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

Background and Purpose Trace amine‐associated TA1 receptors play critical roles in regulating dopamine transmission. Previous studies showed that pharmacologically or genetically manipulating the activity of TA1 receptors modulates addiction‐like behaviours associated with psychostimulants. However, little is known about whether TA1 receptor modulation would regulate the behavioural effects of opioids. Experimental Approach Effects of the selective TA1 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 TA1 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 TA1 receptor activation selectively attenuated the reinforcing, but not withdrawal or antinociceptive effects of morphine, suggesting that selective TA1 receptor agonists might be useful to combat opioid addiction, while sparing the analgesic effects.