1 yr ago I had an epidural steroid injection of 9mg betamethsone placed into my lumbar spine. I should mention that I was at that time also an competitive long distance runner. As the inj didn't do anything for my problem which was motor, I resumed training on day 3, so one half life of betamethasone at M of 10^-6, a least 500x the body's normal concentration, and training inducing hyperthermia and the particular aero position of my spine on a bike which maybe created a pressure gradient "pumping" some of the steroiid upwards, I believe some of the betamethasone diffused into the CSF fluid (hyperthermia increases the permeability of the blood brain barrier) inducing tryptophan hydroxylase activity in the brain (as found in rats who are injected with 10^-7 glucocorticoids into the brain P Sze 1976) because following 1 week of insomnia and a cold possibly due to systemic absorption of the steroid I had one month of symptoms that I now realize are more characteristic of serotonin toxicity than hypercortisolemia and persistent muscular tightness and complete absence of DOMS (delayed onset muscle soreness) that persists to this day, 1 year later, which is extrmemly unusual and which I believe may be due to remaining overstimulation of the 5-HT receptors in the brain, after all betamethasone isn't endogenous and 9mg is1000x the body's normal concentration and because I was taking an SSRI at the time as well and my training meant high body temperatures for prolonged periods of the day 7days a week increasing permeability of the blood brain barrier as well as agitating the steroid through tissue movement. Peripheral injection of supraphysiological amounts of cortisol for inflammation mediated pain like in a tendon causes permanent effects like lipolysis or weakening due to genomic effects. Maybe genomic effects in the brain also last longer.

At that time I thought that my training and the increased heart rate and hyperthermia and tissue movement had caused more of the steroid to be absorbed systemically much as putting a testtube in an agitator would, because after a bout of exercise say 1 hour at 220rpm anerobic intervals on a bike- I had the never-before strangest sensation of the blood vessels in my muscles constricting to the point where if I tried to do a push up there was no feeling of muscle contraction or vasodilation. There was noticeable reduction in muscle size beginning in week 3 and continuing thereon though now I am not certain if the loss was illusory meaning not necessarily loss in bulk but loss in volume from severe either neurological or vascular contraction or constriction- as a runner, the muscles would be highly vascularized so that any vascular constriction would be accompanied by a misleading reduction in volume.

At the time I thought it was the genomic effects of the betamethasone absorbed systemically putting a damper on inflammation or vasodilation but now after researching thte myriad effects of 5-HT in the body including vasoconstriction to the muscles, I am thinking it may be the latter. The fact that the most intense vasoconstriction followed exercise is in accordance with your theory that motor activity induces serotonin (unless the intensity of the exercise at anerobic activity is actually mediating serotonin through cortisol).

Other evidence that I had a higher than normal level of serotonin in the body were altered sleeping patterns following the week of initial insomnia and cold. Normally my sleep pattern lags behind day night and night cycles consistent with over HPA axis activity consistent with "depression". I had better than normal sleep that accorded with day and night cycles, which may also be due to serotonin modulating better sleep quality.

I had initially gastric stasis followed by melena for one week, then increased gastric motility for months. The initial GI prob may have been peripheral uptake of the steroid, but the latter is also in accordance with serotonin's effect on the gut.

I had peculiar altered consciousness following the initial week of insomnia, that I had initially attributed to the steroids, but that now I know is a peculiar high characteristic of serotonin. (I know this because a year later there was a period when I retook the ssris while on st john's wort therefore overloading serotonin in the body and that was the feeling I had following the ESI, and it is nothing like the feeling caused by licorice which increases cortisol).

I had ergogenic athletic effects. Betamethasone is a doping drug in long distance cycling. For one month following the ESI, I could stair climb at level 13 for 2 hours with no pain or feeling of straining whatsoever-my normal level is 7. These effects may have been a combination of increased muscle break down therefore yielding more energy substrate from the steroid, but also possibly from the serotonin as I did have metabolic acidosis at 5 wks when I finally had a blood test but the reason that I did not have kidney problems was that any substrate that made it into the blood was instantly utilized due to constant training.

I also was unknowingly confused. 6 months later the hospital which had administered the ESI banned me for life, ostensibly due to the sheer number of emails I had sent my providers asking for IGF-1, GH, or other androgenergic substances to replace the muscle from 8-10lbs I lost in the month following the ESI and which I had attributed to the steroid being absorbed systemically. The magnitude of my problem was great to me being the loss of many years of work on the body since very young, but my complete lack of foresight in the consequences of my actions may be due to decreased guilt inhibition and social anxiety via serotonin. Either way I was completely fixated on the one idea that the steroids were the cause of my problem and saw no other alternative or explanation for my problems, which certain internet sourcs say-this tunnel vision that is-is a consequence of ssris and its manifestation in me- the consequence of excess serotonin.

I know that serotonin in part contributed to involuntary muscular contraction because I was so fixated on the idea that the steroid was the culprit so there was no potential of placebo effect from coming off ssris as there was no expectation of improvement.Going along with the idea that the steroids caused everything and possibly as a result of confusion was may have been the result of abnormal brain chemistry, I happened to come off of the ssri six months after the injection but only because I happened to come across the fact that it was a cyp450 3a4 inhibitor- (3a4 being the pathway used by steroids). And rather than discontinuing the ssri I merely jumped onto another, St John's wort, research grade, that was still an ssri but was a cyp450 3a4 inducer, because I was still paranoid that all of my symptoms were due to residual genomic steroid effects in my peripheral body cells.

The St. John's wort got rid of the rash, the increased GI motility, but the muscular contraction remained until 6 months later when I happened to realize the error of my thinking when feeling tired on the SJW, I got back onto sertraline so that I was taking both at one time and had resumption of the altered consciousness and increased gastric motility that is peculiar to the ssri and not like food poisoning.

It wasn't until getting off both SJW and sertraline and waiting some weeks that I found that my legs which had been unable to recruit the posterior leg muscles as much due to contracture and feet pointing, were finally properly situated on the ground with weight more able to be borne in the heel. Prior to that if I had tried to train-cycling, first of all the quality was terrible, but secondly the feet were always involuntarily pointed in the pedals due to muscle tightness which turned out to be coming from the brain. The same contracture occurred in the upper body being unable to properly resist contraction from an extended to flexed triceps. And although I had no lumbar pain in my life prior to the ESI I had lumbar pain a month later as I found my tilted forward relative to my pelvis than normal which is consistent with muscles tightening.

Of course the chronic gut problem caused problems of its own and the SJW I didn't find out till later also depletes vitamin D levels as do steroids and vitamin D supplementation has helped somewhat, but I believe the main contributor was the over stimulation of serotonin in the brain due to my eccentric lifestyle of abnormally physically demanding training during the day which in addition to activating serotonin in the brain causes its own fluctuations of peripheral hormones like TSH and glucocorticoids, my history of taking ssris, and the fact that I resumed training before 2 full half lives of betamethasone were up. Or it is the effect of the steroid on other neuroamines in the brain.

Mainstream medicine is not equipped to handle this. In accordance with your finding that exercise increases serotonin, when I was first placed on ssris at 16.5 I was at 50mg then 100mg, tapering down to 25mg over time only because of increased time devotion to the endurance sport. My symptoms cannot be deduced from the typical neurological exam of the neurologist asking me to squeeze his or her fingers to determine "muscle strength" which is a deduction of muscle strength for survival. If I were to assign a number to my level of functionality prior to the ESI, it would be a 7, after, a -10. The reason why is because my basal normal funcitoning is high- I'm was in the top2% of finishing times for women which only would have improved with time because the fastest times are between the ages of 25-29 and I was then 23.5. That is my "normal." Relative to that, compared to my current "muscle weakness" the difference is large as I had adapted to the point of running daily18mile mileage in 87%humidity and 92deg weather here in south florida with ease in addition to being able to maintain anerobic threshold

If depression is always precipitated by a stressful event, as it was in my case-the loss of what had formerly been my training from age 8-age 16.5, then the ultimate therapeutic solution, more effective than meds though helped by meds, is to not only find a substitution to former life purpose that was lost but to be good at new life purpose. Consistent with that the refrain that I had much rather be dead even as the ssris improved my overall functioning as in school, did not quite die down to a lull until my last marathon when I saw undeniable improvement in my times, assurance that my work had yielded results. It is ironic that in seeking medical care to return to sport I have actually managed the destruction of the very engine that allowed me to participate in the sport in the first place and was the result of many years of cumulative work.

My problem cannot be treated by medicine in a manner of speeaking because in a way it should never have been treated in the first place. I never should have obtained an ESI as I never should even have been ordered a spinal mri and then the mri report was read wrong, and my problem is not coming from the spine.

They the providers say I could not have had the results that I did from one ESI. My retort is that I was not a normal candidate for the procedure. If lack of fitness, old or middle age, and excess weight and smoking are the main culprits for back pain and my symptoms were not even pain but motor and not in the back but in the leg. Secondly, my time cohort in the long distance running community puts me in a percentage far closer to 0% than 1. Thirdly, my long usage of ssris-8 years along with the comcomitant interactions with stress of training from over those same 8 years in high heat conditions. Fourthly, my returning to training before 2 half lives were up, whereas most people who get ESIs are limited by pain.

Looking back at my symptoms if they cannot be ascribed to peripheral absorption of the steroid from the back augmented by tissue movement and hyperthermia of exercise and comcomitant use of a cyp450 3a4 inhibitor, then they can only be ascribed to excess serotonin and as I have never had the like symptoms in all of my 8yrs of taking the ssri and did not have the same symptoms when I had a corticosteroid injection into a tendon,it must be due to the placement of the steroid next to my spinal cord diffused into the CSF via increased permeability of the blood brain barrier through hyperthermia from training and egged on by mechanical motion of the tissues during movement and consistent with the many findings of corticosteroid influence of neurotransmitter levels in the brain including serotonin(attached).

I still have a nonnormal level of muscular tightness and the absence of DOMS for over a year now. Of course it could be posited that the lack of DOMS is due to the muscles being unable to contract strongly enough to cause the micro damage that leads to soreness, but when I was given a serotonin antagonist to try out, Abilify, I did notice a slight return of muscle soreness that was extrmely transient, and either way the Abilify needed to be stopped due to unremitting drowsiness.

What is the point of this email? If I were studying depression in depth, then I think I would find a case like this to be interesting. Einstein said "Insanity is doing the same thing and expecting different results." In the beginning I wasted alot of money seeing doctors who really didn't care one way or another, lost alot of money and was banned from the hospital. During that interim and since then I have been doing research much like trying to whittle a needle out of a stone. I started my research on glucocorticoids and read through a huge number of papers on steroid mypathy and the textbook by Goulding and Flower but it wasn't until I entered the world of glucocorticoids and stress and the brain- neuroendocrinology - that I feel like some light is finally gained on the subject- after all no one in the world cares as much for the problem as the patient. I have seen over $5000 worth of doctors and am disheartened over and over again by the lack of care or diagnosis, furthermore most have never heard of a case of mine and don't believe it's important because don't understand the meaning of sport to individuals (Injured athletes and the risk of suicide-Smith).

When the hospital banned me, they essentially said "we don't believe anything you're saying, and sue us if you care" knowing that I'd lose. Why bring in legalese who would distort the truth? I would much rather simply be normal again.

The more that I consider my state prior to the ESI the more I wonder if my serotonin levels may have already been higher than normal anyway. Isn't this even more possible simply given the sheer amount of motor activity I do during the day sometimes 4-8hrs and while taking a selective serotonin reuptake inhibitor at the same time? Furthermore the reason I saw doctors in the first place was because my right foot was turning in inverting and slapping the floor after 5 minutes essentially losing control and over time manifested itself in non impact activities as difficulty walking and asymmetrical muscle tension so that I was lopsided. Of course there are also orthopedic explanations for these as well though certain factors like my foot loss of control is worse after sickness or injury, events which increase the body's own production of cortisol increases and of course cortisol modulates the levels of other neuroamines in the brain including serotonin and excess serotonin manifests as involuntary muscle contractions and myoclonus.

I am even more convinced that 5-HT overstimulation has eomthing to do with my problems because since stopping ssris completely I have noticed less muscle tension on the right leg which formerly had inclined it toward turning in. THere is also unusual smaller range of motion of all muscles from nonnormal tightness which persists in spite of their not being a lull in training hours since all of this started so no intentional deconditioning.

Glucocorticoid regulation of the serotonergic system of the brain.

Sze PY.

Abstract

Glucorticoids at concentrations above 10(-7) M stimulate the uptake of tryptophan by brain synaptosomes. Furthermore, in both developmental and drug-induced (reserpine and ethanol) increases of brain tryptophan hydroxylase activity, glucocorticoids are required in order for the increases to occur. If de novo enzyme synthesis is assumed to take place in such increases, we could adopt the working hypothesis that two loci of glucocorticoid action may exist in serotonergic neurons with respect to their specific function: one in the cell body presumably in a sequence of macromolecular events, and the other directly on nerve terminals. Thus, in its immediate action, the hormone may rapidly regulate 5-HT synthesis through an increased uptake of tryptophan by nerve terminals. In the slow action, the hormone may mainly play a permissive role in the induction of tryptophan hydroxylase by factors yet to be identified.

Neurotransmitter Responses Based on chemical structure, three classes of neurotransmitters are recognized that affect the cellular function of hippocampal cells: amino acids, biogenic amines, and neuropeptides. Of these, the responses to biogenic amines appear to be most sensitive to corticosteroid receptor activation. Corticosteroid effects on amino acid-mediated transmission seem to be diverse and only partly gene-mediated. Neuropeptide actions have largely not been investigated in this respect. The responses to serotonin (5-hydroxytryptamine, 5-HT) are strongly modulated by corticosteroid receptor activation. Serotonin can bind to several types of receptors on CA1 pyramidal neurons, including the 5-HT1A receptor. The activation of this receptor leads, through G-protein-coupling, to the opening of K+ channels, which results in a hyperpolarization of the membrane. With intracellular recording, it was found that the 5-HT1A receptor-mediated hyperpolarization is small under conditions of predominant MR activation. This may be due to a MR-dependent downregulation of 5-HT1A receptor mRNA expression, as was observed in the dentate gyrus and in some studies also in the CA1 region. The activation of GRs in addition to MRs (e.g., after exposure to a physical stressor) induces large 5-HT1A receptor-mediated responses. The molecular mechanism underlying these large responses is unclear because 5-HT1A receptor expression and binding are not increased after GR activation. Potential targets for steroid modulation downstream of the 5-HT1A receptor are probably also not modulated because steroid actions on the G-protein function or the K+ channel opened by the G-proteins cannot explain the changes in 5-HT1A response. In addition to modulation of 5-HT1A receptor-mediated responses, corticosteroids also affect responses or expression of 5-HT4 and 5-HT7 receptors. Depolarizing responses mediated via muscarinic acetylcholine receptors appear to have a similar steroid dependency. Because both serotoninergic and cholinergic responses are relatively large in the absence of corticosteroid hormones, there seems to be a U-shaped dose-dependency for the transmitter responses, as in the case of Ca2+ conductances (see Figure 2). This may signify the existence of a common denominator underlying all these steroid effects. It is possible that corticosteroid receptor activation results in the altered activity of kinases or phosphatases, which affect several membrane components in a comparable way through posttranslational modifications. This does not exclude the development of steroid actions aiming at specific genes. This is supported by the observation that responses to norepinephrine, mediated by β1-adrenoceptors, show an inverse linear steroid dose-dependency rather than the U-shape. Whereas the steroid modulation of biogenic amine responses is slow in onset, persistent, and requires de novo protein synthesis, steroid effects on amino acid-mediated responses seem to have different features. This was mostly investigated by examining the steroid modulation of synaptically evoked responses in the CA1 hippocampal region. The stimulation of Schaffer/commissural fibers in this region leads to a subsequent activation of glutamatergic AMPA and NMDA receptors. It was found that the administration of very high amounts of corticosterone, resulting in concomitant MR and GR occupancy, suppresses field responses mediated by glutamate receptors. With these very high doses of corticosterone a rapid onset of effects is seen and the effects are very prominent when extracellular Ca2+ concentrations are high. Moreover, the steroid effects are particularly evident after the repeated stimulation of the afferent pathway. The data suggest that under these circumstances energy-dependent processes in the signal transduction and cellular integrity may be impaired. When glutamate transmission is recorded under more physiological conditions (i.e., comparable to the design used to study effects on ion currents and aminergic responses), a slow GR-mediated enhancement rather than impairment of the responsiveness to synaptic stimulation becomes apparent. Inhibitory responses mediated by GABAA receptors are affected only by extreme (and probably physiologically not relevant) doses of corticosterone. GABAB receptor-mediated responses were found to be stable with predominant MR activation, but declined rapidly with repeated stimulation both in the absence of steroids and in the presence of very high amounts of corticosterone.

  (2010-04-06). Stress Science: Neuroendocrinology (Kindle Locations 19140-19175). Elsevier Science. Kindle Edition.

Platelets store serotonin (5-hydroxytryptamine), which is released when the cells are activated, and activated platelets synthesize thromboxane A2. Both of these substances may stimulate platelets (positive feedback) and cause vasoconstriction, especially when the vascular endothelium is not functioning normally. Stress may activate platelets.

  (2010-04-06). Stress Science: Neuroendocrinology (Kindle Locations 26419-26422). Elsevier Science. Kindle Edition.

Although the central action of glucocorticoids in moderating HPA activity is mainly on the PVN (see later), the noradrenergic locus coeruleus, the serotonergic dorsal raphe and the dopaminergic ventral tegmental area all express corticosteroid receptors and have been the focus of antidepressant research. All three of these nuclei express glucocorticoid receptor (GR), and the locus coeruleus and dorsal raphe have also been shown to express mineralocorticoid receptor (MR). 51 Monaminergic projections from these brainstem nuclei can also influence the activity of the HPA axis. 32. and 33. Locus coeruleus noradrenergic afferents to the hypothalamus stimulate HPA activity, while serotonergic projections from the raphe nuclei can both facilitate and inhibit HPA activity, depending on the limbic targets of these projections. 32 Dopaminergic projections from the ventral tegmental area affect HPA sensitivity to glucocorticoid feedback inhibition indirectly via the prefrontal cortex. 51

  (2011-08-31). Handbook of Neuroendocrinology (Kindle Locations 3194-3202). Elsevier Science. Kindle Edition.

Serotonin As outlined before, biochemical studies demonstrated that both the synthesis and turnover of serotonin (5-hydroxytryptamine, 5-HT) are affected by corticosteroids, involving the GR, which is expected to change the bioavailability of 5-HT. Moreover, the expression and responsiveness of 5-HT receptors was found to be modulated by corticosteroid hormones. Yet receptor expression and responsiveness are not always coupled: for instance, exposure to a high dose of corticosterone results in a strong 5-HT response of CA1 neurons, 55 but does not increase expression of the 5-HT receptors mediating this response (reviewed by Meijer and de Kloet44). We will focus here on the effect of corticosteroid hormones on 5-HT responses, as measured with electrophysiological techniques. In CA1 hippocampal neurons, 5-HT mostly activates 5-HT1A receptors, which, through a G protein, are coupled to an inwardly rectifying K channel. 88 Binding of 5-HT to this receptor therefore causes hyperpolarization of the membrane. The effects of corticosterone on 5-HT1A-receptor mediated hyperpolarizations display a U-shaped dose-dependency in CA1 pyramidal cells, with large responses both in the absence of corticosterone and several hours after application of a high dose of the hormone, and small responses under conditions of predominant MR activation. 56 The enhancement of 5-HT1A-receptor mediated responses observed several hours after brief administration of a high dose of corticosterone was found to depend on DNA binding of GR homodimers. 55 In dentate granule cells, effects of corticosterone on 5-HT1A-receptor mediated responses were less pronounced. 89 The U-shaped dose-dependency, the involvement of GR homodimers and the regional specificity are highly reminiscent of the hormonal effects on Ca-current amplitude (see above, and Fig.   18.4), suggesting common elements in the intracellular signaling pathway. This is supported by the fact that transcriptional regulation of target genes directly involved in the signaling pathway of 5-HT (e.g., G proteins, the inwardly rectifying K channel), or modulators of this pathway (e.g., RGS4, SGK) could not explain the electrophysiological phenomena. 90.91. and 92. In the raphe nucleus, corticosterone (see also93. and 94.) and various stressors95 resulted in a delayed GR-mediated attenuation of 5-HT1A-receptor dependent autoinhibition, causing disinhibition of 5-HT cell activity. In these cells a linear dose-dependency was found, with the strongest effect seen at the highest dose of the hormone. Although the mechanism appears to be different, the functional consequence is comparable to that seen in the hippocampus: upregulation of 5-HT activity some hours after stress. Interestingly, the response of raphe neurons to acute stress in fact depends on the expression level of the 5-HT1A autoreceptor; mice with high levels of this receptor showed a blunted physiological response to stress which was associated with increased behavioral despair and no behavioral response to antidepressants. 96

  (2011-08-31). Handbook of Neuroendocrinology (Kindle Locations 21038-21064). Elsevier Science. Kindle Edition.

Hyperthermia has detrimental effects on ischemic infarct volumes both during and after the induction of ischemia. Many studies have found increases in BBB permeability along with

  (2010-04-06). Stress Science: Neuroendocrinology (Kindle Locations 16636-16638). Elsevier Science. Kindle Edition.

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