Page - (000174) - in Biomedical Chemistry: Current Trends and Developments

are essentially non-overlapping and distribute to separate sites. Fibers from the DRN primarily project to the SNc, VTA, amygdala, striatum, lateral preoptic area, substantia innominata, nucleus accumbens and several regions of the cortex, while MRN fibers distribute mainly to midline and para-midline structures (Vertes, 1997; 1999). Direct synaptic connections between raphe serotonergic terminals and DA neurons were first demonstrated in the VTA (Herve, 1987), since then, a close relationship between the serotonergic and the dopaminergic systems has been well established. Synthesis of dopamine in DA-neurons starts with the metabolization of L-tyrosine into 3,4-dihydroxiphenylalanine (L-DOPA) by TH (Nagatsu, 1964; 1998), followed by almost immediate conversion of L-DOPA into dopamine by L-aromatic amino acid decarboxilase (L-AADC) (Deutch, 1999). Dopamine is stored into vesicles in the presynaptic terminal of dopaminergic neurons, which not only prevents DA from degrading, but also delays its diffusion to the extracellular space. Dopamine is released into the synapse by calcium dependent exocytotic mechanisms. Once in the synaptic cleft, DA can interact with presynaptic autoreceptors (D2- like receptors that include D2, D3 and D4), regulating DA synthesis, release and neuronal firing-rate; or with postsynaptic receptors (D1-like, that include D1 and D5), modulating the response of the postsynaptic neuron. The D1 receptor is the most widespread receptor, the most expressed and exclusively postsynaptic (Vallone, 2000). The D2 receptor is found mainly expressed by GABAergic neurons (Civelli, 1991). Importantly, these receptors are known to form heteromers, which can have relevant functions in the dopaminergic brain (Hasbi, 2011; Perreault, 2014). The dopamine transporter protein (DAT) seems to be targeted by a complex net of regulation mechanisms, which depend primarily on the extracellular levels of DA. This transporter is a major target for psychostimulant drugs, such as cocaine and amphetamines, which can easily block it or use it to enter the dopaminergic terminal, leading to increased extracellular levels of DA and increased oxidative stress (Reith, 1997; Chen, 2000). DAT increased levels are potentially dangerous to the neuron (due also to its ability to transport toxins). A positive correlation between the levels of DAT expression and