- An internal model of the dynamics of a tool or an object is part of the motor memory acquired when learning to use the tool or to manipulate the object. Changes in synaptic efficacy may underlie acquisition and storage of memories. Here we studied the effect of pharmacological agents that interfere with synaptic plasticity on acquisition of new motor memories and on recall of a previously learned internal model. Forty-nine subjects, divided into six groups, made reaching movements while holding a robotic arm that applied forces to the hand. On day 1, all subjects learned to move in force field A. On day 2, each group of subjects was tested on their ability to recall field A and their ability to learn a new internal model in field B. Four groups participated in the experiments of day 2 under the effects of lorazepam (LZ; a GABA type A receptor-positive allosteric modulator), dextromethorphan [DM; an N-methyl-D-aspartate (NMDA) receptor blocker], lamotrigine (LG, a drug that blocks voltage-gated Na(+) and Ca(2+) channel), or scopolamine (SP; muscarinic receptor antagonist). Two control groups were tested in a drug-free condition: one group that was not exposed to additional experimental protocols (NP) and another group was tested under ~24 h of sleep deprivation between completion of learning on day 1 and start of testing on day 2 (SD). Recall of field A was normal in all groups. Learning of field B was reduced by LZ and DM but not by SP, LG, SD or in the NP condition. These results suggest that a 24-h sleep-deprivation period may have little or no effect on consolidation of this motor memory and that NMDA receptor activation and GABAergic inhibition are mechanisms operating in the acquisition but not recall of new motor memories in humans.