Serotonin/serotonergic system

In addition to the aetions of MDMA and other derivatives at 5-HT2 serotonin reeeptors. some of the effeets on serotonergic systems could be mediated via S-HTja reeeptors, at whieh MDMA has a moderate affinity. Direct agonist effects at this site might eontribute to the mood-altering and calming effects of the drug, sinee similar effects have been reported for novel anxiolyties sueh as ipsaperone and buspirone, which interact with 5-HTia serotonin reeeptors. 

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. 

Serotonergic systems are also affected by adolescent treatment in a sexually dimorphic manner. During adolescence, at doses that produce plasma nicotine doses similar to levels found in smokers, nicotine decreases serotonin receptors specifically in the cortex, in female rats. However, in the midbrain, there was an increase in males (Xu et al. 2002). 

The detection of serotonin in nervous and non-nervous tissue was aided by the development of the Falck-Hillarp histochemical technique, a method whereby freeze-dried sections of tissue, when exposed to formaldehyde vapour cause indoleamines to emit a yellow fluorescence. Dahlstrom and Fuxe used this technique to show that the highest concentration of serotonin in the brain is located in the raphe nuclei, projections from these cell bodies ascending to the forebrain via the medial forebrain bundle. Descending fibres were also shown to project to the dorsal and lateral horns and the intermediolateral column of the spinal cord. Detailed observation of the distribution of the serotonergic system in the brain became possible with... 

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. 

Gammie SC, Nelson RJ (1999) Maternal aggression is reduced in neuronal nitric oxide synthase-deficient mice. J Neurosci 19 8027-8035 Caspar P, Cases O, Maroteaux L (2003) The developmental role of serotonin news from mouse molecular genetics. Nat Rev Neurosci 4 1002-1012 Gobbi G, Murphy DL, Lesch K, Blier P (2001) Modifications of the serotonergic system in mice lacking serotonin transporters an in vivo electrophysiological study. J Pharmacol Exp Ther 296 987-995... 

Panic attacks, dissociative episodes, and flashbacks appear to be related to serotonin function (Southwick et ah, 1991). Thus, there are significant phenomenological overlaps between PTSD symptoms and their comorbid conditions that share mediation by serotonergic systems. 

Some evidence indicates that other drugs with action on the serotonergic system may be associated with efficacy in OCD. Tryptophan, a precursor of serotonin, was shown in a small placebo-controlled study to have an effect size similar to that of the SSRls (S. A. Montgomery et al. 1992). Mianserin, which has 5-HTjq and 5-HT2C receptor affinities, has also been reported in a small placebo-controlled study to be more effective than placebo. This last result raises the possibility that 5-HTjp or 5-HT2C may be the more specific receptors for OCD. The provocation of obsessional symptoms by m-chloro-phenylpiperazine (mCPP), which also has affinities for 5-HT,p and 5-HT2C, reinforces this concept (Zohar et al. 1988a). 

In this chapter, we review the pharmacology of several selective serotonin reuptake inhibitors [SSRIs] and other drugs that act on the serotonergic system. That these developments have enhanced safety and tolerability is now beyond dispute, but it is also clear that these agents are no more effective than the old-style tricyclic antidepressants [TCAs]. [For a comprehensive discussion of serotonergic medication, see Montgomery, Chapter 12, in this volume.] Here, several compounds are discussed in detail. 

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