Subadditive withdrawal from cocaine/κ-opioid agonist combinations in Planaria

We have previously developed and extensively characterized a convenient and sensitive metric for the quantification of withdrawal responses using Planaria. Planaria are particularly valuable for these studies because of their permeable exteriors and their relevant neurotransmitter systems (e.g., dopaminergic, opioid, and serotonergic). In the present study, we used this metric and mathematically rigorous joint-action analysis to investigate poly-drug withdrawal from fixed-ratio cocaine/κ-opioid agonist combinations. The D50 (concentration producing half-maximal effect) for cocaine and U-50,488H was 10.3 and 1.02 μg, respectively. The D50 for 19:1 or 1:19 combinations did not differ significantly (p > 0.05) from expected additive values (11.6 ± 3.0 vs. 9.9 ± 1.4 and 1.1 ± 0.2 vs. 1.5 ± 0.1, respectively), but the 3:1, 1:1, and 1:3 ratios did (34.5 ± 6.9 vs. 7.7 ± 1.1; 55.1 ± 10.0 vs. 5.7 ± 0.7; and 40.8 ± 8.9 vs. 3.3 ± 0.4, respectively), indicating subadditive interaction at these ratios. The finding of subadditivity in this model suggests that abstinence-induced withdrawal from the combination is less intense than that predicted from the individual drug potencies. The concept that certain combinations of drugs leads to attenuated withdrawal might generalize to humans.