dialysis sessions, were significantly greater in women. Reduced FFM of women on dialysis could have also some relationship with a more close long-term adherence to dietary protein restriction. Hyperparathyroidism in chronic renal failure patients could share liability of bone structural abnormalities, cardiac function impairment, excitable tissue disease, and anemia. However, malnutrition, and its consequent relative decrease of lean mass, resulting from kidney disease and, possibly, from nutritional behavioral modifications, could be responsible of the multi-organ involvement of hyperparathyroidism in end-stage renal disease.     

Quantification of lean bodyweight

BACKGROUND: Lean bodyweight (LBW) has been recommended for scaling drug doses. However, the current methods for predicting LBW are inconsistent at extremes of size and could be misleading with respect to interpreting weight-based regimens. OBJECTIVE: The objective of the present study was to develop a semi-mechanistic model to predict fat-free mass (FFM) from subject characteristics in a population that includes extremes of size. FFM is considered to closely approximate LBW. There are several reference methods for assessing FFM, whereas there are no reference standards for LBW. PATIENTS AND METHODS: A total of 373 patients (168 male, 205 female) were included in the study. These data arose from two populations. Population A (index dataset) contained anthropometric characteristics, FFM estimated by dual-energy x-ray absorptiometry (DXA - a reference method) and bioelectrical impedance analysis (BIA) data. Population B (test dataset) contained the same anthropometric measures and FFM data as population A, but excluded BIA data. The patients in population A had a wide range of age (18-82 years), bodyweight (40.7-216.5 kg) and BMI values (17.1-69.9 kg/m2). Patients in population B had BMI values of 18.7-38.4 kg/m2. A two-stage semi-mechanistic model to predict FFM was developed from the demographics from population A. For stage 1 a model was developed to predict impedance and for stage 2 a model that incorporated predicted impedance was used to predict FFM. These two models were combined to provide an overall model to predict FFM from patient characteristics. The developed model for FFM was externally evaluated by predicting into population B. RESULTS: The semi-mechanistic model to predict impedance incorporated sex, height and bodyweight. The developed model provides a good predictor of impedance for both males and females (r2 = 0.78, mean error [ME] = 2.30 x 10(-3), root mean square error [RMSE] = 51.56 [approximately 10% of mean]). The final model for FFM incorporated sex, height and bodyweight. The developed model for FFM provided good predictive performance for both males and females (r2 = 0.93, ME = -0.77, RMSE = 3.33 [approximately 6% of mean]). In addition, the model accurately predicted the FFM of subjects in population B (r2 = 0.85, ME = -0.04, RMSE = 4.39 [approximately 7% of mean]). CONCLUSIONS: A semi-mechanistic model has been developed to predict FFM (and therefore LBW) from easily accessible patient characteristics. This model has been prospectively evaluated and shown to have good predictive performance.     

Enhanced acquisition of cocaine self-administration by increasing percentages of C57BL/6J genes in mice with a nonpreferring outbred background

Rationale Individual differences in the propensity to acquire drug self-administration may have a substantial genetic basis.Objectives To study the genetic contribution to cocaine self-administration by comparing hybrids of cocaine preferring (C57BL/6J) and nonpreferring (ICR) mice.Methods ICR and C57BL/6J parental strains were compared to hybrids with 75% ICR:25% C57BL/6J, 50% ICR:50% C57BL/6J, and 25% ICR:75% C57BL/6J genetic backgrounds for acquisition of sucrose pellet and intravenous cocaine self-administration in 1-h test sessions. Mice that acquired cocaine self-administration were subsequently tested in a between-session self-administration dose-response procedure.Results Increasing presence of C57BL/6J genes increased the percentage of mice that acquired sucrose pellet self-administration in the first test session. In lever-trained mice, only 19% of ICR mice met acquisition criteria for cocaine self-administration after 15 sessions, whereas 76% of C57BL/6J mice met acquisition criteria, although both strains initially sampled a similar number of cocaine injections. Increasing the percentage of C57BL/6J genes in the nonpreferring ICR background to 50 and 75% led to increasing percentages of mice that met acquisition criteria to 31 and 52%, respectively. In mice that acquired self-administration, only mice with 75% C57BL/6J genes showed a typical inverted U-shaped self-administration dose–response curve, whereas the curve was flat across doses for mice with ≤50 and 100% C57BL/6J genes.Conclusions The findings are consistent with a genetically based dose-dependent enhancement of cocaine reinforcement by C57BL/6J genes. These results suggest that heritable traits impart a substantial genetic load that facilitates the propensity for cocaine addiction among individuals in outbred populations.