Activation of the D1 receptors inhibits the long-term potentiation in vivo induced by acute morphine administration through a D1-GluN2A interaction in the nucleus accumbens.

Dopamine D1-like receptors can modulate glutamate-mediated excitatory synaptic neurotransmission, but the underlying molecular mechanism remains elusive. Here, we report that acute in-vivo morphine administration induces the long-term potentiation (Mor-LTP) of field excitatory postsynaptic potentials at the prefrontal cortex-to-nucleus accumbens shell synapses, and this process requires the activation of GluN2A-containing N-methyl-D-aspartate receptors. This Mor-LTP is completely inhibited by the D1-like receptor agonist SKF81297, but not by the D2-like receptor agonist quinpirole. SKF81297-inhibited Mor-LTP is restored by pretreatment with the TAT-conjugated interfering peptide TAT-D1-t3, which is a synthetic blocker of the direct D1-GluN2A receptor interaction. These results indicate that the activation of D1 receptors modulates Mor-LTP by the direct D1-GluN2A interaction at the prefrontal cortex-to-nucleus accumbens shell synapses and might play a role in addiction-related plastic alterations.