A survey of acute and chronic heroin dependence in ten inbred mouse strains: evidence of genetic correlation with morphine dependence

Abstract

Heroin and morphine exposure can cause physical dependence, with symptoms manifesting during their withdrawal. Inter-individual differences in symptom frequency during morphine withdrawal are a common finding that, in rodents, is demonstrably attributable to genotype. However, it is not known whether inter-individual differences characterize heroin withdrawal, and whether such variation can be similarly influenced by genotype. Therefore, we injected mice of ten inbred strains with acute and chronic heroin doses and compared their jumping frequencies, a common index of withdrawal magnitude, during naloxone-precipitated withdrawal. The data revealed significant strain frequency differences (range after acute and chronic heroin injection: 0-104 and 0-142 jumps, respectively) and substantial heritability (h(2)=0.94 to 0.96), indicating that genetic variance is associated with heroin withdrawal. The rank order of strain sensitivity for acute and chronic heroin withdrawal jumping, and for the current heroin and previous morphine strain data, were significantly correlated (r=0.75-0.94), indicating their genetic and, ultimately, physiological commonality. These data suggest that the genetic liability to heroin dependence remains constant across a period of heroin intake, and that heroin and morphine dependence may benefit from common treatment strategies.

Figure 1. Withdrawal jumping frequencies in 10 inbred mouse strains following acute and chronic heroin treatment

Mice undergoing acute heroin treatment (top figure) were injected once with heroin (50 mg/kg) and withdrawal precipitated 2 h later. Chronically treated mice (bottom figure) were injected repeatedly (t.i.d.) with heroin doses of 5, 10, and 20 mg/kg on Days 1, 2, and 3, respectively. Withdrawal was precipitated 1 h after a final 20 mg/kg heroin dose on Day 4. Withdrawal was precipitated by injecting a single naloxone dose (50 mg/kg). Jumping frequencies were tallied for the next 15 min and are presented as strain mean values. Except for 129P3 mice subject to acute heroin treatment (n = 6), each strain was comprised of a minimum of 8 subjects per each treatment condition. (-) Indicates no response; * indicates a significant difference relative to within-strain controls.

Figure 2. Genetic correlation of acute and chronic heroin and morphine dependence

Symbols represent 10 inbred mouse strains arranged by their rank order of naloxone-precipitated withdrawal jumping frequency (1, lowest frequency; 10, highest frequency). Except for 129P3 mice subject to acute heroin treatment (n = 6), each strain was comprised of a minimum of 8 subjects per each treatment condition. As indicated by the labels appearing on the inside of the x and y axis, data are for the correlation between acute and chronic heroin injection (A), acute heroin and acute morphine injection (B), and between chronic morphine and chronic heroin injection (C). The corresponding Spearman rank coefficients (r_s = 0.75-0.94; Table 1) indicate a significant correlation for each pairwise comparison. Some strain names are abbreviated as follows: 129, 129P3; B6, C57BL/6; C3H, C3H/He; D2, DBA/2.