Page - (000176) - in Biomedical Chemistry: Current Trends and Developments

a number of limbic structures, particularly in the hippocampus (Hoyer, 2002). The 5-HT1A receptor was associated with modulation of anxiety- related behaviors (Heisler, 1998) and also with locomotor activity (Carey, 2001). The 5-HT1B receptors are expressed mainly in the basal ganglia, striatum, nucleus accumbens and frontal cortex, and are thought to act as terminal autoreceptors; in addition, they can also serve as terminal heteroreceptors, controlling the release of other neurotransmitters (Hoyer, 2002). The 5-HT2-like receptor class comprises the 5-HT2A, 5-HT2B and 5-HT2C (formerly 5-HT1C) receptors, which couple preferentially to G proteins that employ protein kinase C, (Blaukat, 2000) to increase the hydrolysis of inositol phosphates and increase cytosolic calcium (Hoyer, 2002). In the CNS, the 5-HT2A receptors are mainly located in the cortex, claustrum and basal ganglia, and are particularly important to the behavioral effects of drugs of abuse (Filip, 2001; Munzar, 2002; Porras, 2002). The 5-HT2B and 5-HT2C receptors are restricted to a few brain regions and were reported to be implicated in mediating hypo/hyperphagia, grooming frequency and anxiety behavior (Hoyer, 2002). The 5-HT3 receptors are intrinsic ligand-gated channels, which trigger rapid depolarization due to transient inward current. The 5-HT7 receptor, in accordance with its distribution in the limbic system and thalamocortical regions, plays a relevant role in the pathophysiology of affective and mood disorders (Vanhoenacker, 2000; Hoyer, 2002). Accumulating evidence shows that optimal brain function relies on a complex equilibrium of neurotransmitters and respective receptors in well-organized circuitries. For most of these players, an inverted “U”- shaped curve is the best fit to describe the relation between either sub- optimal or supra-optimal levels and a specific behavioral performance (Cools, 2011; Yadid, 1998). For DA this seems to be particularly relevant. Balanced DA transmission is essential for correct modulation of the cognitive process. Deregulation of the DA function at the frontocortical level will impact on decision-making, judgment capacity, planning, working-memory, attention, cognitive flexibility, and impulsivity (Brozoski, 1979; Cai, 1997; Fischer, 2010). As such, the dopaminergic system is often targeted by pharmacologic approaches meant to improve the cognitive function in several diseases (but also in healthy