Modification of practice-dependent plasticity in human motor cortex by neuromodulators

Practice-dependent plasticity underlies motor learning in everyday life and motor relearning after lesions of the nervous system. Previous studies showed that practice-dependent plasticity is modifiable by neuromodulating transmitters such as norepinephrine (NE), dopamine (DA) or acetylcholine (ACh). Here we explored, for the first time comprehensively and systematically, the modifying effects of an agonist versus antagonist in each of these neuromodulating transmitter systems on practice-dependent plasticity in healthy subjects in a placebo-controlled, randomized, double-blind crossover design. We found that the agonists in all three neuromodulating transmitter systems (NE: methylphenidate; DA: cabergoline; ACh: tacrine) enhanced practice-dependent plasticity, whereas the antagonists decreased it (NE: prazosin; DA: haloperidol; ACh: biperiden). Enhancement of plasticity under methylphenidate and tacrine was associated with an increase in corticomotoneuronal excitability of the prime mover of the practice, as measured by the motor evoked potential amplitude, but with a decrease under cabergoline. Our findings demonstrate that agonists and antagonists in various neuromodulating transmitter systems produce significant and oppositely directed modifications of practice-dependent plasticity in human motor cortex. Enhancement of plasticity occurred through different strategies that either favoured extrinsic (NE, ACh) or intrinsic (DA) modulating influence on the motor cortical output network.