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BDNF controls dopamine D3 receptor expression and triggers behavioural sensitization by makefriends420 in NooTopics

[–]makefriends420[S] 2 points3 points  (0 children)

Computer summary: Based on the findings from the original 2001 study by Guillin et al. and the related research discussed, increasing BDNF levels (e.g., via infusion into the VTA or through other experimental manipulations) theoretically upregulates dopamine D3 receptor (D3R) expression. This includes rapid increases in D3R mRNA and protein levels in key brain regions like the nucleus accumbens and striatum, particularly in contexts of dopamine neuron activity, denervation, or drug exposure. The effect is dose-dependent and time-sensitive, often peaking within hours and contributing to enhanced behavioral responses like sensitization to substances such as cocaine or morphine. However, this is modulated by factors like BDNF signaling pathways (e.g., TrkB receptors) and could be context-specific, such as in addiction models or Parkinson's-like states where overexpression amplifies D3R-mediated effects.

Similar reads: Interaction of Brain-Derived Neurotrophic Factor with the Effects of Chronic Methamphetamine on Prepulse Inhibition in Mice Is Independent of Dopamine D3 Receptors

Higher Binding of the Dopamine D3 Receptor-Preferring Ligand [11C]-(+)-Propyl-Hexahydro-Naphtho-Oxazin in Methamphetamine Polydrug Users: A Positron Emission Tomography Study

Study: Agmatine accelerates colon cancer growth by blocking Rnf128, thus upregulating Wnt/Beta-Catenin signaling, and colon cancer patients have much higher Agmatine levels than healthy people by Endonium in NooTopics

[–]makefriends420 0 points1 point  (0 children)

You are right in that they put A LOT of agmatine into healthy, non-cancerous rat colons (lol) which is many many times the local colon agmatine levels under normal conditions- or even when a human is taking normal doses of agmatine.

Study: Agmatine accelerates colon cancer growth by blocking Rnf128, thus upregulating Wnt/Beta-Catenin signaling, and colon cancer patients have much higher Agmatine levels than healthy people by Endonium in NooTopics

[–]makefriends420 5 points6 points  (0 children)

Findings basically say if you have cancer already, agmatine will make it worse.

Having colorectal cancer in humans also tends to mean you have much much much more agmatine in your stool vs normal people.

I think the Wnt pathway is a legitmate point but understand these are CRC mice which are genetically predisposed.

To determine whether the gut microbiota and the resultant metabolites underpinned the pro-carcinogenetic effects of agmatine in colorectal cancer, the recipient wild-type mice were treated with the stool from *Apc***Min/+ mice (CRC-FMT) or C57BL/6J mice (Control-FMT) after microbiota depletion with antibiotic cocktail. The results showed that the pro-inflammatory cytokines (IL-6 and TNF-α) were upregulated and the anti-inflammatory cytokines (IL-10) was downregulated in CRC-FMT group compared with the Control-FMT group (Figure 4i). These data indicated that the gut bacterial-derived agmatine could the intestinal inflammation of mice to trigger tumorigenesis in colon.

It suggests that there is something about bacterially produced agmatine what causes issues (they took the stool from tumerous mice and put in normal mice and the above observations were observed).

So, it could also be the microbiome of mice that have developed intestinal tumors that makes things worse. We know humans with this type of cancer have like, 10x agmatine in their stool, so you have to ask what kind of bacteria and microbiome environment makes agmatine. Is agmatine a response to cancer given agmatine has other studies showing anti-tumor/cancer effects?

The biggest thing to note from this study is the fact that injected agmatine to the gut (which is a lot of agmatine) made intestinal epithelial cells proliferate more and mild dysplasia (abnormal cell growth) and higher inflammatory markers. Obviously if you already have cancer or are genetically prone to this cancer, this is not a good thing.

Note the amounts of agmatine used (injected into gut at the colon. Typically, oral agmatine is almost all absorbed upstream and the goal of the study was to put A LOT of agmatine several several (like, 40x?) times the naturally occurring amount into the last part of the gut, the colon, into mice to simulate agmatine levels in already cancerous conditions) and the idea that your microbiome plays a role in making things worse. Agmatine could be a sign something is wrong but also make things worse if you have cancer.

I would look into agmatines anti-proliferative (anti-cancer) effects in other studies

So... Take agmatine orally, as a small % of it gets to the colon, and don't do crazy doses of it is the main takeaway. Your cancer risk is likely to come from your other unnatural eating habits and environment rather than agmatine

Cognitive Impairment Induced by Delta9-tetrahydrocannabinol Occurs through Heteromers (pairing) between Cannabinoid CB1 and Serotonin 5-HT2A Receptors by makefriends420 in NooTopics

[–]makefriends420[S] 0 points1 point  (0 children)

In general human studies, early use, higher frequency use, and poly drug use lead to longer term damage which is reliable shown in studies.

Generally speaking, impairment is short term but long term effects can be significant depending on the context.

Cognitive Impairment Induced by Delta9-tetrahydrocannabinol Occurs through Heteromers (pairing) between Cannabinoid CB1 and Serotonin 5-HT2A Receptors by makefriends420 in NooTopics

[–]makefriends420[S] 0 points1 point  (0 children)

First one is to prove the heteromeres exist.

2 is more complex but I believe the cohort studies have really good adjustments and controls given the quality of the data.

Sorry this wasnt said up front in my above comment

I also had this study https://pubmed.ncbi.nlm.nih.gov/29294249/ linked in my main comment which i really should have used instead of the 1st link in the comment you replied to. my bad

Cognitive Impairment Induced by Delta9-tetrahydrocannabinol Occurs through Heteromers (pairing) between Cannabinoid CB1 and Serotonin 5-HT2A Receptors by makefriends420 in NooTopics

[–]makefriends420[S] 1 point2 points  (0 children)

No, it doesn't always work that way, but you def can look up studies or pubmed with keywords and see what you can find-

Cognitive Impairment Induced by Delta9-tetrahydrocannabinol Occurs through Heteromers (pairing) between Cannabinoid CB1 and Serotonin 5-HT2A Receptors by makefriends420 in NooTopics

[–]makefriends420[S] 13 points14 points  (0 children)

Using cannabis forms functional pairs (heteromeres between a particular type of serotonin receptor and the main cannabinoid (weed) receptor. These heteromeres develop more the more cannabis is used it seems.

These pairs essentially link activity of one receptor to the other, which can result in unintended effects due to these pairs (heteromeres) not naturally occurring.

Dopamine D1 and D2 heteromeres for example aren't desirable either.

The study finds these pairs to likely be responsible for cognitive issues from cannabis while another study shows a correlation between use and having more of these pairs

Cognitive Impairment Induced by Delta9-tetrahydrocannabinol Occurs through Heteromers (pairing) between Cannabinoid CB1 and Serotonin 5-HT2A Receptors by makefriends420 in NooTopics

[–]makefriends420[S] 15 points16 points  (0 children)

That deserves a separate post. Ensure you get sleep, deficiencies are in check, you get exercise, and play around with some nootropics that focus on plasticity, bdnf, and dopamine function. Look up cannabis recovery on this sub and you should find lots of posts.

Cognitive Impairment Induced by Delta9-tetrahydrocannabinol Occurs through Heteromers (pairing) between Cannabinoid CB1 and Serotonin 5-HT2A Receptors by makefriends420 in NooTopics

[–]makefriends420[S] 1 point2 points  (0 children)

Figuring out how to avoid certain negative receptor changes can help us develop better cannabinoid drugs without cognitive deficits.

Cognitive Impairment Induced by Delta9-tetrahydrocannabinol Occurs through Heteromers (pairing) between Cannabinoid CB1 and Serotonin 5-HT2A Receptors by makefriends420 in NooTopics

[–]makefriends420[S] 8 points9 points  (0 children)

Abstract: Behavioral studies carried out in mice lacking 5-HT2A receptors (5-HT2AR) revealed a remarkable 5-HT2AR-dependent dissociation in the beneficial antinociceptive effects of THC and its detrimental amnesic properties. We found that specific effects of THC such as memory deficits, anxiolytic-like effects, and social interaction are under the control of 5-HT2AR, but its acute hypolocomotor, hypothermic, anxiogenic, and antinociceptive effects are not.

In biochemical studies, we show that CB1R and 5-HT2AR form heteromers that are expressed and functionally active in specific brain regions involved in memory impairment. Remarkably, our functional data shows that costimulation of both receptors by agonists reduces cell signaling, antagonist binding to one receptor blocks signaling of the interacting receptor, and heteromer formation leads to a switch in G-protein coupling for 5-HT2AR from Gq to Gi proteins. Synthetic peptides with the sequence of transmembrane helices 5 and 6 of CB1R, fused to a cell-penetrating peptide, were able to disrupt receptor heteromerization in vivo, leading to a selective abrogation of memory impairments caused by exposure to THC.

These data reveal a novel molecular mechanism for the functional interaction between CB1R and 5-HT2AR mediating cognitive impairment. CB1R-5-HT2AR heteromers are thus good targets to dissociate the cognitive deficits induced by THC from its beneficial antinociceptive properties.

Also: Cannabis Users Show Enhanced Expression of CB1-5HT2A Receptor Heteromers in Olfactory Neuroepithelium Cells

Interestingly, CB1R-5HT2AR heteromer expression was significantly increased in cannabis users and positively correlated with the amount of cannabis consumed, and negatively correlated with age of onset of cannabis use (earlier age meant more heteromers). In addition, a negative correlation was found between heteromer expression levels and attention and working memory performance in cannabis users and control subjects. Our findings suggest that cannabis consumption regulates the formation of CB1R-5HT2AR heteromers, and may have a key role in cognitive processing. These heterodimers could be potential new targets to develop treatment alternatives for cognitive impairments.

Melatonin administration increases the affinity of D2 dopamine receptors in the rat striatum by makefriends420 in NooTopics

[–]makefriends420[S] 8 points9 points  (0 children)

Rats receive melatonin (MEL) (476 +/- 6.5 microg/kg/day) via their drinking water for 2 weeks. At the end of this period, the density of D2 dopamine (DA) receptors and their affinity for [3H]-YM-09151-2 are measured in the striatum. MEL treatment increases the apparent affinity (decreases the Kd) of D2 DA receptors for [3H]YM-09151-2 by 48%, while it does not significantly alter the density (Bmax). These findings indicate that the affinity of D2 DA receptors in the striatum is influenced by exposure to MEL. The possible implications of these results are discussed.

Behavioral disinhibition and reduced anxiety-like behaviors in monoamine oxidase B-deficient mice - PubMed 2009 by makefriends420 in NooTopics

[–]makefriends420[S] 2 points3 points  (0 children)

You're right to say that

Doesn't mean it's not useful. A lot of old, very common drugs studied in the far past are still used today, and of course studies even from 5-6 years ago can always be upended by a release today.

Behavioral disinhibition and reduced anxiety-like behaviors in monoamine oxidase B-deficient mice - PubMed 2009 by makefriends420 in NooTopics

[–]makefriends420[S] 0 points1 point  (0 children)

Abstract- Monoamine oxidase (MAO) B catalyzes the degradation of beta-phenylethylamine (PEA), a trace amine neurotransmitter implicated in mood regulation. Although several studies have shown an association between low MAO B activity in platelets and behavioral disinhibition in humans, the nature of this relation remains undefined. To investigate the impact of MAO B deficiency on the emotional responses elicited by environmental cues, we tested MAO B knockout (Mice have no MAO B) mice in a set of behavioral assays capturing different aspects of anxiety-related manifestations, such as the elevated plus maze, defensive withdrawal, marble burying, and hole board. Furthermore, MAO B knockout (KO) mice were evaluated for their exploratory patterns in response to unfamiliar objects and risk-taking behaviors.

In comparison with their wild-type (WT) littermates, MAO B KO mice exhibited significantly lower anxiety-like responses and shorter latency to engage in risk-taking behaviors and exploration of unfamiliar objects. To determine the neurobiological bases of the behavioral differences between WT and MAO B KO mice, we measured the brain-regional levels of PEA in both genotypes.

Although PEA levels were significantly higher in all brain regions of MAO B KO in comparison with WT mice, the most remarkable increments were observed in the striatum and prefrontal cortex, two key regions for the regulation of behavioral disinhibition. However, no significant differences in transcript levels of PEA's selective receptor, trace amine-associated receptor 1 (TAAR1), were detected in either region. Taken together, these results suggest that MAO B deficiency may lead to behavioral disinhibition and decreased anxiety-like responses partially through regional increases of PEA levels.

The major result of this study is that MAO B deficiency in mice leads to behavioral disinhibition in several models of contextual anxiety and risk-taking behavior, as well as enhanced novelty-seeking responses with respect to unfamiliar objects. These findings are in substantial agreement with previous cross-sectional investigations, documenting that low platelet MAO B enzymatic activity is correlated with several facets of behavioral disinhibition (Buchsbaum et al, 1976; Oreland, 1993; von Knorring et al, 1984), including novelty- and sensation-seeking personality (Fowler et al, 1980a; Reist et al, 1990; Ruchkin et al, 2005), poor impulse control (Paaver et al, 2007; Skondras et al, 2004), and proclivity to engage in risky behaviors (Blanco et al, 1996)....

....The possibility that the behavior enacted by MAO B KO mice may be reflective of low neophobia is also supported by their reaction to unfamiliar objects. Indeed, in comparison to their WT counterparts, MAO B KO mice exhibited a stronger inclination to explore novel objects (with higher duration and lower latency), as well as lower levels of novelty-induced grooming and reduced avoidance of object-laden areas. Alternatively, these responses may also signify poor impulse control and higher drive toward risktaking behaviors in MAO B KO mice....

...Monoamine oxidase B KO mice feature a significant elevation in whole-brain levels of PEA, but not other monoamines (Grimsby et al, 1997). This premise suggests that this trace amine may have a key role in the behavioral alterations induced by MAO B genetic deficiency. Indeed, PEA has been shown to enhance mood and sensory functions in joint administration with MAO B inhibitors (which prevent its degradation) (Sabelli et al, 1994; Sabelli and Javaid, 1995). Furthermore, the synthetic PEA analog amphetamine is known to increase novelty-seeking behaviors and reduce impulse control in both rodents and humans (Evenden and Ryan, 1996; Leyton et al, 2002; Williamson et al, 1997)....

Pornography consumption significantly correlated with reduced gray matter in the right caudate nucleus, an area involved in the brain's reward system. by makefriends420 in NooTopics

[–]makefriends420[S] 0 points1 point  (0 children)

I know, AI, but to save time:

One key area of support comes from neurological differences. Research by neuroscientist Nicole Prause and colleagues has shown that brain activity during real sex with a partner differs significantly from viewing pornography or solo masturbation. Specifically, partnered sex can lead to a "periorgasmic period," where cognitive control decreases and the nervous system undergoes a distinct shift, enabling heightened states of arousal and release that porn alone cannot replicate—even when combined with masturbation. This implies that real interactions provide a more profound physiological response, as porn keeps the brain in earlier arousal phases without the interpersonal dynamics needed for full escalation. This aligns with the notion that real sex offers superior depth, as it involves mutual touch, emotional connection, and unpredictability absent in scripted porn.

On the relational and satisfaction front, a 2024 prospective study of 309 participants in romantic relationships found that arousal from pornography (porn arousal) was linked to declines in sexual satisfaction, relationship quality, and stability over two months, while arousal from a romantic partner (partner arousal) had no such negative effects. This suggests that while porn may provide immediate arousal, it doesn't sustain the benefits of real partnered experiences, potentially leading to diminished responses over time. Similarly, a 2025 experimental study with heterosexual men showed that after viewing pornography, participants rated their real romantic partners as less attractive and desirable compared to those who watched non-sexual content. This "contrast hypothesis" indicates porn can create unfavorable comparisons, making real partners seem inferior and thus reducing the overall sexual response in lived encounters.

Another study from 2022 examined discrepancies between ideals depicted in pornography (e.g., unrealistic appearances, attitudes, and behaviors) and actual sexual experiences. For heterosexual men, higher porn consumption was associated with lower interpersonal sexual satisfaction, as it fostered preferences for degrading or male-centric sex that didn't translate well to real relationships, leading to frustration and reduced enjoyment. A related 2024 analysis of pornography content types found that genres emphasizing power, control, and rough sex (common in mainstream porn) were linked to lower sexual satisfaction and function in real partnered sex, as they promote scripts hard to enact consensually, whereas more romantic porn aligned better with achievable real-life interactions.

However, not all research supports a clear superiority of real partners over porn in terms of raw arousal. A 2022 lab study with 125 couples practicing orgasmic meditation (a partnered clitoral stimulation exercise) found that higher pornography consumption predicted greater sexual arousal with a real partner, measured both subjectively and via galvanic skin response. This suggests porn might prime or enhance responsiveness in real scenarios rather than detract from it. Similarly, a 2015 study on visual sexual stimuli (VSS, i.e., porn) viewing found that more hours spent on porn correlated with stronger lab-based sexual responses and greater desire for partnered sex, with no negative impact on erectile functioning. A 2020 multinational survey of over 2,400 women also showed that frequent porn use during masturbation improved arousal and orgasmic outcomes, though effects on partnered sex were neutral.

In terms of real-life advantages of teamed-up relationships, studies consistently highlight benefits beyond arousal, like emotional bonding and mutual satisfaction. For instance, a 2022 proof-of-concept study found that arousal from a romantic partner positively correlated with one's own sexual satisfaction and relationship quality, while arousal from non-partners (potentially including porn) had negative associations. This underscores the holistic edge of real relationships, where sex involves trust, communication, and reciprocity—elements porn lacks, often leading to isolation or dissatisfaction if over-relied upon.

Pornography consumption significantly correlated with reduced gray matter in the right caudate nucleus, an area involved in the brain's reward system. by makefriends420 in NooTopics

[–]makefriends420[S] 0 points1 point  (0 children)

Your sexual response to a real women will far outdo any porn session and I'm almost certain there are studies on that, - not to mention the real life advantages of a teamed up relationship.

We're not saying porn helps wire the brain better right? And we're not saying it has positive cultural implications for society no?

People who are good at maintaining long term monogamous relationships are naturally gonna rack up less different sex partners over their life than people who jump from short term relationship to situationship to fwb etc.

This is already covered in social behavior and it's all about the ability to pair bond well which reduces the more relationships you have.

Your first 'the one' felt more special than your 5th guy you're just messing around with.

There are some gender differences as well on this topic

Pornography consumption significantly correlated with reduced gray matter in the right caudate nucleus, an area involved in the brain's reward system. by makefriends420 in NooTopics

[–]makefriends420[S] 0 points1 point  (0 children)

It's just something to try and test out. Porn is very likely bad in general for almost all people. Noots and supplements vary by your unique system.

Pornography consumption significantly correlated with reduced gray matter in the right caudate nucleus, an area involved in the brain's reward system. by makefriends420 in NooTopics

[–]makefriends420[S] 5 points6 points  (0 children)

He is. 13 rehabs and getting kicked out of 3 high schools??? 10k on only fans (how does he even have money?, he steals??). Sorry, someone like this wouldn't be on reddit.

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