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Mesocortical vs Mesolimbic

mental health depression brain health

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#1 Derin105

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Posted 06 October 2017 - 01:02 AM


I just wanted to clarify a few things about these two pathways because I’ve been getting contradicting information.

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!

#2 Ihaveanhedonia

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Posted 08 October 2017 - 01:04 AM

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)

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Edited by Ihaveanhedonia, 08 October 2017 - 01:32 AM.

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#3 Derin105

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Posted 08 October 2017 - 03:17 AM

Very interesting. Thank you for the long elaborate post.

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

#4 Ihaveanhedonia

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Posted 09 October 2017 - 03:09 AM

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."

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Edited by Ihaveanhedonia, 09 October 2017 - 03:27 AM.


#5 Derin105

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Posted 09 October 2017 - 06:42 AM

So basically 5ht2a agonism will increase mesolimbic dopamine in addition to striatal dopamine?

#6 Ihaveanhedonia

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Posted 10 October 2017 - 02:02 AM

First, it's always confusing in the literature when they talk about striatal vs. mesolimbic/nucleus accumbens dopamine because the mesolimbic system and Nucleus accumbens/ventral striatum are PART OF the striatum. Anyways, I have more info now (the tentative answer to your last comment can be found in the last two "my conclusions":
 
"In vivo microdialysis and electrophysiological techniques were used to elucidate the role of the 5-HT(2) receptor family on the control of mesolimbic dopaminergic system exerted by serotonin (5-HT). Administration of RO 60-0175 (1 mg/kg, i.p.), a selective 5-HT(2C) receptor agonist, significantly decreased dopamine (DA) release by 26+/-4% (below baseline) 60 min after injection. Moreover, RO 60-0175 (80-320 microg/kg, i.v.) dose-dependently decreased the basal firing rate of DA neurons in the ventral tegmental area (VTA), reaching its maximal inhibitory effect (53.9+/-15%, below baseline) after the dose of 320 microg/kg. The selective 5-HT(2C) receptor antagonist SB 242084 completely blocked the inhibitory action of RO 60-0175 on accumbal DA release and on the firing rate of VTA DA cells. On the contrary, both (+/-)-DOI, a mixed 5-HT(2A/2C) receptor agonist, and the selective 5-HT(2B) agonist BW 723C86, did not affect either DA release in the nucleus accumbens or the firing rate of VTA DA cells. Taken together, these data confirm that central 5-HT system exerts an inhibitory control on the mesolimbic DA system and that 5-HT(2C) receptors are involved in this effect."
 
My conclusion: 5-ht2c agonism alone will decrease mesolimbic dopamine. BUT 5-h2a+2c agonism together will not affect mesolimbic dopamine.
 
"In conclusion, we have demonstrated that a selective 5-HT2C receptor antagonist does not produce rewarding effects by itself, but can potentiate the positive CPP produced by a low dose of amphetamine. These results indicate that selective 5-HT2C receptor antagonists developed for depression and anxiety could lead to abuse if given in combination with medications that have psychostimulant-like properties. Furthermore, this study illustrates the need for extensive study of 5-HT2C receptor drugs using conditioned place preference or other tests of reward, with concomitant study of dopamine release and dopamine releasing drugs."
 
My conclusion: 5-ht2c antagonists on their own do not increase mesolimbic dopamine, but when combined with low-dose amphetamine (and potentially other stimulants) it will increase it. I guess we can assume that it will increase it with high dose amphetamine as well. This contradicts what I posted in my last comment, although it was a 5-ht2c+2b antagonist in the last comment, not just 5-ht2c. Maybe the 5-ht2b antagonism has an impact.
 
The effects of (±)-DOI (1-(2,5-dimethoxy-4-iodophenyl)-aminopropane) hydrochloride, a mixed 5-HT2A/2C receptor agonist, on the release of dopamine (DA) following d-amphetamine sulfate (AMP) or a DA D2 autoreceptor selective dose of (−)-apomorphine hydrochloride (APO), were investigated in rat striatum (STR) and nucleus accumbens (NAC), using in vivo microdialysis. AMP (1.0 mg/kg, s.c.) produced marked increases in extracellular DA levels in both the STR and the NAC whereas DOI (2.5 mg/kg, i.p.) alone had no significant effect on extracellular DA levels in either region. Pretreatment with DOI 30 min prior to AMP, further enhanced the AMP-induced increase in striatal extracellular DA levels. On the other hand, DOI pretreatment attenuated the APO (50 μg/kg, s.c.)-induced decrease in extracellular DA levels in the STR. Pretreatment with DOI did not affect the ability of either AMP or APO to modulate extracellular DA levels in the NAC. These results provide further evidence that 5-HT2A/2C receptors modulate the release mechanisms of DA in the STR. Possible mechanisms are discussed.
 
My conclusion: 5-ht2a+2c (together) agonism alone will not increase dopamine in the striatum or NAC/mesolimbic system. 5-ht2a+2c (together) agonism combined with amphetamine potentiates amphetamine-induced dopamine release in the striatum but has not effect on amphetamine-induced dopamine increase in the NAC.
 
 
The 5-HT2A agonists DOI and LSD did not produce amphetaminelike responding at any dose tested or time of administration. Simultaneous administration of DOI or LSD with amphetamine was not significantly different from the response produced by amphetamine alone. Preadministration of DOI (3 hours) or of LSD (2 hours) before amphetamine, however, evoked significant enhancement of the amphetamine cue. The results suggested that the enhanced behavioral response to amphetamine may be due either to an increased sensitivity of dopaminergic neurons in the mesolimbic area, or to an enhanced release of dopamine by amphetamine. These studies all show that activation of the 5-HT2A receptor can enhance the response to a drug that produces indirect release of dopamine from neuron terminals. Whether or not these findings would extrapolate to schizophrenia is at present an unknown, but highly relevant issue. If basal dopaminergic tone is enhanced through some pathological process, will the activation of serotonin systems further amplify dopaminergic function? Enhanced efficacy of antipsychotic agents possessing 5-HT2A antagonist activity certainly suggests a parallel to the studies cited above.
 
My conclusion: DOI and LSD are 5-ht2a+2c agonists, not just 5-ht2a. So, 5-ht2a+2c agonism seem to have the potential to be able to potentiate amphetamine-induced dopamine release in the mesolimbic system (NAC), contradicting the study above. Would 5-ht2a agonism alone be able to do that, I don't know. Couldn't find any research on it online...
 
"Subjects receiving 5-HT2A agonists report a range of experiential phenomena. Most common are hallucinations, synesthesia, and ego dissolution: the experience of a diminished sense of self; Nour et al., 2016; Tagliazucchi et al., 2016)." "Studies utilizing 5-HT2A agonists raise legitimate ethical and safety concerns due to risks associated with their hallucinogenic properties."
 
My conclusion: In the article from which I took this quote, not once do they mention "dopamine"... 5-ht2a agonists (that includes a lot of psychedelic drugs) are not famous for inducing effects similar to psychostimulants or for being addictive, meaning that they don't seem to be increasing mesolimbic dopamine, which is the mechanism by which most drugs are thought to be addictive). They are famous for inducing hallucinogenic and transcendental effects. Does 5-ht2a agonism have the potential to indirectly end up affecting mesolimbic dopamine? I don't know for sure but I'd say maybe since psychedelic drugs led me to develop psychosis, and have done it for many other schizophrenics. Psychosis is thought to be related mainly to increased mesolimbic dopamine activity (although I think as of today that they have discovered other mechanisms which might lead to psychotic symptoms), so I guess 5-ht2a agonism could potentially end up affecting mesolimbic dopamine, at least in people genetically vulnerable to mental illnesses like schizophrenia.
 
"5-HT2A receptors located on dopaminergic and/or GABAergic neurons within the striatum and nucleus accumbens might provide an anatomical substrate for a serotonin-mediated psilocybin-induced dopamine release (Palacios et al. 1991)." ### "The serotonin agonist psilocybin binds with high affinity at 5-HT2A (Ki = 6 nM) and to a lesser extent at 5-HT1A (Ki = 190 nM) (McKenna et al. 1990) receptors." "Since psilocybin also acts upon 5-HT1A receptors (Buckholtz et al. 1990; McKenna et al. 1990) and stimulation of 5-HT1A autoreceptors is expected to enhance the dopaminergic tone (Neal-Beeliveau et al. 1993), one might speculate that psilocybin increases striatal dopamine release through a concomitant stimulation of both 5-HT1A and 5-HT2Areceptors. This hypothesis is supported by the finding that 5-HT1A agonists can facilitate dopamine release in the striatum and nucleus accumbens (Benloucif and Galloway 1991), while 5-HT1A antagonist have been reported to inhibit dopamine release in these brain regions (Parson and Justice 1993; Boulenguez et al. 1996; Nomikos et al. 1996)." ### "Nevertheless, the present findings suggest that stimulation of 5-HT, presumably 5-HT2 and 5-HT1 receptors, can lead to an increase in striatal dopamine efflux which may contribute to the psychotomimetic effects of psilocybin. Of particular interest to the present study are indications that abnormalities in the number of 5-HT1A and 5-HT2A receptors have been found in the frontal cortex, nucleus accumbens, striatum, and hippocampi of schizophrenic patients (Mita et al. 1986; Arora and Meltzer 1991; Joyce et al. 1993; Laruelle et al. 1993; Gurevich and Joyce 1997)." ### "Thus, it may be argued that, in psilocybin psychosis, specifically those aspects of psychotic symptoms related to euphoria and alertness may be mediated by striatal dopamine release, but that striatal dopamine release alone cannot account for the occurrence of psilocybin-induced psychotic symptoms. In this respect, it is of note that haloperidol had virtually no effect on psilocybin-induced hallucinations (VUS) and even increased anxious ego-dissolution (AIA) in psilocybin subjects, while ketanserin, a preferential 5-HT2A receptor antagonist, dose-dependently prevented psilocybin psychosis (Vollenweider et al. 1998)." ### " Furthermore, consistent with this possibility, we recently found that the D2 antagonist haloperidol attenuated psilocybin-induced depersonalisation, derealisation and euphoria (Vollenweider et al. 1998)."
 
 
My conclusion: We cannot know how much of the 5-ht1a agonism vs 5-ht2a agonism is responsible for euphoric symptoms (i.e. indirect increase in mesolimbic dopamine) in the psilocybin mushroom experience (I guess psychedelic drugs can induce euphoria and in that regard be similar to psychostimulants after all). Psychosis induced by psilocybin was prevented by 5-ht2a antagonism alone so I guess it's safe to say that 5-ht2a plays a large role in the overall psychosis induced by the drug (including the euphoria I guess)

 


Edited by Ihaveanhedonia, 10 October 2017 - 02:40 AM.


#7 Ihaveanhedonia

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Posted 11 October 2017 - 01:16 AM

"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)"

 
"5-HT1A receptor activation by atypical APDs may also contribute to their effects as antipsychotics by diminishing APD-induced DA release in the NAC [nucleus accumbens] since R(I)-8-OH-DPAT [a 5-ht1a agonist] inhibits the ability of clozapine and risperidone to increase DA release in the NAC (Ichikawa and Meltzer 2000)."
http://onlinelibrary...01.00154.x/full

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).
 
"Schmidt et al. (1995) reported that M100907 [highly selective 5-HT2a antagonist, formerly known as MDL 100907] increased DA release in the prefrontal cortex and attenuate the amphetamine analog MDMA – induced increase in striatal DA release. Taken together, these data suggest that 5-HT2a antagonism by itself may have antipsychotic action when dopaminergic activity is slightly to moderately increased, but as mentioned above some D2 receptor blockade may also be needed when DA efflux is very high."

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)
 
"Thus, the 5-HT2c antagonist effects of some of the atypical antipsychotic drugs may contribute to their ability to increase dopaminergic activity in the prefrontal cortex."
https://www.nature.c...370a.html#bib26 

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)
 
"In addition, increases in mPFC DA activity produced by 5-HT2A receptor antagonism may contribute to the antipsychotic efficacy of these atypical antipsychotic drugs by decreasing excessive subcortical DA activity (Schmidt et al 1995)." [subcortical = mesolimbic I think]

My conclusion: 5-ht2a antagonism reduces mesolimbic dopamine probably by increasing dopamine in the prefrontal cortex (mesocortical). 
 
"This study was conducted to determine whether dopamine (DA) release in the nucleus accumbens (NACC) following 5-HT2A receptor stimulation is potentiated by intermittent cocaine. Rats received daily injections of either saline or cocaine (30 mg/kg, s.c.) for 14 days. At the 7th day after withdrawal, microdialysis was performed in the NACC. Infusion of (±)-1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane (DOI, 50 μM), a 5-HT2 receptor agonist, into the NACC produced greater and longer-lasting increases in extracellular DA in the rats pretreated with cocaine than in the rats pretreated with saline. The DOI-induced increases in NACC DA were attenuated by co-perfusion with ketanserin (50 μM), a 5-HT2A receptor antagonist. The results are consistent with the concept that intermittent cocaine may cause enhanced sensitivity of 5-HT2A receptors within the NACC."

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.


#8 Galaxyshock

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Posted 11 October 2017 - 06:40 AM

Makes sense. 5-HT2A agonist psychedelics in threshold doses have been reported to work for anhedonia.



#9 Ihaveanhedonia

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Posted 13 October 2017 - 03:02 AM

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:

 
 
"The mesolimbic pathway, in particular, was identified as the key component in reward assessment. This pathway originates with dopaminergic cell bodies in the ventral tegmental area (VTA), a dopamine-rich nucleus located in the ventral portion (or tegmentum, meaning “covering”) of the midbrain. These dopaminergic axons project and primarily terminate in the nucleus accumbens (NAc) in the ventral striatum, but also extend into the amygdala, bed nucleus of stria terminalis (BNST), lateral septal area, and lateral hypothalamus. The VTA is in, close proximity to the substantia nigra, another dopamine-rich nucleus. Whereas the substantia nigra projects primarily to the dorsal striatum (via the mesostriatal pathway) and mediates motor activity, the mesolimbic pathway mediates reward.11" https://www.ncbi.nlm...les/PMC1920543/
 
So in this one, they say that mesostriatal pathway = nigrostriatal pathway only.
 
"Aging of the rat mesostriatal system: differences between the nigrostriatal and the mesolimbic compartments."
 
In this one, they say that mesostriatal = both nigrostriatal and mesolimbic pathways
 
"Striatal dopamine, reward, and decision making in schizophrenia"
 
In this article, they use the term striatal pretty much exclusively referring to the mesolimbic pathway/ventral striatum. They do mention "dorsal striatum" once but all the rest of the article talks about ventral striatum.
 
 
Additionally, I won't copy-paste them here but in my previous comments, there are 3 article quotes which seem to talk about the striatum and NAC (nucleus accumbens/ventral striatum) as being independent of each other. In those cases, I think they implicitely refer to the striatum as being part of the nigrostriatal pathway only. Basically for them the striatum = dorsal striatum. And I think to do that is wrong and adds confusion because the striatum has in fact two parts, the ventral striatum (also called nucleus accumbens), which is the primary place where the mesolimbic dopamine pathway ends, and the dorsal striatum (which has two parts: the caudate nucleus and the putamen) which is the place where the nigrostriatal dopamine pathway ends. Edit: From this article: https://www.ncbi.nlm...les/PMC2134972/, we learn that prior to the introduction of the concept of ventral striatum (they don't say in what year), "striatum" used to implicitely refer to dorsal striatum (part of the nigrostriatal pathway). Although "striatal" seems to still be sometimes used as an equivalent to dorsal striatum even in recent articles, beware. They really should always specify dorsal or ventral, unless they want to refer to both at the same time...
 
Lastly, I also stumbled upon the term "mesoaccumbens dopamine pathway", which by definition specifically refers to dopamine traveling from the VTA to the nucleus accumbens, and which could therefore be considered part of the mesolimbic pathway. In practice however, a lot of the literature seem to talk as though mesolimbic = mesoaccumbens. Mesoaccumbens could be seen as more precise than "mesolimbic pathway" when talking about nucleus accumbens (ventral striatal) dopamine because the mesolimbic pathway does not only affect the nucleus accumbens.
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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#10 Ihaveanhedonia

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Posted 14 October 2017 - 11:58 PM

I'd like to revisit the first example that I shared, for a more precise conclusion regarding 5-ht2a antagonism:
 
"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-HT(2A) antagonist SR 46349B (0.5 mg/kg s.c.), but not affected by the 5-HT(2C/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. Furthermore, morphine (0.1-10 mg/kg i.v.)-induced increase in DA neuron firing rate in both the ventral tegmental area and the substantia nigra pars compacta was unaffected by SR 46349B (0.1 mg/kg i.v.) but significantly potentiated by SB 206553 (0.1 mg/kg i.v.). These results show that 5-HT(2A) and 5-HT(2C) receptors regulate specifically the activation of midbrain DA neurons induced by amphetamine and morphine, respectively. This differential contribution may be related to the specific mechanism of action of the drug considered and to the neuronal circuitry involved in their effect on DA neurons."
 
My conclusion: 5-ht2a antagonism will reduce both mesolimbic and nigrostriatal dopamine release induced by amphetamine but will have no effect on mesolimbic and nigrostriatal dopamine release induced by morphine (I'm thinking maybe it has no effect on morphine-induced dopamine release because morphine induces dopamine release via an indirect mechanism, i.e. gaba inhibition). I don't want to get into the 5-ht2c+5-ht2b antagonism discussed in this example because 5-ht2c antagonism alone seems to behave differently than those 2 together: as seen in a previous example, 5-ht2c antagonism would increase mesolimbic dopamine induced by low dose amphetamine, yet here in this example, 5-ht2c+5-ht2b antagonism together has no effect on mesolimbic (and nigrostriatal) dopamine release induced by amphetamine (so 5-ht2b antagonism probably plays a role). 5-ht2c+5ht2b antagonism will however potentiate mesolimbic (and nigrostriatal) dopamine release induced by morphine...Clearly all of this shows that morphine-induced dopamine release (and possibly other opiates/opioids) and amphetamine-induced dopamine release will be affected differently from alterations in 5-ht neurotransmission, at least with respect to 5-ht2a and 5-ht2c+2b. Notice that here like in some of the previous examples I shared, they use striatum implicitely referring to dorsal striatum (part of the nigrostriatal dopamine pathway), and nucleus accumbens refering to ventral striatum (part of the mesolimbic pathway).

 


Edited by Ihaveanhedonia, 15 October 2017 - 12:08 AM.






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