4 replies to this topic

[lemon_]

hi,

 

does nmda increase dopaminein Nac CORE 

[treonsverdery]

Your idea about regiospecifically amplifying the nucleus accumbens is nifty. Researchers have described this as a pleasure center, then with further research it is possible it is a renforcement as well as pleasure center.  If you look at it on imges, it is fairly large and different areas light up on fMRI of various cognitive or rewarding things.  verifiably making the nucleus accumbend more chemically responsive could then be described with language to suggest more about what this are feels like, when amplified You might like visiting http://www.hedweb.org

 

so yeah  you actually asked, does nmda up dopamne at the nucleus accumbens core area

Edited by treonsverdery, 24 June 2016 - 11:29 PM.

[treonsverdery]

here is a phrase

We hypothesize that co-activation of NMDA and D(1) receptors in the nucleus accumbens core is a key process for acquisition of appetitive instrumental learning.

from pubmed http://www.ncbi.nlm....pubmed/11027236

 

 

I just read part of a paper that said that they think n methy d apsartate (NMDA) receptors then go on to amp up dopamine at the nucleus accumbens.  There are a bunch of things going on here, reinforcement, separate from learning, possibly reward from rienforcement. (dopamine activity _after_ nmda) here are a bunch of references unrelated to what i just typed all nucleaus accumbens nmda

 

https://www.google.c...cleus accumbens

 

 

this is nifty are for new nootropic research.  they er, went the route opposite i might favor research at, when they write "Co-infusion of low doses of the D(1) receptor antagonist SCH-23390 (0.3 nmol) and AP-5 (0.5 nmol) into the accumbens core strongly impaired acquisition of instrumental learning (lever pressing for food), whereas when infused separately, these low doses had no effect."   they could have also utilized a dopamine (D1) activator to find out if they created heightened learning ability from amplifying that area. I have thought that combining an antibody area known as an aptamer with a drug could localize to just particular regions of the brain, so dopamine (or dopamine drug) with an aptamer that reaches the nucleus accumbens could be a nootropic or possibly a feel good while learning nootropic

Edited by treonsverdery, 25 June 2016 - 11:08 PM.

[gamesguru]

Thank you for the wonderfully insightful idea, on restricting medicines to certain brain locales!

 

Another idea is to attack other upstream targets, which promote the desired effect in one region without affecting global function too dramatically.  These upstream targets may exert opposite effects in two different regions [such as alpha 7 agonists (e.g. GTS-21, or rhamnetin)], and if luck is on our side, these may be perfectly in accordance with the parameters of the disease in question.  However, in the case of alpha 7 agonists, it appears to do the exact opposite of what you were hoping, namely a decrease in accumbal dopamine accompanied by an increase in frontal dopamine:

Understanding the role α7 nicotinic receptors play in dopamine efflux in nucleus accumbens.
Maex R1, Grinevich VP, Grinevich V, Budygin E, Bencherif M, Gutkin B. (2014)

Neuronal nicotinic acetylcholine receptors (NNRs) of the α7 subtype have been shown to contribute to the release of dopamine in the nucleus accumbens. The site of action and the underlying mechanism, however, are unclear. Here we applied a circuit modeling approach, supported by electrochemical in vivo recordings, to clarify this issue. Modeling revealed two potential mechanisms for the drop in accumbal dopamine efflux evoked by the selective α7 partial agonist TC-7020. TC-7020 could desensitize α7 NNRs located predominantly on dopamine neurons or glutamatergic afferents to them or, alternatively, activate α7 NNRs located on the glutamatergic afferents to GABAergic interneurons in the ventral tegmental area. Only the model based on desensitization, however, was able to explain the neutralizing effect of coapplied PNU-120596, a positive allosteric modulator. According to our results, the most likely sites of action are the preterminal α7 NNRs controlling glutamate release from cortical afferents to the nucleus accumbens. These findings offer a rationale for the further investigation of α7 NNR agonists as therapy for diseases associated with enhanced mesolimbic dopaminergic tone, such as schizophrenia and addiction.

alpha7 and non-alpha7 nicotinic acetylcholine receptors modulate dopamine release in vitro and in vivo in the rat prefrontal cortex.
Livingstone PD1, Srinivasan J, Kew JN (2009)

Nicotine enhances attentional and working memory aspects of executive function in the prefrontal cortex (PFC) where dopamine plays a major role. Here, we have determined the nicotinic acetylcholine receptor (nAChR) subtypes that can modulate dopamine release in rat PFC using subtype-selective drugs. Nicotine and 5-Iodo-A-85380 (beta2* selective) elicited [(3)H]dopamine release from both PFC and striatal prisms in vitro and dopamine overflow from medial PFC in vivo. Blockade by dihydro-beta-erythroidine supports the participation of beta2* nAChRs. However, insensitivity of nicotine-evoked [(3)H]dopamine release to alpha-conotoxin-MII in PFC prisms suggests no involvement of alpha6beta2* nAChRs, in contrast to the striatum, and this distinction is supported by immunoprecipitation of nAChR subunits from these tissues. The alpha7 nAChR-selective agonists choline and Compound A also promoted dopamine release from PFC in vitro and in vivo, and their effects were enhanced by the alpha7 nAChR-selective allosteric potentiator PNU-120596 and blocked by specific antagonists. DNQX and MK801 inhibited [(3)H]dopamine release evoked by choline and PNU-120596, suggesting crosstalk between alpha7 nAChRs, glutamate and dopamine in the PFC. In vivo, systemic (but not local) administration of PNU-120596, in the absence of agonist, facilitated dopamine overflow in the medial PFC, consistent with the activation of extracortical alpha7 nAChRs by endogenous acetylcholine or choline. These data establish that both beta2* and alpha7 nAChRs can modulate dopamine release in the PFC in vitro and in vivo. Through their distinct actions on dopamine release, these nAChR subtypes could contribute to executive function, making them specific therapeutic targets for conditions such as schizophrenia and attention deficit hyperactivity disorder.

[treonsverdery]

well, being impulsive the first thing i noticed was that there is a halogenated drug that works on nicotine aCh receptors.  so, noting nicotine is a nootropic I wonder if 5-Iodo-A-85380 is a higher effect at dose nootropic from the halogen atom, (kind of a impulsive first thought, "find the nootropic!") .  also, the scientists localization of schizophrenia to the PFC was novel to me.  PFC is genetically influenced (like all body sytems), so there could be a gene therapy approach to minimizing schizophrenia.  Another thing that is impulsive is the possibility that BDNF could cause neural growth or preservation at the SN, somewhat like deprenyl, possibly amplifying longevity; so a thing that brings BDNF to the SN could possibly grow (or freshen) the SN to cause greater longevity.  so the imminst longecity items of longevity and greater cognition are "hey, it might work" described.

 

Reducing illness: pubmed strongly supports PFC genetics linked to schizophrenia"

We found robust age-dependent changes in gene expression in the PFCs of humans (2281 transcripts). The GAD analysis revealed that schizophrenia was an over-represented disease class, with 42 susceptibility genes included (p < 0.001, fold enrichment = 1.66, FDR = 1.5%). Among the 42 genes, glutamate receptor genes (GRIA1, GRIK1, GRIK2, GRIN2D, GRIP1, GRM5, GRM7 and SLC1A6) were consistently downregulated across age. We confirmed microarray gene expression changes by the quantitative polymerase chain reaction experiment.

LIMITATIONS:

Although numerous genes undergo robust changes in expression during the PFC development, some of the changes may be confounded by known and unknown factors that are intrinsic to the postmortem brain studies.

CONCLUSION:

Multiple schizophrenia susceptibility genes undergo age-dependent expression changes in the human PFC, and any disruption in those genes during the critical period of development may predispose the individuals to schizophrenia."

at http://www.ncbi.nlm....pubmed/19949721

 

that suggests that renormalization of output, with gene therapy (at the PFC of the brain) might well reduce the symptoms of schizophrenia.  I have read that lamotrigne effects glutaminergic neurons and reduces schizophrenia.  I perceive this is usually lamotrigne coadministered with a dopamine modulating drug (I am on latuda with lamotrigine; the pills reduce 9/10 of the symptoms)

 

so as the original topic person was thinking about the nucleus accumbens, I thought I would look up glutaminergic neurons at the NAc, well there is molecule (mk-801) https://en.wikipedia...iki/Dizocilpine that is thoughtful reading.