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. 2020 Sep 18;7(5):ENEURO.0146-20.2020. doi: 10.1523/ENEURO.0146-20.2020

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Copyright © 2020 Severino et al.

This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.

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Figure 3. — Selective MOR deletions define specific roles of D1 and A2a MOR populations in opioid-induced locomotion. A, Oxycodone (0, 1, 3, 10 mg/kg) induced a dose-dependent increase in locomotion in flMORs, D2flMORs, A2aflMORs, and ChATflMORs, but not D1flMORs (a: p < 0.01 vs 0, b: p < 0.001 vs 0). In comparison with the control genotype, flMORs, D1flMORs showed a reduced effect of oxycodone at 10 mg/kg (*p < 0.05 vs flMOR of the same dose), whereas A2aflMORs showed an enhanced effect of oxycodone at 3 and 10 mg/kg (***p < 0.001 vs flMOR of the same dose). There was no effect of genotype following the vehicle (0) injection showing no effect of any of these deletions on basal locomotor activity. B, Morphine (0, 1, 10, 15 mg/kg) also induced a dose-dependent increase in locomotor activity in flMORs, D2flMORs, and A2aflMORs but not in D1flMORs or ChATflMORs (a: p < 0.01 vs 0, b: p < 0.001 vs 0). Compared with control flMORs, this effect was enhanced in A2aflMORs (**p < 0.001 and ***p < 0.0001 vs flMOR of the same dose). C, Cocaine (0, 15 mg/kg) induced hyperlocomotion in all lines when compared with saline (0; ***p ≤ 0.001), an effect that was enhanced in ChATflMORs (a: p < 0.001 vs flMORs). D–H, Sensitization. After three consecutive days of repeated opioid injections, flMORs (D) and D2flMORs (F) showed an enhanced, or sensitized, response to both oxycodone and morphine. D1flMORs (E) did not show this enhanced effect to either opioid whereas A2aflMORs (G) and ChATflMORs (H) sensitized to oxycodone but not morphine (*p < 0.05 and **p < 0.01, respectively, vs day 1). I–L, Intrasession locomotor analysis. This analysis assessed the locomotor response to oxycodone or morphine during each 60-min session on day 1 and day 3. I, A single injection of oxycodone (10 mg/kg) on day 1 increased locomotor activity in D2flMORs (p < 0.05) and A2aflMORs (p < 0.0001), whereas flMORs, D1flMORs, and ChATflMORs showed no change in activity during the session. J, After 3 d of repeated oxycodone administration, the locomotor activity of D1flMORs (p < 0.001) declined through the session and all other genotypes showed no change across time. K, A single injection of morphine (15 mg/kg) on day 1 resulted in a within-session increase in locomotor activity in flMORs (p < 0.0001), D2flMORs (p < 0.0001), A2aflMORs (p < 0.0001), and ChATflMORs (p < 0.01), but not D1flMORs. L, After 3 d of repeated morphine administration, a similar pattern emerged as on day 1 with flMORs (p < 0.0001), D2flMORs (p < 0.0001), A2aflMORs (p < 0.0001), and ChATflMORs (p < 0.05), but not D1flMORs, showing a within session increase in locomotor activity. Refer to Table 4 for statistical analyses. All data are shown as mean ± SEM, and individual datapoints are shown in Extended Data Figure 3-1 for which this legend also applies.