Mesocortical vs Mesolimbic
Derin105 06 Oct 2017
I always thought the Mesocortical system had to do with executive function and cognition. But seems the be the pathway involved with the negative symptoms of schizophrenia, IE. apathy, alogia, flat affect.
But it seems that an Overactive mesocortical function inhibits the limbic system from forming emotional coloring. Basically saying that the mesocortical system would be blunting you.
Can someone clarify the actual difference between the two? Particularly someone with detailed knowledge of the two pathways and how 5ht2c or 5ht2a play into these pathways
Thanks all!
Ihaveanhedonia 08 Oct 2017
The original theory that negative symptoms are caused by a mesocortical (prefrontal cortex) dopamine deficiency doesn’t really hold true anymore, especially for those that suffer specifically from anhedonia/apathy for example. My belief is that they loosely counted people suffering from cognitive deficits as people suffering from negative symptoms (i.e. they put cognitive deficits and negative symptoms in the same basket) when they first came up with the mesocortical dopamine deficiency theory of negative symptoms. 5-HT1A agonist drugs, as well as 5-ht2a antagonist drugs, increase dopamine in the prefrontal cortex (mesocortical pathway), not in the reward center of the brain (mesolimbic dopamine pathway). Abilify, Seroquel, Olanzapine, and I think pretty much all of the atypical antipsychotics are both 5-ht1a agonist and 5-ht2a antagonists and clearly, in practice, they do nothing for the majority of people with anhedonia and negative symptoms unrelated to any sort of cognitive dysfunction…For marketing purposes though, it looks good to say that atypical antipsychotics correct the chemical imbalance (mesocortical dopamine deficiency) and therefore improve negative symptoms… When I first met my pdoc she told me right off the bat that they didn’t have any effective medication for negative symptoms and the solution was to do physical exercise and behavioural activation, yet if you look on the website of Abilify and all atypical antipsychotics they will claim that they all work for negative symptoms (by increasing mesocortical dopamine)…Anhedonia in schizophrenia, and anhedonia in pretty much all other diseases, has been proven to be associated with a decrease in mesolimbic/ventral striatal dopamine, not mesocortical.
The problem is that the scales that they use to measure negative symptoms in schizophrenia in clinical trials include items that won't necessarily be related to apathy (anhedonia) or diminished expression (blunted affect and alogia), which are thought to be the 2 main negative symptoms, at least in the recent literature. The only item of the PANSS negative subscale for example that specifically measures motivation and pleasure is N4: Passive/apathetic social withdrawal … Lots of the other items could be at least partly explained by positive symptoms or cognitive deficits. Antipsychotics may reduce paranoia (positive symptoms) which may have an impact on the Emotional withdrawal or Poor rapport items of the PANSS negative subscale but none whatsoever on apathy/anhedonia/motivation. And as I said above, atypical antipsychotics increase dopamine in the prefrontal cortex (mesocortical), the area of the brain generally understood to be responsible for cognition and executive functionning, and thus they may improve the Abstract thinking item of the PANSS negative subscale item for example. At the end of the day the company developing the drugs will be able to say that they improve negative symptoms "in general" and won't go out of their way to specify which sub-symptom might not be particular improved.
Some of the atypical antipsychotics like ziprasidone are also 5-ht2c antagonists, and in practice they are no more effective for negative symptoms than the other ones. I think I read somewhere that 5-ht2c antagonism mostly lead to an increase in mesocortical dopamine (not sure)
Attached Files
Edited by Ihaveanhedonia, 08 October 2017 - 01:32 AM.
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Derin105 08 Oct 2017
Is it not true that atypicals and some antidepressants with 5ht2c antagonist activity increase dopamine release in the mesocortical, mesolimbic, and other structures like the hypocampus and amygdala?
Not too sure about 5ht2a but I’m inclined to think that antagonism would not be beneficial for increasing mesolimbic/Ventral Striatal dopamine release.
Please correct me if I’m wrong
Ihaveanhedonia 09 Oct 2017
I'd like to rectify some of the things I said in my last comment: First, I checked the monographs (the official document given by the pharma companies to psychiatrists explaining how to use the each meds) of almost all of the atypicals and none of them explicitly say that they work on negative symptoms because they increase mesocortical dopamine. They only say that in clinical trials they improved negative symptoms scores on the scales measuring schizophrenia symptoms. They don't give any official rationale as to why it might be able to do so. The only place I saw where it says that an atypical worked on negative symptoms because of incread mesocortical dopamine was on the psychopharmacologyinstitute website, seemed like a pretty legit website, and it was for Abilify where they say: that it increases low mesocortical dopamine to improve negative symptoms and at the same time decreases high mesolimbic dopamine to reduce positive symptoms both via D2 partial agonism. I checked what they had to say for a couple of the other atypicals and they don't say such a thing for the others.
Secondly, here's a quote from an article called "Atypical antipsychotics and the negative symptoms of schizophrenia" by David J. King: "The results of the trials of the atypical antipsychotics discussed above suggest that these drugs are superior to the traditional antipsychotics in the treatment of negative schizophrenic symptom-atology. However, since negative symptoms may be secondary to positive symptomatology, EPS,depression or sedation, and in the majority of the trials such secondary negative symptoms were not differentiated from the primary negative symptoms of the disease, there is little evidence to substantiate an independent effect of any of the atypical antipsychotics on primary negative symptomatology at the present time. Of the 15 trials summarised in Table 1, only four selected patients with 'predominantly negative symptoms', and the best evidence of efficacy to date appears to be for amisulpride." http://apt.rcpsych.o...4/1/53.full.pdf
(it covered all the atypicals except for latuda, abilify, rexulti and vraylar, which are the newer ones).
So basically what was missing from my explanation was "secondary negative symptoms" ( caused by positive symptoms, depression, eps, sedation, and cognitive symptoms); is what atypicals are potentially better at vs the typicals. No strong evidence that they improve the primary ones (except maybe for low-dose amisulpride)
As for the 5-ht2a ad 5-ht2c question, I think 5-ht2a definitely will reduce mesolimbic dopamine. The atypicals often have higher 5-ht2a antagonism than D2 antagonism and they work just as well as the typicals for positive symptoms. For 5-ht2c I'm not sure. I've tried to research it and found contradicting theories. Some say it won't be bad for mesolimbic dopamine, while others say it will prevent it. If you read the following it seems like 5-ht2c antagonism did not affect mesolimbic (nucleus accumbens) dopamine release in the amphetamine experiment, increased it in the morphine experiment, and attenuated it in the cocaine experiment. Also look at the attached picture (basically says that 5-ht2c has anti-psychotic properties meaning it reduces mesolimbic dopamine). So personally I have no clue at the end of the day what it does in a sober human being. We should ask the opinion of a psychopharmacologist.
"The increase in DA release induced by amphetamine (2 mg/kg i.p.) in the nucleus accumbens and striatum was significantly reduced by the selective 5-HT2A antagonist SR 46349B (0.5 mg/kg s.c.), but not affected by the 5-HT2C/2B antagonist SB 206553 (5 mg/kg i.p.). In contrast, the enhancement of accumbal and striatal DA output induced by morphine (2.5 mg/kg s.c.), while insensitive to SR 46349B, was significantly increased by SB 206553."
"Moreover, intra-NAc infusion of [the 5-ht2c antagonist] RS 102221 (0.05–1.5 μg/side) dose-dependently attenuated the stimulus effects of cocaine. These data reinforce the hypothesis that 5-HT2CR plays a role in the regulatory neurochemistry of the NAc (nucleus accumbens) shell that is important to the full expression of the behaviors evoked by cocaine."
Attached Files
Edited by Ihaveanhedonia, 09 October 2017 - 03:27 AM.
Derin105 09 Oct 2017
Ihaveanhedonia 10 Oct 2017
Edited by Ihaveanhedonia, 10 October 2017 - 02:40 AM.
Ihaveanhedonia 11 Oct 2017
"Selective 5-HT1A receptor agonists, e.g. R(I)-8-OH- DPAT, increase DA release in the mPFC [medial Prefrontal Cortex] (Tanda et al. 1994; Kuroki et al. 1996; Gobert et al. 1998; Rollema et al. 2000; Sakaue et al. 2000)"
My conclusion: It appears that 5-ht1a agonism does not increase mesolimbic dopamine, on the contrary it might reduce it/ have antipsychotic properties. Thus, it is probably the 5-ht2a agonism that is responsible for the euphoria/striatal (mesolimbic) dopamine release induced by psilocybin mushrooms (referring to my previous comment), not 5-ht1a agonism. 5-h1a agonism increases dopamine but in the prefrontal cortex (mesocortical).
My conclusion: 5-ht2a antagonism increases dopamine in the prefrontal cortex and reduces mesolimbic dopamine (may not be able to entirely reduce it when it's highly elevated)
My conclusion: 5-ht2c antagonism increases dopamine in the prefrontal cortex (mesocortical). (but it can potentially increase mesolimbic dopamine when combined with stimulants as seen in my previous comment)
My conclusion: 5-ht2a antagonism reduces mesolimbic dopamine probably by increasing dopamine in the prefrontal cortex (mesocortical).
My conclusion: 5-ht2a agonism on its own increases mesolimbic dopamine. (and the increase in mesolimbic dopamine by 5-ht2a agonism is potentiated when combined with a stimulant like cocaine)
Edited by Ihaveanhedonia, 11 October 2017 - 01:47 AM.
Galaxyshock 11 Oct 2017
Makes sense. 5-HT2A agonist psychedelics in threshold doses have been reported to work for anhedonia.
Ihaveanhedonia 13 Oct 2017
I found more info on the difference between striatal and mesolimbic dopamine. When they talk about striatal dopamine, some will talk about it referring to the nigrostriatal dopamine pathway (the third dopamine pathway, mainly responsible for movement), some will talk about it referring to the mesolimbic dopamine pathway, and some will use it to refer to both. Additionally, I found out that they will also sometimes use the term "mesostriatal pathway", which in some instances will be used as an equivalent to nigrostriatal pathway, and in other instances will be used to refer to both the nigrostriatal and mesolimbic pathways. I found some examples of all that:
Mesolimbic = VTA dopamine --> nucleus accumbens + amygdala, bed nucleus of stria terminalis (BNST), lateral septal area, and lateral hypothalamus.
Mesoaccumbens= VTA dopamine --> nucleus accumbens
One last technicality: ventral striatum is not exactly the same thing as nucleus accumbens; the NAC (also sometimes written as NAc, NA, NAcc, NAcb) is part of the ventral striatum which is comprised of two parts: the nucleus accumbens and the olfactory tubercle. According to this article: https://www.ncbi.nlm...les/PMC2894302/, the olfactory tubercle is part of the mesolimbic system as well. The olfactory tubercle is said to be partly responsible for the reinforcing effects of cocaine and possibly drug reward in general, according to this article https://www.ncbi.nlm...les/PMC2134972/ . In the article, they also introduce the concept of "meso-ventromedial and meso-ventrolateral striatal dopamine systems" which also sound pretty precise. In it, they really talk about which specific parts of the nucleus accumbens and olfactory tubercle are responsible for feelings of reward/pleasure etc.
Edited by Ihaveanhedonia, 13 October 2017 - 03:07 AM.
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Ihaveanhedonia 14 Oct 2017
Edited by Ihaveanhedonia, 15 October 2017 - 12:08 AM.