Serotonin/serotonergic system depression

There is evidence for the contribution of serotonin dysfunction to mania, and in the mechanism of action of mood stabilizers [19], however, specific data on the serotonergic system and mania are fewer and variable. Moreover, altered functioning of other neurotransmitters in mania such as norepinephrine, dopamine, acetylcholine, and GABA, and their interaction with serotonin, are also likely to be involved in the pathogenesis of mood disorders. Differences in these neurotransmitter systems possibly underlie differences in the pathogenesis of depressive and manic episodes. 

The role of serotonin (5-hydroxytryptamine, 5-HT) has also been extensively studied in depressed patients. Whereas the overall psycho-physiological effects of noradrenaline in the CNS appear to be linked to drive and motivation, 5-HT is primarily involved in the expression of mood. It is not surprising therefore to find that the serotonergic system is abnormal in depression. This is indicated by a reduction in the main 5-HT metabolite, 5-hydroxy indole acetic acid (5-HIAA), in the cerebrospinal fluid of severely depressed patients and a reduction in 5-HT and 5-HIAA in the limbic regions of the brain of suicide victims. The 5-HT receptor function also appears to be abnormal in depression. This is indicated by an increase in the density of cortical 5-HT2a receptors in the brains of suicide victims and also on the platelet membrane of depressed patients. Platelets may be considered as accessible models of the nerve terminal. 

Additionally, COX-2 inhibitors influence—either directly or via CNS-immune mechanisms—the CNS serotonergic system. In a rat model, treatment with rofecoxib was followed by an increase of serotonin in the frontal and the temporo-parietal cortex (Sandrini et al., 2002). Since the lack of serotonin is one of the pinpoints in the pathophysiology of depression, a clinical antidepressant effect of COX-2 inhibitors would be expected due to this effect. A possible mechanism of the antidepressant action of COX-2 inhibitors is the inhibition of the release of IL-1 and IL-6. Moreover, COX-2 inhibitors also protect the CNS from effects of quinolinic acid (Salzberg-Brenhouse et al., 2003). 

The effect of systemic administration of these amphetamine metabolites on the content of DA and its metabolites and on 5-HT was then examined. When pOHA was administered systemically (5, 15, or 30 mg/kg), the concentration of DA and its metabolites in the neostriatum was depressed. The effect on the neostriatal serotonergic system was not as pronounced as that on the dopaminergic system hippocampal serotonin content was altered only at the higher dose of pOHA and hypothalamic 5-HT concentrations were decreased at both the 15 mg and 30 mg doses. The authors then determined the effect of the monoaminergic uptake inhibitors amfonelic acid and cocaine on the response to systemically administered pOHA. The decrease in DA and its metabolites was attenuated by amfonelic acid (1 mg/kg, administered 30 minutes before pOHA), but cocaine failed to alter the effects of systemic pOHA administration. 

Several psychological disorders are currently being discussed in terms of the effect of the physical state of the membrane lipids on neurotransmitter receptor function. Hibbeln and Salem (1995) suggest that serotonin levels and membrane 22 6n-3 content are directly linked, whereby low 22 6n-3 yields low serotonin. This results in an individual being susceptible to depression or other affective diseases. These authors suggest that the depletion of 22 6n-3 induces a change in membrane physical properties, which, in turn, influences the function of either serotonergic receptors or serotonin reuptake systems. 

Monoamine oxidase inhibitors, such as SSRIs, have been shown to be effective in the treatment of depression, and they have become among the most widely used prescription drugs in the United States. Prozac is used not only to treat major depressive disorders but also bulimia nervosa, obsessive-compulsive disorder, panic disorder, and premenstrual dysphoric disorder. Multiple serotonin receptor subtypes are involved. Specific serotonin receptor subtype agonists and antagonists have been radiolabeled with positron-emitting tracers to assess the state of the serotonergic system. 

In this section the emphasis is placed on the serotonergic system in the context of the CNS. The chemical manipulation of the serotonergic system within the CNS can be achieved either directly, for example by the use of S-hTT receptor agonists (e.g. migraine, depression) or antagonists (e.g. emesis), or indirectly by the manipulation of serotonin synthesis and turnover. The latter principle is of particular importance when treating a variety of depressive disorders. 

Brain serotonergic neurons are involved in numerous diffuse functions such as mood, sleep, appetite, and temperature regulation, as well as the perception of pain, the regulation of blood pressure, and vomiting (see Chapter 21). Serotonin also appears to be involved in clinical conditions such as depression, anxiety, and migraine. Serotonergic neurons are also found in the enteric nervous system of the gastrointestinal tract and around blood vessels. In rodents (but not in humans), serotonin is found in mast cells. 

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