Motor-learning Impairment by Amantadine in Healthy Volunteers

Abstract

NMDA receptor antagonists impair learning and memory in animal models, presumably by inhibiting long-term potentiation in the motor cortex. Human studies are limited and restricted by the paucity of safe NMDA antagonists. Here, we investigated the contribution of glutamatergic neurotransmission to the capacity of acquiring motor-adaptation learning in humans. In a double-blind design, 200 mg of amantadine (a low-affinity NMDA receptor channel blocker) or a matching placebo were given orally to groups of 14 and 13 human healthy young volunteers, respectively. Blood samples were collected 3 h after treatment to assay plasma concentrations, and the subjects were then tested using a motor-adaptation paradigm consisting of an eight-target-pointing task. To rule out drug-related generalized impairments such sedation, tests measuring motor dexterity and attention were also administered pre-and post-treatment. Comparison of the mean performance levels on the motor-adaptation task revealed that subjects in the amantadine group performed at a lower level than those in the placebo group, but this difference did not reach significance. Interestingly, however, despite plasma amantadine concentrations being relatively low, ranging from 2.09 to 4.74 mM (mean ¼ 3.3 mM), they nevertheless correlated negatively with motor learning. Furthermore, when the amantadine group was divided into low-performance and high-performance subgroups, subjects in the former subgroup displayed mean amantadine concentrations 36% higher than the latter subgroup, and performed significantly worser than the placebo group. No change in performance was found on the motor-dexterity and attention tests. Altogether, our results lend support to the hypothesis that normal NMDA receptor function is necessary for the acquisition of motor adaptation.

Current intensity‐ and polarity‐specific online and aftereffects of transcranial direct current stimulation: An fMRI study

“…Modulation of cortical neuroplasticity in humans—the process responsible for learning, memory and repair—stands as a critical learning objective in the fields of clinical neurology and cognitive neuroscience. Classic techniques, such as the use of extracellular stimulation and recording electrodes in animal models and pharmacological modulation of central neurotransmitters in human models, have revealed substantial insights into mechanisms of long‐term plasticity, such as the fundamental role of the synaptic glutamatergic system in inducing long‐term potentiation (LTP) or long‐term depression (LTD) (Bliss, Cooke, Ii, & Cooke, ; Cooke & Bliss, ; Lüscher & Malenka, ; Rowland et al, ; Tahar, Blanchet, & Doyon, ). Moreover, the recent development of noninvasive brain stimulation methods has provided the capability to bi‐directionally modulate and probe these alterations at a system level in a safe and controlled manner (Bikson et al, ; Huang, Lu, et al, ; Stefan, Kunesch, Cohen, Benecke, & Classen, ; Ziemann et al, ).…”

Resting-state brain network features associated with short-term skill learning ability in humans and the influence of N-methyl-d-aspartate receptor antagonism

“…Here, many studies have focused on the effects of a common functional polymorphism (Val66Met) in the brain-derived neurotrophic factor (BDNF) gene (Fritsch et al, 2010 ; McHughen et al, 2010 ), a downstream modulator of the molecular cascade supporting synaptic plasticity linked to motor learning impairments and altered motor cortical activations in the plasticity-impaired Met allele carriers (Fritsch et al, 2010 ; McHughen et al, 2010 ; Thomason, Yoo, Glover, & Gotlib, 2009 ). For the evidence in humans, a study by Hadj Tahar et al further showed that the NMDA receptor antagonist amantadine significantly impairs motor learning in healthy subjects (Hadj Tahar, Blanchet, & Doyon, 2004 ).…”

DNA damage in brain cells and behavioral deficits in mice after treatment with high doses of amantadine

“…2). Other studies have shown that NMDA receptor antagonists may impair retention of many tasks (Miserendino et al, 1990;Olney et al, 1991;Morris et al, 1986;Tahar et al, 2004). Memantine disrupted both memory and locomotor behaviors in rats in high doses (Creeley et al, 2006).…”