Subject serotonin

Recent evidence indicates that the 5-HT transporter is subject to post-translational regulatory changes in much the same way as neurotransmitter receptors (Blakeley et al. 1998). Protein kinase A and protein kinase C (PKC), at least, are known to be involved in this process. Phosphorylation of the transporter by PKC reduces the Fmax for 5-HT uptake and leads to sequestration of the transporter into the cell, suggesting that this enzyme has a key role in its intracellular trafficking. Since this phosphorylation is reduced when substrates that are themselves transported across the membrane bind to the transporter (e.g. 5-HT and fi -amphetamine), it seems that the transport of 5-HT is itself linked with the phosphorylation process. Possibly, this process serves as a homeostatic mechanism which ensures that the supply of functional transporters matches the demand for transmitter uptake. By contrast, ligands that are not transported (e.g. cocaine and the selective serotonin reuptake inhibitors (SSRIs)) prevent the inhibition of phosphorylation by transported ligands. Thus, such inhibitors would reduce 5-HT uptake both by their direct inhibition of the transporter and by disinhibition of its phosphorylation (Ramamoorthy and Blakely 1999). 

There is a recent clinical report by Emil Coeearo and colleagues that I think might be relevant to the kind of thing you have done in rats. They have been looking at endocrine responses to fenfluramine in humans as a marker of central serotonergic function. And they have observed an increase in serum prolactin concentration, which is felt to be due to serotonin release. They reported that, in subjects who received a seeond dose of fenfluramine within 12 days after the first dose, that there was a blunted response to serum prolactin. 

While brain serotonin systems may play a key role in mediating some of the effects of MDMA on analgesia and body temperature as well as in the reported anxiolytic-like and mood-altering subjective effects of the drug, additional neurotransmitter systems may contribute to some of the unique subjective experiences reported for MDMA and other drugs in this class. 

In light of this, studies of CSF 5-HIAA have been initiated in a cohort of human volunteers with a history of extensive MDMA use. Most participants in the study are individuals who have recently learned of the neurotoxic properties of MDMA and have asked to be evaluated for possible serotonergic damage. To qualify for the study, subjects must (1) have used MDMA on at least 20 to 25 occasions, (2) be drug-free for at least 2 weeks prior to participating in the study, and (3) not have a history of neuropsychiatric illness thought to involve alterations in serotonin metabolism. To date, 34 individuals have participated in the study. The study is now in progress, and completion is anticipated by 1991. At this time, it would be premature to comment on the results. 

A fourth approach to evaluating the intactness of dopamine and/or serotonin neurons in human subjects who have taken one of the amphetamine analogs might be to use a probe for labeling a constituent of those neurons in position emission tomography scanning studies. A label for the serotonin or dopamine uptake carrier, or a label for tryptophan hydroxylase or tyrosine... 

Gelernter, J., Kranzler, H. etal. (1997). Serotonin transporter protein (SLC6A4) allele and hap-lotype frequencies and linkage disequilibria in African- and European-American and fapanese populations and in alcohol-dependent subjects. Hum. Genet., 101(2), 243-6. 

Smeraldi, E., Zanardi, R. et al. (1998). Polymorphism within the promoter of the serotonin transporter gene and antidepressant efficacy of fluvoxamine. Mol. Psychiatry, 3(6), 508-11. Wang, S. L., Huang, J. D. et al. (1993). Molecular basis of genetic variation in debrisoquin hydroxylation in Chinese subjects polymorphism in RFLP and DNA sequence of CYP2D6. Clin. Pharmacol. Ther., 53(4), 410-18. 

Neurotransmitter depletion has been attempted in at least 90 studies and has been the subject of a number of systematic reviews, the most recent and comprehensive of which is a metaanalysis conducted by a research team at the University of Amsterdam.24 The hypotheses of these studies were based on the premise that lowered monoamine levels cause depression, in which case depletion of these neurotransmitters ought to trigger depression in people who are not depressed. Here is what actually happens. Experimentally lowering the level of available serotonin, or of norepinephrine and dopamine, in healthy volunteers who have never been depressed does not affect their mood in the slightest. 

There is only one group of research subjects in whom rapid depletion of serotonin sometimes produces clinical depression. These are depressed patients in remission who are currently taking SSRIs. About half of these patients relapse when serotonin is depleted. Note that this only happens if they are still taking antidepressant medication. If they have stopped medication, depleting... 

Oberndorfer, S., Saletu-Zyhlarz, G. Saletu, B. (2000). Effects of selective serotonin reuptake inhibitors on objective and subjective sleep quality. Neuropsychobiology 42, 69 81. 

The profound effects of Li+ upon phosphoinositide metabolism and cell signaling have been the subject of several recent reviews [54,81,85,86]. These effects are dependent upon receptor stimulation of the phosphoinositide cycle by a range of stimuli, including norepinephrine, serotonin, and carbachol the basal turnover of this cycle is largely unaffected by Li+ [82,87,88]. 

Results of studies on the role of serotonin-in the action of LSD, which were conducted on human subjects, may be more easily interpreted because they directly examined the hallucinogenic effects of LSD. Prior depletion of brain serotonin with reserpine accentuated the effects of LSD (34,71). As described above, prior treatment with a MAOI attenuated the effects of LSD (38,70) and... 

In contrast, much is known about the catabolism of catecholamines. Adrenaline (epinephrine) released into the plasma to act as a classical hormone and noradrenaline (norepinephrine) from the parasympathetic nerves are substrates for two important enzymes monoamine oxidase (MAO) found in the mitochondria of sympathetic neurones and the more widely distributed catechol-O-methyl transferase (COMT). Noradrenaline (norepinephrine) undergoes re-uptake from the synaptic cleft by high-affrnity transporters and once within the neurone may be stored within vesicles for reuse or subjected to oxidative decarboxylation by MAO. Dopamine and serotonin are also substrates for MAO and are therefore catabolized in a similar fashion to adrenaline (epinephrine) and noradrenaline (norepinephrine), the final products being homo-vanillic acid (HVA) and 5-hydroxyindoleacetic acid (5HIAA) respectively. 

Dewey SL, Smith GS, Logan J, Brodie JD, Simkowitz P, MacGregor RR, Fowler JS, Volkow ND, Wolf AP. (1993). Effects of central cholinergic blockade on striatal dopamine release measured with positron emission tomography in normal human subjects. Proc Nat Acad Sci USA. 90(24) 11816-20. Dhahir HI. (1971). A comparative study of the toxicity of ibogaine and serotonin. Dissertation Abstract Int. 32(4-B) 2311. 

---