• N&PD Moderators: Skorpio | thegreenhand

  • Neuroscience & Pharmacology Discussion Welcome Guest
    Posting Rules Bluelight Rules
    Recent Journal Articles Chemistry Mega-Thread
    FREE Chemistry Databases! Self-Education Guide

Can anyone help explain how olanzapine could increase dopamine ?

D

d1nach

Bluelighter
Joined
Oct 12, 2016
Messages
3,232
More specifically I came across this research
https://link.springer.com/article/10.1007/s002130050551 where after administration of a olanzapine a increase in dopamine in the prefrontal, stratium, and nucleus accumbens.

The reason I am confused is I thought antagonism of 5 ht2 receptors and dopamine d2 receptors decreased dopaminergic activity especially in the stratium and nucleus accumbens.

Anyone with any information would be greatly appreciated.
 
Going by simplistic logic, antagonism of dopamine receptors would trigger a feedback mechanism that would increase dopamine concentration to offset the antagonist's effects, explaining that observation.
 
d1nach said:
More specifically I came across this research
https://link.springer.com/article/10.1007/s002130050551 where after administration of a olanzapine a increase in dopamine in the prefrontal, stratium, and nucleus accumbens.

The reason I am confused is I thought antagonism of 5 ht2 receptors and dopamine d2 receptors decreased dopaminergic activity especially in the stratium and nucleus accumbens.

Anyone with any information would be greatly appreciated.
Click to expand...

Autoreceptors, maybe?

When a neuron releases neurotransmitters, these will bind not just to receptors on other cells, but also to so-called "autoreceptors" on the the neuron itself; activation of these autoreceptors essentially tells the neuron that it has successfully released the neurotransmitters, and can stop dumping more of them into the synapse.

Consequently, blocking these autoreceptors with an antagonist will cause more neurotransmitters to be released; and since some antipsychotics have a higher affinity for these autoreceptors, they can actually exert an antidepressant/anti-anhedonic effect when used at low doses.
 
Great input. Thank you.

If it is due to autoreceptors why didnt haloperidol increase dopamine? Despite both olanzapine and haloperidol antagonizing d2 receptors?

I notice both olanzapine and clozapine causing a increase in dopamine and are atypical antipsychotics and haloperidol being typical antipsychotic.
 
Thank you seppi. I notice the lower value for binding at the d2 receptor is 2. And the lower value for d2 long and d2 short are in the 20s. Is their other d2 receptors or something? Or just an average is about the same for d2 as d2 long and d2 short
 
I've often wondered if an extremely selective antagonist/inverse agonist at the D2s isoform of the D2 receptor would make for an acceptable recreational, similar to how say, clonidine or tizanidine make for really very pleasant drugs, both being alpha2 adrenoreceptor agonists, blocking noradrenaline release.
 
One thing I wouldn't overlook is that antagonism/inverse agonism at 5-HT2C can lead to increases in DA/NE cell firing, it could be that haloperidol's 5-HT2C antagonism/inverse agonism isn't as appreciable as olanzapine's
 
d1nach said:
Thank you seppi. I notice the lower value for binding at the d2 receptor is 2. And the lower value for d2 long and d2 short are in the 20s. Is their other d2 receptors or something? Or just an average is about the same for d2 as d2 long and d2 short
Click to expand...

IIRC, there's a 3rd d2 receptor isoform called like "very long" or something like that, but it's postsynaptic and not well studied. In any event, the different lower bounds for D2, D2S, and D2L likely just reflect values from a different binding experiment. The takeaway is that its binding affinity at D2 receptor isoforms is in the low nanomolar range.
 
Olanzapine is a pretty promiscuous ligand. Like most neuroleptics, it only got a license because it is used to treat a serious illness. Only quadriplegia is considered more disabling than schizophreniform disorders. That it is used as a general sedative is criminal and in the UK charges have been made for this form of misuse. So often bipolar disorders and other non-psychotic disorders are being treated with non-classic (what is the difference?) neuroleptics. I spent several months finding what physiological Li+, valporate, Lamotragine and neuroleptics had in common. Put simply, increased N-[2-(5-Methoxy-1H-indol-3-yl)ethyl]acetamide expression was the common action and is now becoming seen as the specific cause so specific medications are now in human trials.

Sometimes neuroleptics are the only group of medications likely to work but now big pharma has sold the class as a medication for BD. That 'treatment creep' is becoming much more common. Guess what? If someone's memory is in tatters, it is no surprise that they cannot make the neuronal connections causing for BP but guess what? From the 1930s to the 1960s, barbiturates were the most prevalent medication for BP (in England at least). People like Spike Milligan said barbs helped them but the testimony of everyone around him was that the barbs made him worse. I can attest to that because I obtained seconal and tried it. In the short term, dreamless sleep FEELS like it is helping but if everyone sees you WORSE then you have to take that into account.

BD only has one decend treatment drug, melatonin. Of course, that more or less means putting a tablet under your tongue every 20 minutes but having done so for a 10 day period, I DID get better. Of course, the amides with longer alkyl groups are better (more potent, longer acting) but that cannot be patented... so nobody is doing the work.

But if anyone finds something that works for them then make it publc; it really could be important.
 
clubcard said:
N-[2-(5-Methoxy-1H-indol-3-yl)ethyl]acetamide
Click to expand...

You could just have said "melatonin", you know :)

specific medications are now in human trials.
Click to expand...

Agomelatine has been available in Europe for a few years now, but I don't think it ever really caught on; in the US, they didn't even bother trying to introduce it after a few disappointing Phase III trials. IMO, Servier's previous antidepressant offering, tianeptine, is clearly superior, atleast for depression. Then again, who knows - maybe agomelatine really does shine for Bipolar.
 
You must log in or register to reply here.
Top