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The etiology of late-onset Alzheimer's disease (AD) and idiopathic Parkinson's disease (PD) is not known. In both disorders there is an extensive degeneration of serotonergic neurons, with corresponding losses of the serotonin (5HT) transporter (5HTT), which is responsible for the reuptake of 5HT from the synaptic cleft. An increasing body of evidence indicates that allelic variation of the 5HTT gene promoter (5HTT gene-linked polymorphic region, 5HTTLPR) determines high or low 5HT uptake in normal human brain. Association studies show that the low-activity allele of the 5HTTLPR is a risk factor for late-onset AD. In PD, the 5HTTLPR influences the risk of developing depression, a common symptom in PD patients. A compromised serotonergic system thus plays an important role in the pathophysiology of both AD and PD.

Neurotransporters are high-affinity transport proteins located in the plasma membrane of both presynaptic nerve and glial cells that mediate the removal of neurotransmitters from the synaptic cleft or represent intracellular transport systems that concentrate neurotransmitters in synaptic vesicles. They comprise three subgroups, Na+/Cl(-)- or Na+/K(+)-dependent cell surface transporters and H(+)-dependent transporters associated with synaptic vesicles. The new insights into neurotransporter diversity provide the means for novel approaches of studying neurotransmitter uptake processes at the molecular level, such as substrate translocation and antagonist binding as well as regulation of gene expression, of intracellular trafficking, and of posttranslational modification. Moreover, modeling neurotransporter-related disorders and therapeutic strategies in genetically engineered animals are now feasible research strategies. Through an improved understanding of the modulation of neurotransporter function in the brain, it may be possible to identify the molecular factors underlying the etiopathogenesis and pathophysiology of neurodegenerative disorders. Due to their specificity for distinct neuronal systems, neurotransporters and their genes are potential targets for novel therapeutic strategies.

The effect of chronic treatment with the selective and reversible MAO-A-inhibitor moclobemide (MOC) vs. the norepinephrine reuptake inhibitor maprotiline (MAP) on alpha 2-adrenoceptor responsivity was studied by clonidine (CLON)-evoked growth hormone (GH) release in major depressive disorder. Compared to matched controls the depressed patients showed attenuated CLON-induced GH responses before treatment with MOC or MAP. Chronic treatment with both MOC and MAP significantly improved the depressive symptomatology. Although a trend toward increased GH responses to CLON was demonstrated after treatment in both groups, neither MOC nor MAP had a complete effect on restoration of alpha 2-adrenoceptor responsivity. No difference in insulin-like growth factor I (IGF-I) plasma concentrations before and after treatment with MOC or MAP was found. Our results support the view that antidepressants with different mechanisms of action may be capable of restoring alpha 2-adrenoceptor function during recovery from a major depressive episode.

N = 53 inpatients with major depressive disorder have been treated with the reversible, selective MAO-A-inhibitors moclobemide (double-blind versus maprotiline) and brofaromine (open study), respectively. Clinically, significant improvement of depression and an activating profile of action could be observed, typical side effects were sleep disturbances, agitation and weight loss. The neurobiochemical data showed an increase of noradrenaline plasma concentrations under treatment with moclobemide. Visual reaction times improved with antidepressant treatment. MAO-A inhibitors proved to be effective antidepressants in the treatment of hospitalized patients with predominantly endogenous depressions.