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.