Dopaminergic Modulation of Neuroplasticity in Humans- Contribuition of Receptor Subtypes and Dosage

From infancy up to adulthood and beyond, the brain reacts adaptively to the continuously changing environment. This capacity is termed “plasticity” and describes the ability of the brain to develop, react to environmental demands by producing proper behavior and repair itself after a disease or injury. Neuroplastic modifications of brain structure and functions are also thought to be important physiologic mechanisms of learning skills and remembering events in our life. Two functional changes taking place at the glutamatergic but also other synapses, namely long term potentiation (LTP) and long term depression (LTD), are considered as synaptic correlates of learning and memory processes (Jay, 2003). Pioneering attempts to study and understand the basic mechanisms of LTP and LTD induction and expression were conducted in slice preparations and in vivo animal studies. However, over the last decades, non-invasive brain stimulation (NBS) techniques such as transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS) and paired associative stimulation (PAS) (Barker et al., 1985; Nitsche and Paulus, 2000; Stefan et al., 2000) emerged, which allow the induction and exploration of plasticity which share some properties with plasticity induced in animal models also in humans. Recently, combining these techniques with central nervous system (CNS) active drugs and imaging techniques (Ziemann, 2004; Ko et al., 2013; Saiote et al., 2013) has given us additional opportunities to study mechanisms and effects of cortical plasticity in the intact human brain. Neuroplasticity is influenced by substances termed neuromodulators. Among these neuromodulators, dopamine has received the most attention since the discovery that L-3,4-dihydroxyphenylalanine (L-DOPA), the synthetic precursor of dopamine, can alleviate the motor symptoms of Parkinson’s disease (Abbott, 2010), and that antagonizing dopamine receptor subtypes can relieve positive symptoms of schizophrenia (Seeman, 1987). In physiological and cognitive studies in animals, a complex, heterogeneous, sometimes opposing pattern of effects of alteration of dopaminergic activity emerges, depending on dosage, affected receptor subtypes, and basal brain activity (Seamans and Yang, 2004). The results of human electrophysiological studies improved our knowledge about the impact of dopamine on neuroplasticity (Kuo et al., 2008; Monte-Silva et al., 2009; Nitsche et al., 2009; Monte-Silva et al., 2010; Thirugnanasambandam et al., 2011), however, it is still far from being complete. Specifically, the impact of dopamine receptor subtypes on neuroplasticity in humans was not explored systematically so far. Given the presumed relevance of neuroplasticity for cognition and behavior in health and disease, improving this knowledge might enhance our understanding of respective processes. In this project we were interested to explore the dosage-dependent, specific effects of dopamine receptor subtype activation on functional plasticity of the human brain. The first chapter will give an introduction into the basic concept of plasticity, its relation to cognitive processes, and modulation by dopamine, and the techniques of inducing and evaluating plasticity in humans. The second chapter contains the main component of the thesis; each subchapter consists of published projects or projects accepted for publication. Finally, the last chapter will discuss the main findings of the present work, including limitations, and future directions for research.