Regulation Of Dopamine On Synaptic Plasticity Of Nucleus Accumbens Under Morphine

Although the brain circuitry underlying addiction is complex, it is unequivocal that the mesolimbic dopamine system, involving in reinforcement and reward processing, are critical substrates for the neural adaptations that underlie addiction. Mesolimbic dopamine system consist of the ventral tegmental area (VTA) and associated limbic structures receiving descending dopaminergic projections from VTA, such as nucleus accumbens (NAc), prefrontal cortex (PFC), hippocampus, amygdala, ventral paillidum et al. An influential hypothesis is that drugs of abuse can co-opt synaptic plasticity mechanisms in brain circuits of mesolimbic dopamine system. NAc receives descending limbic glutamatergic projections from diverse forebrain areas that include the amygdala, hippocampus, and PFC and ascending dopaminergic projections from VTA. These inputs converge onto single accumbens neurons, making the NAc a critical site for the integration of the limbic and cortical information that acquires control over motivated, goal-directed behaviours. Numerous findings also suggest that the long-lasting adaptations in these dopamine and glutamate transmissions resulting from psychostimulant administration are responsible for addiction-related behaviours. Changes in the efficacy of glutamatergic synaptic transmission in the NAc mediate reward processes and contribute to the perseveration of drug-seeking behaviours. Besides, adaptive changes in mesolimbic dopamine system function are paralleled by behavioural sensitisation to psychostimulants. Dopaminergic transmission has been proposed to modulate the effects of glutamatergic inputs, but the underlying molecular mechanism remains elusive.Here, to investigate dopamine modulate glutamate-mediated excitatory synaptic neurotransmission induced by acute morphine administration, in vivo recordings of the field excitatory postsynaptic potentials (fEPSPs) at prefrontal cortex-to-NAc shell (PFC-NAcSh) synapses were performed by electric stimulating PFC-NAcSh projection fibers in anaesthetised rats. The change in the amplitude of fEPSPs was analyzed during experments when the agonists or antagonists of recelatvie receptors and morphine were administrated. The results indicate that acute in vivo morphine administration induces the long-term potentiation (Mor-LTP) of fEPSPs at PFC-NAcSh synapses, and this process requires the activations of μ-opoid receptors and GluN2A-containing N-methyl-D-aspartate (NMDA) receptors. This Mor-LTP is completely inhibited by avtivation of the D1-like receptors and the activation of D1receptors modulates Mor-LTP via the direct D1-GluN2A interaction. The main results are as follows:1. Acute morphine administration induces LTP at PFC-NAcSh synapses in vivoIn vivo recordings of the fEPSPs of the PFC-NAcSh synapses of anaesthetised rats revealed that the intra-NAc infusion of morphine induced robust LTP of fEPSPs. Besides, single subcutaneous injection of morphine (10mg/Kg) also induced robust LTP (Mor-LTP), which was blocked by the selective antagonist of μ-opioid receptors naloxone but not by vehcle. Moreover, neither the infusion of naloxone nor that of naloxone, which were intra-NAc infused30min prior to morphine administration, had significant effects on basal synaptic transmission.2. The presynaptic mechanism of Mor-LTPIn Mor. group and vehicle group, acute morphine treatment reduced PPR significantly. In naloxone group, naloxone could reverse the decreased PPR induced by acute morphine treatment.3. Mor-LTP requires the activation of GluN2A-containing NMDA receptorsThree antagonists the selective NMDA receptor antagonist AP-5, the GluN2A-preferring antagonist NVP-AAM077and the GluN2B-preferring antagonist Ro25-6981were microinjected into NAcs of the rats30min prior to morphine administration, and had no significant effects on the amplitudes of the fEPSPs. The Mor-LTP was completely blocked by AP-5and NVP-AAM077, but not by Ro25-6981.4. Endogenous dopamine had no significant effects on Mor-LTPThe selective D1-like receptor antagonist SCH23390and the D2-like receptor antagonist sulpiride were microinjected in the NAcs of the rats30min prior to morphine administration. None of these two antagonists had significant effects on basal synaptic transmission or expression of Mor-LTP. Besides, neither SCH23390nor sulpiride had the significant effects on the strength of Mor-LTP. 5.Exogenous dopamine activating D1but not D2receptors results in the inhibition of Mor-LTPThree agonists DA, the D1-like receptor agonist SKF81297, and the D2-like receptor agonist quinpirole were microinjected in the NAcs of the rats30min prior to morphine administration. None of these three agonists had significant effects on basal synaptic transmission. Surprisingly, Mor-LTP was fully inhibited by pretreatment with DA or SKF81297, but not with quinpirole.6. Activation of D1receptors inhibits Mor-LTP via the direct D1-GluN2A interactionThe TAT-conjugated interfering peptide TAT-D1-t3, which interrupts the direct Dl-GluN2A receptor interaction, and its scrambled control TAT peptide were microinjected into the NAcs of rats90min prior to SKF81297infusion. As expected, the inhibition of Mor-LTP by SKF81297was restored in the TAT-D1-t3group. In contrast, the scrambled peptide (TAT) had no significant effects on the inhibition of Mor-LTP by SKF81297.Conclusion:In present study, we found that acute morphine administration induces in vivo LTP that requires the activation of GluN2A-containing NMDA receptors and that this LTP is inhibited by the activation of D1receptors via the direct D1-GluN2A interaction. Taken together with the previous findings, our results indicate that direct the D1-GluN2A interaction might play a role in the development of addiction-related plastic alterations.