Are noradrenergics used in schizophrenia treatment to mitigate negative symptoms?

[JohnBoy2000]

Been reading on Stahls book and, a lot of it explains the premise of a-typical anti-psychotics, in terms of alleviating the psychotic aspect of schizophrenia primarily, but in such a way that does not exacerbate the negative symptoms associated with sedation, cognitive impairment, reduced executive function etc.

Now - it seems that noradrenaline acting in the prefrontal cortex, the area of the brain mainly responsible fore executive function, concurrently raises DA levels there, given that, what - there are no actual DA neurons in the PFC, right?

So - there is a lot of focus whilst using anti-psychotics, to incorporate actions such as 5HT2c recepter subtype blocking, to disinhibit NA and DA in certain brain regions, whilst maintain 80%+ dopamine occupancy blockade in the mesolimbic DA channel.
Is it the striatum that's responsible for the negative symptoms associated with DA blockade of anti-psychotics?

In any case - could compensation not be offered by using noradrenaline based drugs to raise DA levels in brain regions not including the limbic region?
I'm sure that's been explored in psychiatry somewhat already, no?

Even the addition of the a-typical AD's like mianserin/mirtazapine to potentiate the 5HT2c blockade in addition to AP use - kind of a polypharmalogical approach to creating an a-typical dopamine blocker, on steriods, as it were.

There doesn't seem to be a vast array of clinical data on that approach.

Also - has anyone got a link for a good diagram outline of the brain with its various regions and channels relative to neuropharmacology?


PS - Of course also - serotonergics are not applicable in this situation - I just wanted to highlight that, cause I know AD's are often prescribed in tandem with AP's, and I assume they're mostly serotonin based.

 

[JohnBoy2000]

Is this such a silly question, that no one has dignified it with a response?

 

[Cotcha Yankinov]

There are dopamine releasing terminals and dopamine receptor expressing cells in the PFC but there is limited expression of the DAT, the NET handles reuptake there. NE can actually bind to DA receptors with some affinity as well. But in other words, DA receptors in the PFC would be useless if there weren't pre-synaptic terminals (axons) to release DA to the post-synaptic terminal (dendrite).

5-HT2C antagonists are used to reduce negative symptoms, see for example Risperidone or Seroquel. But I think NRI would be too psychotomimetic and could worsen the morphological changes seen in schizophrenia long term even if it helped short term. Another benefit of AAPs is that antagonism of 5-HT2A helps decrease sensitization of D2 receptors, which is at least partially responsible for the decreased risk of extrapyramidal symptoms with AAPs compared to APs.

Issues with dopamine in the mesolimbic pathway may mediate some positive symptoms while issues with dopamine in the mesocortical pathway may mediate some negative symptoms, but the effect of D2 blockade on mood is probably from many regions, just as the effect of 5-HT2C blockade on mood is probably from many regions.

"In any case - could compensation not be offered by using noradrenaline based drugs to raise DA levels in brain regions not including the limbic region?"

I think the morphological changes that occur with excess catecholaminergic signaling are going to be the greater evil. At any rate, schizophrenics often have too much dopamine and that may apply to NE. Too much DA/NE in the PFC will decrease cognitive performance, see the Yerkes-Dodson law for example.

We may eventually see more selective antagonists/inverse agonists of 5-HT2 approved for mood disorders but for now I think adrenergic a2 antagonism might cause release of too many neurotransmitters (including DA) that could be psychotomimetic. On that note, I believe Pimavanserin, a 5-HT2A antagonist, just finished phase II trials for Alzheimer's disease psychosis (its already approved for Parkinson's disease psychosis).