Neurosteroid modulation of respiratory rhythm in rats during the perinatal period

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#1

Interesting study showing positive and negative control of autonomic breathing by allopregnanolone and DHEA-S

The principal finding of this study was that the efficacy of GABAA receptor-mediated modulation of respiratory membrane potential and rhythmogenesis is markedly enhanced by allopregnanolone and depressed by dehydroepiandrosterone sulphate. These data demonstrate that the modulation of breathing via GABAA receptor activation will be determined by the overall balance of negative and positive neurosteroid modulators within respiratory nuclei

#2

Very interesting find.
“The level of neurosteroid synthesis in the CNS is particularly high during the perinatal period (Brown & Papadopoulos, 2001; Mellon & Vaudry, 2001) and increases during periods of physiological stress (e.g. hypoxia, parturition, infection; Barbaccia et al. 2001).”

This might be the reason as to why people report recoveries after stressful events or when they are ill.

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#3

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3245370/ - Another interesting study:
’Upregulation of neurosteroid biosynthesis as a pharmacological strategy to improve behavioral deficits in a putative mouse model of PTSD’

A few excerpts:

  1. “In depressed patients, the cortical level of 5α-reductase mRNA was dramatically decreased to about 50% of the levels measured in non-psychiatric comparison subjects”

  2. " Our laboratory and others have indeed determined that exposure of mice or rats to protracted social isolation stress for 4–8 weeks induces a decrease in allopregnanolone levels in several corticolimbic structures as a result of a downregulation of the mRNA and protein expression of 5α-reductase type I… Indeed, socially isolated mice show a 70% reduction in the rate of allopregnanolone and 5α-DHP biosynthesis compared to group-housed mice"

  3. Administration of a racemic mixture of the R- and S-isomers of fluoxetine induced increases in corticolimbic allopregnanolone levels and normalized the righting reflex loss induced by pentobarbital in mice (36–38). Importantly, at the doses used, fluoxetine failed to change the behavior and allopregnanolone levels of group housed mice (36; 37). In addition, inhibition of serotonin synthesis by treatment with p-chlorophenylalanine failed to block the positive behavioral effects of fluoxetine, suggesting that the action of fluoxetine might be exerted by the ability of this drug to increase corticolimbic allopregnanolone levels (74).
    “This study thus clearly demonstrated that neither the behavioral action nor the normalization of corticolimbic allopregnanolone content by S-fluoxetine and S-norfluoxetine is related to their intrinsic SSRI activity.”

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#4

Yeah, hard to believe the exact mechanism of action of SSRIs is still unknown.

Increasing allopregnanolone does seem to be an emerging focus of antidepressant research, but I have only picked up on decreases in 5-ar metabolites of T and Progesterone during SSRI treatment while browsing-through related studies. It’s like SSRIs achieve an effect similar to finasteride by inducing the conversion of 5-ar products to 3a-HSD products in certain cells and possibly block the reverse reaction. (results in low DHT and low DHP)

There has also been a decrease in 3a-HSD products observed after long-term SSRI use and a decrease in efficacy after prolonged use that might be related to this.

I posted this study partially in response to @axolotl mentioning trouble with autonomic breathing in his member story and because I remember feeling as if I was suffocating on occasion during my crash and shortly after. Maybe “suffocating” is a bit of an exaggeration, but I definitely felt a sensation as if my normal breathing wasn’t quite satiating my need for oxygen/air.

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#5

The question I have is whether the decreased neurosteroids PFS sufferers seem to have simply correlates with depressed individuals. The study compared them to a control group, but not a group which suffered from depression with it’s associated reduction of neurosteroids.

Do PFS sufferers present with a differing neurosteroid profile to those suffering from depression or are they similar?

#6

Off hand, I remember Melcagni’s study finding “undetectable” levels in some of the PFS patients. This is far more profound than what is seen in depression or social isolation.

This might seem like a chicken and egg conundrum, but when the drug itself blocks 5-ar activity, and silenced AR signal has been associated with reduced 3a-HSD activity, it is far more likely that the drug either directly, or by causing PFS, reduced neurosteroids and this leads to depressive symptoms and neurological problems.

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#7

This study is really interesting and show many similarities with PFS patients.

Enzymatic changes (low 5AR metabolites in CSF) and changes to Gaba subunits have been shown to be persistent changes in PFS.

Sadly they didn’t do a study if the allopregnanolone would increase again in the socially isolated mice after they was reintroduced to other mice.

Wonder if I can find a study about that.

#8

days after my crash I had a lot of difficulty breathing, I reported in my story. This symptom disappeared over the course of days.