Catecholamine hypothesis studies

The catecholamine hypothesis was then modified to include 5-HT in the etiology of depression (9,10). It should be noted, however, that not all Inhibitors of monoamine reuptake are antidepressants, because cocaine, a potent inhibitor of NE and dopamine reuptake, is not an antidepressant but, rather, an addictive stimulant. Subsequent studies with inhibitors of monoamine biosynthesis appear to confirm Kielholz s opinion and Schiidkraut s modified theory that clinical depression is the result of a deficiency in both 5-HT and NE and that the antidepressive mechanism of action most likely affects levels of both. 

Selected for clinical trials as a compound to calm agitated patients, imipramine was relatively ineffective. However, it was observed to be effective in the treatment of certain depressed patients (38). Early studies on the mechanism of action showed that imipramine potentiates the effects of the catecholamines, primarily norepinephrine. This finding, along with other evidence, led to the hypothesis that the compound exerts its antidepressant effects by elevating norepinephrine levels at central adrenergic synapses. Subsequent studies have shown that the compound is a potent inhibitor of norepinephrine reuptake and, to a lesser extent, the uptake of serotonin, thus fitting the hypothesis that had been developed to explain the antidepressant actions ofMAOIs. 

COMT hypothesis. According to this hypothesis. St. John s wort increases the levels of catecholamines at the brain synapses by inhibiting their inactivation by oxidative deamination (MAOl) and by catechol functionalization (catechol-0-methyltransferase [COMTl). Recent studies have shown that hypericins possess such activities only at pharmacologically excessive concentrations. If true, these effects at normal doses are small and do nothing to alleviate depression. Other hypotheses suggest hormonal effects or effects on the dopaminergic system. Hyperforin has become a candidate for the major antidepressant constituent of St. John s wort. 

In an in vitro rabbit carotid body preparation, Bairam et al. found that hypoxia-induced DA release was minimal in 1-15-day-old rabbits and only became significant after 25 days of age (49). Similarly, using carbon fiber electrodes in rat carotid bodies, peak free tissue catecholamine levels in response to anoxia were low in newborns and increased >10 fold over the frrst month of life (10). Thus, studies to date indicate low baseline DA levels and increasing DA release during the frrst weeks of life in rabbits and rats, which does not support the hypothesis that declining carotid body catecholamine levels account for the maturational increase in nerve activity or O2 sensitivity. However, catecholamine release by nerve terminals (56) may be altered in an in vitro cut-CSN preparation and, therefore, the question has not been fully resolved. 

The above findings do not convincingly support the hypothesis that disturbed brain catecholamine metabolism plays much part in abnormal mood states. However, the reversal by dopa of reserpine sedation in animals [364] has led to the trial of dopa as an antidepressant but until recently with little or no success [304, 365, 366, 367]. However, the successful treatment of parkinsonism with large amounts of L-dopa (5.4.3) has encouraged further investigation and some depressed patients studied benefited from treatment with L-dopa plus a peripheral decarboxylase inhibitor [368] though others became more psychotic. Depressive symptoms worsen in some parkinsonian patients given L-dopa [185]. 

---