In the current study, U50,488H at 2 mg/kg vs saline did not change BSR thresholds at all 4 time points within one hour post treatment while it attenuated the maximum rates time-dependently in the mouse ICSS test. The observations are different from our previous findings [8], in which U50,488H (s.c.) at 0.5, 1.0 and 2.5 mg/kg increased the BSR thresholds to ~ 1.2-1.3-fold level of saline without changing the maximum rates [8].
The previous % BSR threshold data were shown as the average of those at two time points (30 min, 45 min) [8]. When the current data were presented the same way, no difference was found between saline- and U50,488H-treated groups of mice (115.9 ± 3.5 vs 119.5 ± 4.8, p = 0.54, Student’s t-test). On the other hand, we showed that compared with saline, cocaine enhanced the BSR dramatically, reminiscent of several previous findings using C57BL/6J mice [20–22], demonstrating the validity of our mouse ICSS models.
It should be noted that, in the previous study [8], 2.5 mg/kg of U50,488H showed a trend of decreasing maximal wheel-spinning rates, but did not reach statistical significance. In the current study, with more animals used for each treatment group (N = 18 vs 12 [8]), we observed that 2 mg/kg of U50, 488H decreased the maximum rates in a time-dependent manner with peaked effects at 30 min post treatment, which was in accord with our data from mouse rotarod tests [8] and locomotor tests (unpublished). It should be emphasized that U50,488H failed to affect BSR thresholds even when the wheel-spinning rates were decreased at 30, 45, and 60 min time points, which was likely due to poorer motor coordination induced by U50,488H.
Roth and colleagues used a similar ICSS paradigm to evaluate two other selective KOR agonists in male C57BL/6 mice [16]. They found that U69,593 and salvinorin A increased BSR threshold in time- and dose-dependent manners. However, at time points and doses that the drugs increased BSR thresholds (U69,593 0.3 mg/kg at 15 and 30 min, 1 mg/kg at 15, 30, 45 and 60 min post treatment; salvinorin A 1 mg/kg at 30 min post treatment), they also decreased the maximum wheel-spinning rates, thus confounding data interpretation. Moreover, U69,593 0.3 mg/kg at 45 min decreased the maximum rate significantly, but still failed to affect the BSR threshold, implying that if there was any aversive effect induced by U69,593, the effect was too little to be detected by the ICSS test in mice. One exception is 1 mg/kg salvinorin A at 15 min, in which it increased BSR threshold without affecting maximal spinning rate, demonstrating the anhedonia unambiguously [16]. In contrast, both U69,593 and salvinorin A at 1 mg/kg produced robust CPA in mice in the same study [16]. In fact, Brust et al. reported similar findings in rats that U50,488H increased BSR threshold at doses that decreased the maximal spinning rates [11].