Posted by SLS on February 7, 2012, at 13:01:27
In reply to Re: Adding Parnate and prazosin. » SLS, posted by ed_uk2010 on February 7, 2012, at 10:24:22
Research on the NE alpha-1 receptor subtypes is limited.
However...
NE alpha-1b: Brain cortex (including frontal), hippocampus, and amygdala
TCA = Potent NE alpha-1a; NE alpha-1d
TCA = Weak NE alpha-1bMy guess is that TCA does not effectively antagonize enough brain NE alpha-1b receptors to modulate brain monoaminergic neurotransmission. It just doesn't hit the right spots. NE alpha-1b receptors are known to be impaired in depression.
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http://www.ncbi.nlm.nih.gov/pubmed/20363235
"Amitriptyline, nortriptyline and imipramine are much weaker antagonists of rat and human alpha(1B)-adrenoceptors than of alpha(1A)- and alpha(1D)-adrenoceptors. The differential affinities for these receptors indicate that the alpha(1)-adrenoceptor subtype which activation is most increased by the augmented noradrenaline availability resultant from the blockade of neuronal reuptake is the alpha(1B)-adrenoceptor. This may be important for the behavioural effects of these drugs."
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http://www.nature.com/npp/journal/v28/n8/full/1300222a.html
"Currently, most basic and clinical research on depression is focused on either central serotonergic, noradrenergic, or dopaminergic neurotransmission as affected by various etiological and predisposing factors. Recent evidence suggests that there is another system that consists of a subset of brain alpha1B-adrenoceptors innervated primarily by brain epinephrine (EPI) that potentially modulates the above three monoamine systems in parallel and plays a critical role in depression."
"Binding affinities were obtained from the literature by computing the average of all published values (311 studies) for these antagonists at cloned alpha1A-, alpha1B-, and alpha1D-receptors. The results showed a high and significant correlation for alpha1B (0.89), with none for either the alpha1A- (0.27) or alpha1D-receptors (0.13). This finding agreed with a previous study that showed that agonists of alpha1B-receptors, but not of alpha1A or alpha1D were effective in the reversal of cataplexy in narcoleptic dogs (Nishino et al, 1993)."
"New behavioral and neuropharmacological evidence has implicated a subgroup of brain alpha1B-adrenoceptors as a key factor in positively motivated behavioral activity. Most of these 'motoric' alpha1-receptors are located in or close to monoamine-containing neuron cell bodies (NE and 5HT) or their terminal targets (nucleus accumbensDA) and appear to receive EPI as their neurotransmitter. It is speculated that this 'EPI-innervated-alpha1-system' activates behavior by producing a coordinated excitation of the major monoaminergic systems of the brain. There is evidence that this system is impaired or inhibited in depressive illness from the findings of low levels of EPI in the CSF and of altered responsiveness of brain alpha1-receptors in depressed patients. There is also evidence that its impairment may facilitate CNS brain atrophic effects in depression as it is linked to growth factor induction and MAPK activation. As a number of antidepressant agents are capable of restoring or enhancing its function, the EPI-alpha1-system would appear to represent a new target for this illness."
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I still haven't figured out how prazosin modulates monoamine tracts via NE alpha-1b receptors. However, it is a wild guess of mine that prazosin might reduce the activity of NE neurons along the brain subgenual cingulate cortex (Brodmann Area 25), a region known to be hyperactive in depression. If so, then prazosin might mimic the action of DBS in that area.
Of course, I would love to have prazosin be a wonder drug for more people with depression, but I am not ready to recommend it generally. I hope a few people read this stuff and decide to try prazosin. It would be interesting to see a few more guinea pigs get well with it.
I wonder if the anti-PTSD properties of prazosin are due to its blocking the NE alpha-1b receptors in the amygdala. Maybe I should look into that.
- ScottSome see things as they are and ask why.
I dream of things that never were and ask why not.- George Bernard Shaw
poster:SLS
thread:1005781
URL: http://www.dr-bob.org/babble/20120202/msgs/1009565.html