Journal Article

NMDA receptor involvement in dopaminergic modulation of neuroplasticity induced by paired associative stimulation

Beaupain, Marie C, Ghanavati, Elham, Kuo, Min-Fang, Frese, Amba M, Nitsche, Michael A, Melo, Lorena

2025

Overview

Abstract Background Dopamine (DA) modulates long-term potentiation (LTP)-like neuroplasticity. While particularly D1 and D2 receptors are thought to influence neuroplasticity through glutamatergic N-methyl-D-aspartate (NMDA) receptor and gamma-aminobutyric acid (GABA) modulation, the exact mechanisms are not completely clarified. Objective We aimed to explore the relevance of NMDA receptor activity for DAergic modulation of focal LTP-like plasticity induced by excitatory paired associative stimulation (ePAS). Methods In a double-blinded, randomized, and placebo-controlled design, 17 healthy participants received DAergic agents (100 mg L-Dopa for general DAergic enhancement, 10 mg bromocriptine for selective D2 receptor activation, or placebo) with different doses of the partial NMDA receptor agonist D-cycloserine (CYC; 50, 100, 200 mg, or placebo) and underwent ePAS. Cortical excitability was monitored via motor-evoked potentials induced by TMS over the left motor cortex for up to 2 hours post-stimulation. Results We did not find significant interactions between DAergic agents, CYC, and time across the entire sample, but significant group differences depending on sensitivity to ePAS. In high-sensitivity, but not low-sensitivity participants, ePAS induced LTP-like effects. CYC produced nonlinear, dose-dependent effects on plasticity in both groups. In the high-sensitivity group, LTP-like effects persisted under both DAergic agents, but were significantly reduced under bromocriptine. CYC had a nonlinear effect when combined with bromocriptine. In the low-sensitivity group, ePAS under DAergic agents did not induce LTP-like effects, and only additional intervention with medium-dose CYC restored facilitatory effects under L-Dopa. Conclusions These findings suggest that optimal NMDA receptor activation is necessary for ePAS-induced neuroplasticity and that D2 receptor activity may reduce LTP-like effects by downregulating NMDA receptor function.

• Publisher: Oxford University Press
• Subject: Adult / Analysis / Bromocriptine / Bromocriptine - pharmacology / Cycloserine - administration & dosage / Cycloserine - pharmacology / Dopamine - metabolism / Dopamine Agents - pharmacology / Dopamine Agonists - pharmacology / Dosage and administration / Double-Blind Method / Evoked Potentials, Motor - drug effects / Evoked Potentials, Motor - physiology / Female / Humans / Levodopa - pharmacology / Long-Term Potentiation - drug effects / Long-Term Potentiation - physiology / Magnetic brain stimulation / Male / Methyl aspartate / Motor Cortex - drug effects / Motor Cortex - physiology / Neuronal Plasticity - drug effects / Neuronal Plasticity - physiology / Neuroplasticity / Patient outcomes / Receptors, Dopamine D2 - metabolism / Receptors, N-Methyl-D-Aspartate - agonists / Receptors, N-Methyl-D-Aspartate - metabolism / Receptors, N-Methyl-D-Aspartate - physiology / Transcranial Magnetic Stimulation / Young Adult