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Benzodiazepine Pharmacology

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BirdOfPrey

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I have been on benzodiazepines on a therapeutic daily dosage since a recent concussion and the anxiety that ensued thereafter. I have read many conflicting articles regarding the effects of these drugs on the brain. I understand that the activation of GABA (an inhibitory molecule in the brain) inhibits the release of serotonin and dopamine, but that this can also cause dopamine neurons to fire more rapidly; a possible mechanism for the underlying addictive potential of them. If this is the case with dopamine, is the same true with serotonin? I am just a bit confused because I know that SSRI's are effective at treating anxiety due to inhibiting the re-uptake of serotonin and thus allowing more serotonin to be available in the synapse. How could these be effective drugs for anxiety if they DECREASE serotonin? Any direction to medical journals or scholarly articles would be greatly appreciated. I am glad to be joining the Bluelight community!
 
SSRIs probably work by an indirect method. There is also a selective serotonin re uptake enhancer that is effective too, interestingly.

The two prominent theories on how SSRIs are (I probably have some of the details wrong b/c I am writing this from memory):

Increased 5-HT in the inter synaptic cleft down regulates a 5HT auto receptor subtype that functions to inhibit 5-HT release downstream, causing another 5-HT subtype receptor to up regulate 5-HT release which then enhances dopamine transmission in certain parts of the brain (something like that).

The other is that they cause nerve growth in the hippocampus and up regulate corticosteroid receptors, making negative feedback inhibition of cortisol release more effective.

The point being it is very difficult to draw conclusions based on how SSRIs work, since we don't really know.
 
The addictiveness of drug and their effect on mood isn't so simple. It's usually pretty pointless to look at everything in terms of "if it increased the activity of neurotransmitter system x, then y effect will occur." For example SSRIs increase synaptic serotonin, but don't necessarily cause a significant mood lift (or at least not an instantenous one), yet MDMA is also a serotonergic and its effects at this system almost certainly contribute to its immediate high. Likewise, not all dopaminergics are euphoric - e.g., amphetamine is, but not most dopamine agonists, yet they're both technically dopaminergics that cause activation of dopamine neurons.

In the case of benzos, I don't think they're addictive due to direct activity in the reward centers as most other drugs abuse seem to be. It might be more due to its anxiolytic effect, the ability to take away stress, etc - in other words, not anything directly rewarding. Finally, I'm not sure benzos do have significant effects on serotonin.
 
BirdOfPrey said:
I have been on benzodiazepines on a therapeutic daily dosage since a recent concussion and the anxiety that ensued thereafter. I have read many conflicting articles regarding the effects of these drugs on the brain. I understand that the activation of GABA (an inhibitory molecule in the brain) inhibits the release of serotonin and dopamine, but that this can also cause dopamine neurons to fire more rapidly; a possible mechanism for the underlying addictive potential of them. If this is the case with dopamine, is the same true with serotonin? I am just a bit confused because I know that SSRI's are effective at treating anxiety due to inhibiting the re-uptake of serotonin and thus allowing more serotonin to be available in the synapse. How could these be effective drugs for anxiety if they DECREASE serotonin? Any direction to medical journals or scholarly articles would be greatly appreciated. I am glad to be joining the Bluelight community!
Click to expand...

And we're glad to have you!

A line, pulled from this text:


Activation of GABA-Rs can decrease dopaminergic and serotonergic neurotransmission, while inhibition of GABA-R can increase it (D’Hulst et al., 2009, Kiyatkin and Rebec, 1998 and McKernan and Whiting, 1996).
Click to expand...

You could probably find more if you pull those references.

Citations for those references:
C. D’Hulst, J.R. Atack, R.F. Kooy. The complexity of the GABAA receptor shapes unique pharmacological profiles. Drug Discov Today, 14 (2009), pp. 866–875
E.A. Kiyatkin, G.V. Rebec. Heterogeneity of ventral tegmental area neurons: single-unit recording and iontophoresis in awake, unrestrained rats. Neuroscience, 85 (1998 ), pp. 1285–1309
R.M. McKernan, P.J. Whiting. Which GABAA-receptor subtypes really occur in the brain?. Trends Neurosci, 19 (1996), pp. 139–143
 
sekio said:
because GABA-A receptor activation does not directly modulate serotonin release
Click to expand...

Do you know why clonazepam has serotonergic properties? Is it just a direct 5-HT effect, independent of its GABA-A receptor activation?
 
Tussmann said:
Do you know why clonazepam has serotonergic properties? Is it just a direct 5-HT effect, independent of its GABA-A receptor activation?
Click to expand...

An agonist acting directly on gaba will have a dopaminergic effect, but does not make it a dopamine agonist--same goes for any effect on serotonin.
 
I was more just asking based on the idea that I am well aware that benzodiazepines are not dopamine or serotonin agonists. I was more concerned with the idea that GABA-A activation indirectly modulates both dopamine and serotonin in the brain, as an inhibitory molecule. My concern was the possible reduction in serotonin causing depression through the duration of using diazepam at theraputic, prescirbed levels.
 
BirdOfPrey said:
I was more just asking based on the idea that I am well aware that benzodiazepines are not dopamine or serotonin agonists. I was more concerned with the idea that GABA-A activation indirectly modulates both dopamine and serotonin in the brain, as an inhibitory molecule. My concern was the possible reduction in serotonin causing depression through the duration of using diazepam at theraputic, prescirbed levels.
Click to expand...

Did you get a chance to check out the three papers I linked? All of those should discuss that interaction to some extent.
 
BirdOfPrey said:
I was more just asking based on the idea that I am well aware that benzodiazepines are not dopamine or serotonin agonists. I was more concerned with the idea that GABA-A activation indirectly modulates both dopamine and serotonin in the brain, as an inhibitory molecule. My concern was the possible reduction in serotonin causing depression through the duration of using diazepam at theraputic, prescirbed levels.
Click to expand...
If benzos are causing your depression, its most likely not their effect on serotonin that is the culprit. (my "common-sense" answer not backed up by any science, so feel free to disregard)
 
completely off topic, but i wonder what effect long-term use of diazepam or benzodiazepines has on psychedelics.
 
SSRI's don't 'work' as an anti-depressant directly because of Serotonin in the synapse. Example: an anti-depressant raises 5HTP synaptic levels within 20 minutes of being taken but therapeutic effects of SSRI's are said to take weeks to kick in. The therapeutic effect is hypothesized to be upregulation of Brain Derived Neurotrophic Factors that result from the increased level of serotonin. The BDNF's are thought to aid brain plasticity and neurogenesis in the hippocampus. BDNF is a good thing. It's more of a long term strategy than the GABA you get from Benzos. Gaba is a major inhibitory Neurotransmitter that inhibits neurons causing you to feel anxious; a more short term solution.
 
Thank you to all who answered with scientific literature, it definitely provided some insight. I am at the tail end of a diazepam taper, and have only been on it for 3 months. Do any bluelighters who have been on benzos in the long term thing this is a long enough time that the tail of this taper will be hell? I was only on 20mg a day.
 
The very end of the taper is often the most difficult, as you can't just keep stepping down by ~25% forever (cf. Zeno's 'paradox' :P).

ebola
 
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