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Biocast Episode 13
In this podcast so be looking at the effects of serotonin on anxiety. In the previous podcasts I’ve been looking at endotoxin, and in the last podcast up in looking at the effects of endotoxin on increasing serotonin and causing depression. Most of the references in this podcast are specifically on serotonin, a potential link to endotoxin is implied, so to understand the effects of endotoxin you should listen to the previous podcast.
The homepage for this podcast is www.resonantfm.com, and there you will find links to the Patreon page for more content, the iTunes feed and the Facebook page. References and transcript for this show will be on the resonant FM Patreon page, for Patreon supporters. If anyone else needs the references you can message me through the Facebook page. I am currently releasing a series on lowering endotoxin through the Patreon page.
In the previous podcast I looked at how serotonin is largely generated in the gastrointestinal system and picked up by the platelets were can go into general circulation. I also looked at some of the data on serotonin regarding metabolism and depression.
Serotonin Synthesis and Reuptake in Social Anxiety Disorder
This first paper looks at social anxiety disorder, this is also known as social phobia and it is characterised by fear in social situations causing distress and impaired ability to function. Physical symptoms include swelling palpitations and nausea, is believed to be a potential cause or corollary factor in alcoholism and eating disorders.
The paper opens up with the usual confusion you find in these papers on serotonin, due to the fact that it seems the theory that they are working on regarding how serotonin works and how SSRI drugs work seems to be incorrect. So they report that previous studies show an indicator of increased serotonin in social anxiety disorder, which to them is complicated by positive effects on the disorder by SSRIs which are thought to increase serotonin activity.
The study attempted to assess the levels of serotonin synthesis in a live human brain by using a pet scan technology assessing carbon labelled 5 hydroxytryptophan (5-HTP), the immediate precursor to serotonin(5-HT), and similarly measure in marker of serotonin transport. They enrolled 18 patients with social anxiety disorder and 18 healthy controls for the pet scans.
The result of the paper showed evidence for an increased rate of serotonin synthesis in patients with social anxiety disorder compared to controls in multiple regions of the brain, a correlation with social anxiety symptom scores and serotonin in the part of the brain known as the right amygdala was also found. Increased serotonin transporter availability was also found in multiple regions of the brain in people with social anxiety disorder. Another interesting finding was that the females had a lower serotonin synthesis rate and higher serotonin transporter availability than men on average.
In the end the paper found that the previous day and the data from this study pointed towards increased serotonin synthesis in people with social anxiety disorder, particularly the rate of serotonin synthesis in the dorsal amygdala, roughly around the region of the brain that is thought to mediate fear and anxiety. They mention number of studies in animal models including some showing that increased serotonin activity in rodents led to anxiety like behaviours.
Role of 5-HT in stress, anxiety, and depression
The next paper looks at some experiments in rodents, and humans. The paper, published in 1996, opens with an acknowledgement that serotonin is generally acknowledged to play a prominent role in anxiety and depression disorders. The paper centres around the effect of serotonin in two regions of the brain and uses various tests in rodents and in humans to show that serotonin is involved in anxiety and conditioned fear in both species.
Estrogen selectively increases tryptophan hydroxylase-2 mRNA expression in distinct subregions of rat midbrain raphe nucleus: association between gene expression and anxiety behaviour in the open field.
The next paper looks at the effect of the steroid hormones oestrogen and progesterone on TPH2 expression in the raphe nucleus part of the brain in rats. TPH2 is a form of the tryptophan hydroxylase (TPH) enzyme, this converts tryptophan to serotonin and it is known to be present in human brains as well as rats. The rats were ovariectomized and then were supplemented with either a placebo or a replacement of estrogen or estrogen plus progesterone. They were then exposed to a behavioural test known as the open field test and had measurements of the TPH2 enzyme quantified.
The estrogen supplemented rodents had increased TPH2 in multiple regions of the brain, the rodents supplemented with estrogen and progesterone had levels similar to the placebo controls. The TPH2 enzyme was associated with increased anxiety -like behaviour in one region of the brain, however in another region of the brain increased amounts of TPH2 was associated with decreased anxiety -like behaviour.
Serotonin engages an anxiety and fear-promoting circuit in the extended amygdala
The next paper look at the effect serotonin part of the brain called the dorsal raphe nucleus, this is located on the brainstem and is thought to be the largest serotonergic nucleus in the brain, providing a lot of the serotonin innervation to the forebrain. The paper looks at serotonin production in the dorsal raphe nucleus (DRN) and how it affects another part of the brain known as the bed nucleus of the stria terminalis, or BNST.
In a rodent model of aversive foot shock stimulus, a technique used to induce pathological fear learning behaviours the scientists tracked markers of increased serotonin neurones from the DRN to the BNST. They then ran experiments on the BNST during experiments of fear conditioning and recall and found increased activity in the BNST for both. Further experiments backed up both of those findings.
The scientists used implants of optical fibres which would fire light in the blue spectrum, 473 nm, into the BNST of some live rodents, this was combined with a noise and shock to the rodents foot. The optical stimulus was seen to heighten both acute and contextual fear recall in the rodents with the optical stimulation to the BNST. Tests addressing anxiety -like behaviour in rodents showed increased anxiety -like behaviour upon stimulation with light.
The serotonergic effects emanating from the DRN and through the BNST were shown to have further effects on other parts of the brain, signalling of the inhibitory coming neurotransmitter GABA was dampened in the ventral tegmental area and the lateral hypothalamus, regions thought to be involved in reward, motivation and alertness signalling in the brain.
One of the topics mentioned in the article is the observed effect of increased anxiety from SSRI drugs in the initial stages of medication.This may be because SSRIs initially increased serotonin synthesis in the brain, which is then followed by an adaptive response lowering serotonin synthesis which I mentioned in the previous podcast. Another important finding in this paper was that the increase in serotonergic activity travelling from one region of the brain to another was also correlated with an increase in corticotropin releasing factor, or CRF. This hormone or neurotransmitter is known to be centrally involved in the stress response, it stimulates the pituitary synthesis of ACTH, which in turn increases the glucocorticoids, which themselves may be independently causal in anxiety. In another investigation they looked at blocking CRF and found that when they had increased anxiety behaviours in the rodents caused by an SSRI, prozac, that blocking CRF could mitigate this somewhat.
The serotonin receptors that were focused on where the 5-HT 2C type. SomeAntagonists of this receptor have been studied somewhat in anxiety. For example ketanserin can have and anxiety effects in rodents, though that seems dependent on the levels of estrogen and progesterone, while another antagonist Ritanserin seems to have antianxiety effects in humans. Include some links to both of those.
Ketanserin and anxiety levels: influence of gender, estrous cycle, ovariectomy and ovarian hormones in female rats.
The influence of ritanserin, a serotonin antagonist, in anxiety disorders: a double-blind placebo-controlled study versus lorazepam.
Ritanserin in the treatment of generalized anxiety disorders: A placebo-controlled trial
Social separation and diazepam withdrawal increase anxiety in the elevated plus-maze and serotonin turnover in the median raphe and hippocampus.
The next paper investigates the effects of inducing acute or separately chronic stress on serotonin turnover in some brain structures in rodents, it focused in on the median raphe and hippocampus. The paper describes two different contexts for the effects of serotonin. In acute stress serotonin is believed to enhance what is called the behavioural inhibition syndrome, which generates anxiety, further stress or serotonin, leading to what would be termed chronic stress is proposed to build up a resilience to the effect of serotonin which can result in depression in certain instances.
To induce a model of chronic stress some of the rodents were subjected to social separation for 14 days prior to the experiments. To induce a model of acute stress rodents were withdrawn from a 14 day diazepam treatment. Increased serotonin turnover was found in rodents with social separation and in rodents who were kept in grouped housing that the drug withdrawals. The 5-HIAA/5-HT ratio I mentioned in the previous podcast was used as an index of 5-HT turnover, 5HIAA is a metabolite of serotonin, it seems a reasonable but indirect measure. Both of these groups also showed increased behavioural models of anxiety. The association then with increased serotonin turnover and chronic and acute stress was found.
Alcohol preference in the rat: reduction following depletion of brain serotonin.
The next paper investigates the effects of serotonin depletion on alcohol preference in rodents. The effects of both alcohol and serotonin on the brain are very complex and not entirely understood, however there seems to be an inhibitory effect from alcohol acting on the GABA system. GABA is an inhibitory, or calming neurotransmitter, serotonin can be either inhibitory or excitatory. Alcohol’s effect on the GABA system explain the association with various types of anxiety and alcoholism.
Previous experiments had shown that repeated infusions of alcohol into brain would produce a dose-dependent preference for alcohol in rodents. This experiment started out with that previous procedure and then altered the concentrations of serotonin alone or all of the catecholamines which includes serotonin. The study found that the serotonin reducing drug which was a tryptophan hydroxylase inhibitor reduced preference for alcohol during dosing and then further reduced alcohol preference when the dosing period had finished. The catecholamine depleting drug treatment had some moderate protective effect.
Antianxiety profile of ondansetron, a selective 5-HT3 antagonist, in a novel animal model.
The next paper I look at is on a serotonin antagonist for the 5-HT3 serotonin receptor, in the previous podcast I mentioned in analysis of 14 different types of serotonin receptors modulating energetic metabolism in different tissues. Ondansetron is the serotonin antagonist in question. The experiment assessed the anxiety -related behaviours of rodents in a mirrored chamber. Ondansetron was seen to lower anxiety in all of the dose ranges tested, it was not as inhibitory anxiety as diazepam, which is thought to work mainly on the GABA system. A further experiment provided more data to suggest that ondansetron’s mechanism was different from the benzodiazepine.
I will include some other relevant links on the page and page are a few other serotonin modulating substances and other studies. I will end this episode off here as I wanted to look at some of the other behavioural effects of serotonin that may not specifically fall under the heading of anxiety. The references and transcript with the show will be on the resonantfm Patreon page. if you find these programs useful please check them around and consider supporting the show on Patreon.… Thanks to everyone who is supporting show on Patreon already, I have some articles coming out now shortly on more endotoxin antagonists on the Patrion page. Thanks for listening.
The effect of the antihistaminic drugs on the central action of 5-hydroxytryptophan in mice.
Lysine as a serotonin receptor antagonist: Using the diet to modulate gut function
l-Lysine acts like a partial serotonin receptor 4 antagonist and inhibits serotonin-mediated intestinal pathologies and anxiety in rats
Oral treatment with L-lysine and L-arginine reduces anxiety and basal cortisol levels in healthy humans.
[Effects of theanine on monoamine neurotransmitters and related genes in cerebral ischemia-reperfusion injury rats].
L-theanine relieves positive, activation, and anxiety symptoms in patients with schizophrenia and schizoaffective disorder: an 8-week, randomized, double-blind, placebo-controlled, 2-center study.
Effects of chronic l-theanine administration in patients with major depressive disorder: an open-label study.
Theanine is a candidate amino acid for pharmacological stabilization of mast cells.
Effects of L-Theanine on Posttraumatic Stress Disorder Induced Changes in Rat Brain Gene Expression
EFFICACY OF ONDANSETRON IN THE TREATMENT OF GENERALIZED ANXIETY DISORDER
The effect of ketotifen in rodent models of rticlenxiety and on the behavioural consequences of withdrawing from treatment with drugs of abuse.
Cimetidine and ketotifen inhibit stimulated aggregation and histamine liberation from rabbit blood platelets.
The effect of ketotifen on nitric oxide synthase activity
Treatment of depression with cyproheptadine.
Intracranial dehydroepiandrosterone blocks the activation of tryptophan hydroxylase in response to acute sound stress.
Psychogenic fever: how psychological stress affects body temperature in the clinical population