Considering the origin of the noradrenergic, serotonergic, and dopaminergic neurones in the brain and their projections into many areas of the brain, it is clear that monoaminergic systems are responsible for many behavioral symptoms, such as mood, vigilance, motivation, fatigue, and psychomotor agitation or retardation. Abnormal function and the behavioral consequences of either depression or the manic state may arise from altered synthesis, storage, or release of the

neurotransmitters, as well Inhibitors,research,lifescience,medical as from disturbed sensitivity of their receptors or subcellular messenger functions.37 Neurotransmitter concentration Many attempts have been made to prove the hypothesis of reduced monoamine availability by measurement of neurotransmitters and/or their

metabolites in postmortem brain tissues and body fluids, such as cerebrospinal fluid (CSF), blood, and urine.38 Although repeated data showing decreased levels of the NE metabolite a-methoxy-4-hydroxyphenylglycol Inhibitors,research,lifescience,medical (MHPG), which indicates NE. turnover in brain, support the hypothesis of a deficient noradrenergic system,38 the results are inconsistent.39 Similarly to the noradrenergic system, the data on determinations of 5-HT and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) could not prove the hypothesis of exclusively reduced serotonergic Inhibitors,research,lifescience,medical transmission. Many studies reported decreased central serotonergic turnover in major depression;40,41 but findings also suggested that reduced 5-HT function may not be present Inhibitors,research,lifescience,medical in all depressed patients.42 These discrepancies between studies may reflect both methodological problems, such as difficulties in measuring the amines after various postmortem delays, and the fact that determinations of neurotransmitters or their metabolites in CSF or blood reflect a summation of many events in many brain areas Inhibitors,research,lifescience,medical and not in restricted nuclei.43

Similarly to the data on neurotransmitter concentrations, the results on the possibility of impaired activity of the enzymes for synthesis and degradation of monoamines are not convincing. Tyrosine hydroxylase and tryptophan to hydroxylase are essential for NE and 5-HT synthesis, respectively, and were found to be up- or downregulated in postmortem brain samples, suggesting a minor importance for transmitter synthesis. Similarly, no conclusive abnormalities were found in the degrading activity of MAO.42 The paradigm of monoamine depletion, which links clinical state to monoamine deficiency, nicely offers the possibility of investigating the effect of decreased monoamine concentration on behavior and gives us much additional information on its impact on the psych opathology of depression. Addition of α-methylparatyrosine, which inhibits the NE-synthesizing enzyme tyrosine hydroxylase, leads to a click here depletion of NE in the synapse.