Pharmacological Modulation of Plasticity

Cortical plasticity plays an important role in learning. Understanding of the mechanisms of plasticity would facilitate strategies to improve learning. CNS active drugs can modify plasticity and learning. Here we tested the effects of neuromodulators [dopamine (DA), norepinephrine (NE), serotonin, acetylcholine ACH)] and, in a different series of experiments, the effects of antiepileptic drugs (AED) on associative long-term potentiation (LTP)-like plasticity and motor learning in eight healthy subjects. LTP was induced by paired associative stimulation (Stefan et al. Brain 2000; 123: 572). Motor learning was investigated in a repeated thumb movement practice protocol (Classen et al. J Neurophysiol 1998; 79: 1117). Single oral doses of the following drugs were tested in a placebo-controlled double-blind crossover design. Neuromodulators: 2mg of cabergoline (DA agonist), 2.5mg of haloperidol (DA antagonist), 40mg of methylphenidate (indirect DA and NE agonist), 1mg of prazosine (NE antagonist), 100mg of sertraline (selective serotonin reuptake inhibitor), 8mg of biperiden (ACH antagonist) and 40mg of tacrine (ACH agonist). AED: 15mg of tiagabine (TGB), 20mg of diazepam (DZP), 1100mg of gabapentin, 3600mg of pirazetam, 300mg of lamotrigine, 100mg of topiramate, and 3000mg of levetiracetam (LEV). Drugs were tested in separate sessions at least one week apart in pseudo-randomized and balanced order. LTP and motor learning were enhanced by cabergoline and methylphenidate, but depressed by haloperidol, prazosine and biperiden. Tacrine had no effect on LTP but enhanced motor learning. LTP was depressed by those AED which enhance gamma-butyric acid (GABA) dependent inhibition (TGB, DZP, in addition LEV) while other AED had no significant effect. The testing of effects of AED on motor learning is work in progress. In conclusion, manipulation of neuromodulatory systems leads to enhancement or depression of LTP and motor learning in the human motor cortex. The congruence of neuromodulatory effects on LTP and motor learning suggests that these two processes share common mechanisms. Neuromodulators may be used to guide cortical plasticity in humans. GABAergic AED interfere negatively with LTP induction and may therefore be detrimental in LTP-dependent learning.