Neuromodulatory Neurotransmitters Influence LTP-Like Plasticity in Human Cortex: A Pharmaco-TMS Study

Abstract

Long-term potentiation (LTP) of synaptic efficacy is considered a fundamental mechanism of learning and memory. At the cellular level a large body of evidence demonstrated that the major neuromodulatory neurotransmitters dopamine (DA), norepinephrine (NE), and acetylcholine (ACh) influence LTP magnitude. Noninvasive brain stimulation protocols provide the opportunity to study LTP-like plasticity at the systems level of human cortex. Here we applied paired associative stimulation (PAS) to induce LTP-like plasticity in the primary motor cortex of eight healthy subjects. In a double-blind, randomized, placebo-controlled, crossover design, the acute effects of a single oral dose of the neuromodulatory drugs cabergoline (DA agonist), haloperidol (DA antagonist), methylphenidate (indirect NE agonist), prazosine (NE antagonist), tacrine (ACh agonist), and biperiden (ACh antagonist) on PAS-induced LTP-like plasticity were examined. The antagonists haloperidol, prazosine, and biperiden depressed significantly the PAS-induced LTP-like plasticity observed under placebo, whereas the agonists cabergoline, methylphenidate, and tacrine had no effect. Findings demonstrate that antagonists in major neuromodulatory neurotransmitter systems suppress LTP-like plasticity at the systems level of human cortex, in accord with evidence of their modulating action of LTP at the cellular level. This provides further supportive evidence for the known detrimental effects of these drugs on LTP-dependent mechanisms such as learning and memory.

Visual Attentional Load Influences Plasticity in the Human Motor Cortex

“…It is noteworthy that attention exerts effects on sensory processing through just such a focusing effect. A similar role for dopamine has been suggested (Kuo et al, 2008;Korchounov and Ziemann, 2011;Thirugnanasambandam et al, 2011). Interestingly, the neuromodulators involved in reinforcement-based learning are also implicated in attentional processes, suggesting a common mechanistic basis for attention-and reinforcement-based learning.…”

TMS and drugs revisited 2014

“…For cathodal tDCS-, but not for PAS-induced LTD-like plasticity, these effects were largely reproduced by selective stimulation of D1Rs and D2Rs (Fresnoza et al, 2014;Monte-Silva et al, 2009). In addition, data from studies blocking D2R activity by sulpiride or haloperidol showed a consistent suppression of tDCS-, PAS-, and TBS-induced plasticity (Korchounov and Ziemann, 2011;Monte-Silva et al, 2011;Nitsche et al, 2006). Thus, a certain amount of background dopamine activity seems necessary for induction of plasticity.…”

“…With regard to the contribution of mAChRs vs. nAChRs, nicotine abolished anodal tDCS-induced, but prolonged PASinduced LTP-like plasticity, while it abolished LTD-like plasticity in both stimulation protocols (Thirugnanasambandam et al, 2011a). Finally, the mAChR antagonist biperiden reduced LTP-like plasticity induced by PAS (Korchounov and Ziemann, 2011). In summary, cholinergic activity seems to exert important modulatory effects on NIBS-induced plasticity, but the knowledge about receptor-and dose-dependent effects is still limited.…”

“…In contrast, tacrine, another cholinesterase inhibitor, had no effect on PAS-induced plasticity (Korchounov and Ziemann, 2011). The reason for these conflicting results might have been a dose-dependent effect of cholinergic activation on plasticity, which has not yet been explored.…”

Deleterious Effects of a Low Amount of Ethanol on LTP-Like Plasticity in Human Cortex

“…Only those subjects with RMTp50% of maximum stimulator output (n ¼ 22) were retained for a second screening step (PAS LTP screening) because RMT450% of maximum stimulator output is associated with a low probability for a LTP-like response after PAS LTP (Müller-Dahlhaus et al, 2008). After a second screening step, nine subjects were retained and enrolled into this study that exhibited a significant PAS LTP -induced increase in MEP amplitudeX1.2 (ratio of MEP amplitude post-PAS/pre-PAS) (Heidegger et al, 2010;Korchounov and Ziemann, 2011). Therefore, this selection excluded subjects with a long-term depression-like MEP decrease or no MEP change following PAS LTP (Müller-Dahlhaus et al, 2008), as the explicit aim of this study was to study drug effects on LTP-like plasticity, a process with significant relation to motor learning (Jung and Ziemann, 2009;Kang et al, 2011;Rosenkranz et al, 2007;Ziemann et al, 2004), rather than exploring drug effects on a great variety of magnitudes and directions of PAS LTP -induced plasticity in the general population.…”