Page - (000178) - in Biomedical Chemistry: Current Trends and Developments

Loss of DA neurons in the SNc (and also in the VTA) and consequent reduction of dopaminergic innervation is a hallmark of Parkinson Disease (PD). As PD progresses these patients display several primary motor symptoms characteristic of decreased DA function within the basal ganglia, such as palsy (tremor), bradykinesia, muscular rigidity, plus postural instability at later stages (Moore, 2003; Samii, 2004). Cognitive decline can be seen in mild progressive stages, often accompanied by depression and anxiety (Riedel, 2010). Apathy, anhedonia, helplessness and impaired concentration were also reported. Loss of DA neurons results from either genetic or environmental causes, leading to formation of cytoplasmatic insoluble protein aggregates, resulting from mutated forms of different proteins that cannot be degraded by proteossomic activity. Although α-synuclein is the most studied of these mutated proteins, this not the most common form of mutation. These aggregates were associated with increased oxidative stress, mitochondrial dysfunction and cell death. It is noteworthy that recent studies suggest components of serotonergic, noradrenergic, cholinergic and glutamatergic disruption in PD patients (Bohnen, 2007; Kish, 2008). Also of relevance for the present review is the role of DA in memory formation. Mesolimbic dopaminergic signaling was shown to act on memory encoding at the CA1 hippocampal region through D1 and D5 modulation of long term potentiation (LTP) (Swanson-Park, 1999) These mechanisms revealed the role VTA-mediated rewarding events in memory encoding and recalling, highlighting the relevance of DA and the reward system in associative learning, and the role of prediction and expectation in long-term memory (Rossato, 2009; Singer, 2009). Serotonin also plays a key role in cognitive function. The relevance of the serotonergic system in learning and memory formation is well documented. While agonists on the 5-HT1 receptor were seen to impair memory retention, stimulation of the 5-HT7 receptors or blockage of 5- HT3, 5-HT4 and 5-HT6 receptors improves memory formation (Seyedabadi, 2014). Although, multiple serotonergic intracellular pathways are involved in neuronal plasticity and memory formation, 5- HT seems to act through modulation of cholinergic, dopaminergic, GABAergic or glutamatergic transmission. In accordance, in memory