Attenuation by dextromethorphan on the higher liability to morphine-induced reward, caused by prenatal exposure of morphine in rat offspring

Abstract

Co-administration of dextromethorphan (DM) with morphine during pregnancy and throughout lactation has been found to reduce morphine physical dependence and tolerance in rat offspring. No evidence was presented, however, for the effect of DM co-administered with morphine during pregnancy on morphine-induced reward and behavioral sensitization (possibly related to the potential to induce morphine addiction) in morphine-exposed offspring. Conditioned place preference and locomotor activity tests revealed that the p60 male offspring of chronic morphine-treated female rats were more vulnerable to morphine-induced reward and behavioral sensitization. The administration of a low dose of morphine (1 mg/kg, i.p.) in these male offspring also increased the dopamine and serotonin turnover rates in the nucleus accumbens, which implied that they were more sensitive to morphine. Co-administration of DM with morphine in the dams prevented this adverse effect of morphine in the offspring rats. Thus, DM may possibly have a great potential in the prevention of higher vulnerability to psychological dependence of morphine in the offspring of morphine-addicted mothers.

Figure 1

A: Time schedule of the CPP test. B: Time schedule of the locomotor activity test.

Figure 2

Effect of morphine (1 mg/kg) to induce rewarding in the male offspring rats (p60) from different groups, which was measured by conditioned place preference (CPP) tests (A: Control group; B: Morphine group; C: M + DM group; D: DM group). Data were expressed as preference for the drug-paired compartment, which was determined by time spent in the drug-paired compartment minus time spent in the saline-paired compartment. Data were presented as mean ± SEM., and paired t-test was used to analyze the data (**p < 0.01 for day 6 vs. day 0; n ≧ 8).

Figure 3

Effects of morphine (1 mg/kg) on behavioral sensitization of total locomotor activity in the male offspring rats (p60) from different groups (A: Control group; B: Morphine group; C: M + DM group; D: DM group). Data were presented as mean ± SEM. Student t-test was used to analyze the data for the significance of the difference from the activity on day 0 (**p < 0.01, ***p < 0.001 compared with the data on day 0; n ≧ 7).

Figure 4

Effects of morphine (1 mg/kg) on behavioral sensitization of ambulatory locomotor activity in the male offspring rats (p60) from different groups (A: Control group; B: Morphine group; C: M + DM group; D: DM group). Data were presented as mean ± SEM. Student t-test was used to analyze the data for the significance of the difference from the activity on day 0 (*p < 0.05 compared with the data on day 0; n ≧ 7).

Figure 5

Effects of morphine (1 mg/kg) on the dopamine turnover rate ([DOPAC+HVA]/[DA]) of the male offspring rats (p60) from different groups in the (A) nucleus accumbens (NAc), (B) dorsal striatum (DS), (C) medial prefrontal cortex (mPFC), and (D) olfactory tubercle (OT). Data were presented as means ± SEM. One-way ANOVA followed by Newman-Keuls test was used to analyze the data (*p < 0.05 for the morphine group vs. the control group; ^#p < 0.05 for the M + DM group vs. the morphine group; n ≧ 6).

Figure 6

Effects of morphine (1 mg/kg) on the dopamine turnover rate ([5-HIAA]/[5-HT]) of the male offspring rats (p60) from different groups in the (A) nucleus accumbens (NAc), (B) dorsal striatum (DS), (C) medial prefrontal cortex (mPFC), and (D) olfactory tubercle (OT). Data were presented as means ± SEM. One-way ANOVA followed by Newman-Keuls test was used to analyze the data (*p < 0.05 for the morphine group vs. the control group; ^#p < 0.05 for the M + DM group vs. the morphine group; n ≧ 5).