HT functions

It is obvious that strenuous efforts have been invested in the research of 5-HT receptors and, in particular, in the development of receptor-selective agonists and antagonists. All this has been done in the hope that it might be possible to control a specific switch in the brain that governs a particular aspect of 5-HT function and which would be beneficial therapeutically. A further ambition is that, by avoiding activation of other 5-HT receptors, the risk of any unwanted side-effects would be eliminated. Of course, it is equally possible that reduction in non-specific receptor interactions could actually unmask some side-effects. 

Gillman, PK (1999) The serotonin syndrome and its treatment. J. Psychopharmacol. 13 100-109. Heal, DJ, Cheetham, SC, Prow, MR, Martin, KF and Buckett, WR (1998) A comparison of the effects on central 5-HT function of sibutramine hydrochloride and other weight-modifying drugs. Brit. J. Pharmacol. 125 301-308. 

All these animal models express behavioural deficits that are paralleled by some abnormality in noradrenaline and/or 5-HT function but it is unlikely that the monoamines are the only neurotransmitters to influence these complex behaviours. Nevertheless, the behavioural deficits all respond, with varying degrees of specificity, to established antidepressants and central monoamines appear to have a crucial role in the therapeutic effects of these drugs. For a more detailed review of this subject see Stanford (1995). 

Figure 22.9 Summary of the influence of varying factors on sleep and waking. The EEG is shown diagramatically in the typical arousal (awake) state and in both non-REM (slow wave) and REM sleep. Appropriate activity levels, high or low, are shown for the different factors such as light input, melatonin secretion or ACh, NA, and 5-HT function in the different phases...

With regard to an alternative hypothesis (Jouvet, 1984), there is no firm evidence to support the proposal that 5-HT released during W might act as a neurohormone and induce the synthesis and/or release of hypnogenic factors secondarily responsible for SWS and REMS occurrence. Therefore, based on neurochemical, electrophysiological, and neuropharmacological approaches, it is currently accepted that 5-HT functions to promote W and to inhibit REMS. 

The amino acid L-tryptophan is the precursor for the synthesis of 5-HT. The synthesis and primary metabolic pathways of 5-HT are shown in Figure 13-5. The initial step in the synthesis of serotonin is the facilitated transport of the amino acid L-tryptophan from blood into brain. The primary source of tryptophan is dietary protein. Other neutral amino acids, such as phenylalanine, leucine and methionine, are transported by the same carrier into the brain. Therefore, the entry of tryptophan into brain is not only related to its concentration in blood but is also a function of its concentration in relation to the concentrations of other neutral amino acids. Consequently, lowering the dietary intake of tryptophan while raising the intake of the amino acids with which it competes for transport into brain lowers the content of 5-HT in brain and changes certain behaviors associated with 5-HT function. This strategy for lowering the brain content of 5-HT has been used clinically to evaluate the importance of brain 5-HT in the mechanism of action of psychotherapeutic drugs. 

Several compounds affecting various 5-HT functional parameters (uptake inhibition (fluoxetine), metabolism (tranylcypromine) or synthesis (5-OH tryptophan, 5-HTP)) had no effect on subemetic doses of cisplatin [110]. In fact, tranylcypromine and 5-HTP antagonized emesis of cisplatin. Thus these results would favour an inhibitory role of 5-HT instead of emetogenic. It is conceivable that an excess of 5-HT may desensitize 5-HT3 receptors that may result in a reduced sensitivity to emetogenic stimuli. 

Possible gene-interactive alterations in 5-HT function and BDNF expression was recently evaluated in mice with a combined manipulation of the genes for 5-HTT and BDNF. Male but not female 5-FlTT -BDNF DKO mice showed further decreases in brain 5-HT concentrations as well as further increases in anxiety-like behavior and stress reactivity compared to 5-HTT -BDNF controls (Murphy et al. 2003). These findings support the notion of critical role of gene-gene interaction in brain plasticity related to anxiety and related disorders. 

Serotonin involvement. There is substantial evidence supporting abnormal 5-HT function in autism, particularly with regard to both the social deficit and repetitive behavior dimensions of this disorder. Many studies of the neurobiology of autism have focused on 5-HT, which is implicated in the regulation of many functions relevant to autism, such as learning, memory. 

Anderson, I.M., Parry-Billings, M., Newsholme, E.A., et al. (1990) Dieting reduces plasma tryptophan and alters brain 5-HT function in women. Psychol Med 20 785-791. 

Abnormalities in 5-HT function have been identified in subjects with autistic disorder and other PDDs... 

The neurotransmitter serotonin (5-hydroxytryptamine [5-HT]) is widely distributed in the CNS, subsuming a variety of functions including drive satiety, mood, aggression, anxiety, and compulsive and impulsive behaviors. It may be an important neurotransmitter in psychiatric symptoms commonly associated with PTSD such as aggression, obsessive/intrusive thoughts, alcohol and substance abuse, and suicidal behavior (Friedman, 1990). Suicidal behavior is known to be associated with both childhood maltreatment and low 5-HT functioning (Van der Kolk et ah, 1991 Benkelfat,... 

Anecdotal case reports and small sample size trials have shown some benefit for the use of psychostimulants to manage episodes of excitability in mania. This counterintuitive, paradoxical effect parallels their beneficial use in children with hyperactivity ( 277). The theoretical basis may be related to an indirect effect of these agents that leads to enhancement of 5-HT functioning. 

Tyramine acts as an indirect sympathomimetic to cause release of catecholamines from nerve terminals. It is present in a number of foods mature cheese, yeast extracts, some red wines, hung game, pickled herrings, broad bean pods. Normally, MAO-A in the intestinal mucosa will metabolise tyramine absorbed from the gut. In patients on the older MAOls, considerable amounts of tyramine will enter the circulation and this will lead to increased release of catecholamines stored in nerve terminals because the MAOI prevents their metabolism. For patients on RIMA drugs, high concentrations of tyramine can compete for MAO-A, thus mitigating some of the effects, and MAO-B is still available to metabolise noradrenaline (norepinephrine). MAO-B, however, has relatively much less effect on 5-HT and thus 5-HT function is still enhanced. 

Dolan M, Anderson IM, Deakin JF. Relationship between 5-HT function and impulsivity and aggression in male offenders with personality disorders. Br J Psychiatry 2001 178 352-359. 

Stamford JA, Davidson C, Mclaughlin DP, Hopwood SE. Control of dorsal raphe 5-HT function by multiple 5-HT(l) autoreceptors parallel purposes or pointless plurality Trends Neurosci 2000 23 459-465. 

I Blocks Na and Ca channels and is a weak carbonic anhydrase inhibitor. It facilitiates DA and 5-HT function. 

HT function loss present in later stages rrray relate to aggressiort, mood change. 

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