Activation of trace amine‐associated receptor 1 selectively attenuates the reinforcing effects of morphine

Abstract

Background and Purpose Trace amine‐associated https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=3641 receptors play critical roles in regulating dopamine transmission. Previous studies showed that pharmacologically or genetically manipulating the activity of https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=3641 receptors modulates addiction‐like behaviours associated with psychostimulants. However, little is known about whether https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=3641 receptor modulation would regulate the behavioural effects of opioids. Experimental Approach Effects of the selective https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=3641 receptor partial agonist RO5263397 on the addiction‐related and antinociceptive effects of morphine were systematically assessed in male rats and mice. Key Results RO5263397 attenuated the expression of morphine‐induced behavioural sensitization in wildtype but not https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=3641 receptor knockout mice. RO5263397 shifted the dose‐effect curve of morphine self‐administration downward and reduced the breakpoint in a progressive ratio schedule of reinforcement but did not affect food self‐administration in rats. RO5263397 decreased the cue‐ and drug‐induced reinstatement of morphine‐seeking behaviour in rats. RO5263397 alone did not trigger reinstatement of morphine‐seeking behaviour or change locomotor activity in rats with a history of morphine self‐administration. However, RO5263397 did not affect the expression of morphine‐induced conditioned place preference in mice or rats. RO5263397 did not affect naltrexone‐precipitated jumping behaviour or naltrexone‐induced conditioned place aversion in morphine‐dependent mice. Furthermore, RO5263397 did not affect the analgesic effects of morphine in an acute nociception model in mice and a chronic pain model in rats. Conclusion and Implications These results indicated that https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=3641 receptor activation selectively attenuated the reinforcing, but not withdrawal or antinociceptive effects of morphine, suggesting that selective https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=3641 receptor agonists might be useful to combat opioid addiction, while sparing the analgesic effects.

The selective TAAR1 partial agonist RO5263397 promoted novelty recognition memory in mice

“…The increased discrimination ratio of RO5263397 treatment group was not likely due to potential sedative effect of the treatment, since the doses (0.03 and 0.1 mg/kg) of RO5263397 used in the present study were shown not to affect the locomotor activity in our previous studies (Liu et al 2021;Wu et al 2020). Thus, it is not possible that mice that showed less time exploring the familiar object in the RO5263397 group were due to decreased locomotion caused by the treatment.…”

“…The enhancement of novel object recognition induced by RO5263397 was dependent on TAAR1. Firstly, the partial agonist RO5263397 was shown to be highly selective on TAAR1 as it demonstrated high affinity at mouse, rat, and human TAAR1 expressed in HEK293 cells but not many other receptors (Liu et al 2021;Revel et al 2013). Meanwhile, while RO5263397 increased the firing rate of VTA dopamine and dorsal raphe nucleus (DRN) 5-HT neurons in WT mice, it did not affect the firing frequency in slices from Taar1 −/− mice, demonstrating a TAAR1-specific effect Fig.…”

“…Doses of RO5263397 (0.03 mg/ kg and 0.1 mg/kg; i.p.) were selected based on previous studies (Liu et al 2021;Revel et al 2013) and reported no effect on the locomotor activity in mice (Wu et al 2020). RO5263397 was dissolved in the vehicle, which contains 1 part absolute ethanol, 1 part Emulphor-620 (Rhodia), and 18 parts physiologic saline ).…”

Activation of trace amine‐associated receptor 1 attenuates nicotine withdrawal‐related effects

“…It plays a crucial role of negatively regulating dopamine transmission and thus is widely involved in drug addiction 58,59 . In fact, previous studies have shown that activation of TAAR1 attenuates cocaine, methamphetamine, morphine and nicotine self‐administration, cue‐ and drug‐induced reinstatement and ethanol‐ and nicotine‐induced behavioural sensitization 26,29,30,60–62 . Moreover, in our recent study, we showed that TAAR1 agonists were able to reduce the positive reinforcing effects of nicotine by extensive behavioural assay including nicotine self‐administration, behavioural sensitization, nicotine discrimination and cue‐ and drug‐induced reinstatement 30 .…”

“…did not affect the naltrexone-induced jumping behaviour and conditioned place aversion (CPA) in morphine-dependent mice. 60 In addition, the fact that RO5263397 alone did not affect the analgesic effect of morphine 60 while remarkably reduced mechanic hypersensitivity in LA rats after abstinence suggest the effect of RO5263397 on nociception is dependent on the progressive neuroadaptations involved in nicotine withdrawal. Moreover, the effects of RO5263397…”