Loss of mu and delta opioid receptors on neurons expressing dopamine receptor D1 has no effect on reward sensitivity

Opioid signaling controls the activity of the brain’s reward system. It is involved in signaling the hedonic effects of rewards and also has essential roles in reinforcement and motivational processes. Here, we focused on opioid signaling through mu and delta receptors on dopaminoceptive neurons and evaluated the role these receptors play in reward-driven behaviors. We generated a genetically modified mouse with selective double knockdown of mu and delta opioid receptors in neurons expressing dopamine receptor D1. Selective expression of the transgene was confirmed using immunostaining. Knockdown was validated by measuring the effects of selective opioid receptor agonists on neuronal membrane currents using whole-cell patch clamp recordings. We found that in the nucleus accumbens of control mice, the majority of dopamine receptor D1-expressing neurons were sensitive to a mu or delta opioid agonist. In mutant mice, the response to the delta receptor agonist was blocked, while the effects of the mu agonist were strongly attenuated. Behaviorally, the mice had no obvious impairments. The mutation did not affect sensitivity to the rewarding effects of morphine injections or social contact and had no effect on preference for sweet taste. Knockdown had a moderate effect on motor activity in some of the tests performed, but this effect did not reach statistical significance. Thus, we found that knocking down mu and delta receptors on dopamine receptor D1-expressing cells does not appreciably affect reward-driven behaviors.Highlights–It is well accepted that opioid signaling controls the brain’s reward system–We generated mutant mice with mu and delta receptor knockdown in D1 neurons–Knockdown made dopaminoceptive neurons insensitive to mu and delta opioid receptor agonists–The mutation did not cause obvious behavioral impairments–The loss of mu and delta receptors on D1 neurons does not affect reward sensitivity