In the first instance, proteins such as enzymes, transporters, and receptors more specifically devoted to the serotonergic functions will be described. Methodological limits of the classical postmortem approaches in the human and new 5-HT in vivo imaging modalities will also be considered. At the present time, more than 100 000 scientific publications concern 5-HT (PubMed). Wherever

possible, we have tried Inhibitors,research,lifescience,medical to include up-to-date references dealing with the human brain. The main molecular protagonists in 5-HT neurotransmission From tryptophan to serotonin In the brain, neuron subpopulations have a set of enzymes permitting the two-step synthesis of 5-HT from its precursor tryptophan, an essential aminoacid provided

by nutrients and Inhibitors,research,lifescience,medical actively cotransported with other neutral large amino acids from the blood to the brain.53 The consequences of tryptophan depletion or loading on physiological functions, including memory, cognition, mood, facial expression of emotion, and sleep, have been reported in detail Inhibitors,research,lifescience,medical elsewhere.53-56 Contrasting with the peripheral glandular serotonergic systems (eg, the enterochromafin cells or the pineal gland) that uses a first tryptophan hydroxylase form (TPOH1), 5-HT synthesizing click here neurons in the brain express another tryptophan hydroxylase (TPOH2) recently evidenced from knockout studies in mice.57 The respective sequences of these isoenzymes revealed 30% heterology, offering the perspective of a selective modulation Inhibitors,research,lifescience,medical by appropriate drugs in central or peripheral pathologies.57 Some 5-HT-related neuropsychiatric disorders are possibly correlated with genetic variants of TPOH2.57-61 Additionally, recent analyses indicate that TPOH1 polymorphisms could increase susceptibility to schizophrenia62 and suicidal behavior.63 5-hydroxytryptophan

formed during the first rate-limiting step by TPOH1 or TPOH2 is then transformed into 5-HT Inhibitors,research,lifescience,medical via an aromatic L-amino acid decarboxylase (AADC) also present in catecholaminergic neurons. Rare AADC point mutations reported in humans result in deficiency of catecholamines and serotonin with severe neuropsychiatric symptoms.64 In the nervous system, 5-HT is mainly metabolized by the monoamine oxidase A (MAOA) and Linifanib (ABT-869) a 5-HT half-life of only a few minutes is reported.65 Thus, reciprocal 5-HT exchanges between the central nervous system (CNS) and other tissues appear to be limited, although a brain 5-HT efflux through the blood-brain barrier was observed in rat species.66 Abnormality in 5-HT metabolites, especially low 5-hydroxyindolacetic acid (5-HIAA) levels in the cerebrospinal fluid (CSF) was correlated with suicidality and severity of aggressive behaviour.67,68 Furthermore, an association between CSF 5-HIAA and cholesterolemia was described in certain suicidal patients.