Dynorphin

I believe dynorphin to be a missing link that can bind the dopaminergic and glutamatergic hypotheses of schizophrenia together. Not only this, but dynorphin may bind together behavioral and circumstantial theories together as well. In essence, dynorphin seems to mediate suffering, and suffering can eventually lead to dissociative and psychotic symptoms, especially after prolonged periods of time. Dynorphin is not alone in this process as may already be apparent, but rather a plethora of downstream mechanisms such as both dopaminergic and glutamatergic mechanisms, as well as modulation of tachykinins combine and evolve over time to create the problems of schizophrenia. The spectrum of schizophrenic disorders seem to be extreme states of suffering that sensitize you to fear suffering much more than a typical person might. Dynorphin even appears to be a key player in the outcomes of intelligence, where increased dynorphin reduces cognitive functioning and memory. Deviations in intelligence may be partially due to sensitivities to reward and suffering and be modulated in either increased of decreased direction depending on the ratio of good and bad life experiences.

And so that is where we will begin.

Intelligence

The role of dynorphin in cognition is to modulate future behaviors based on present circumstances. During negative circumstances, dynorphin activity will prevent learning of behaviors that lead to suffering, and enhance behaviors that pull away from suffering because dynorphins anti-learning effect will cease more and more as you pull away from negative stimuli, thus restoring or even enhancing learning by a rebounding mechanism. So as you pull away from the aversive stimuli, learning occurs, but when you are approaching aversive stimuli, this behavior can not be habituated or learned. This is why we can use kappa agonists to prevent reward learning in cocaine use. In this sense, dynorphin helps us to learn NOT to do things. The aversion neurotransmitter. Dynorphin functions by binding as an agonist to kappa opioid receptors and also blocking NMDA receptors.

It appears that dynorphin may generally decrease cognitive ability and intelligence, although there may be an argument to be made that it changes cognition towards a direction that intelligence tests are typically biased against. Let’s start with evidence supporting the hypothesis that dynorphin decreases intelligence. Dynorphin seems to mediate age-related cognitive decline, which was shown when prodynorphin knockout mice did not experience cognitive decline. Dynorphin mediates alcohol-related spatial learning and memory impairment. This occurs by disrupting glutamate neurotransmission in the hippocampus. Another study found stress-induced learning and memory impairment was mediated by dynorphin. This one is interesting because it is not limited to spatial cognition. Occlusal disharmony, a problem that can cause neck stiffness and psychiatric depression, was shown to cause memory and learning impairments mediated by dynorphin activity in the amygdala. It may be that pain aversion is mediated by dynorphin as well, which would explain this effect of the occlusal disharmony on learning and memory. Stress was negatively correlated to academic performance in high IQ students.

Dynorphin inhibits NMDA glutamate receptors and inhibits dopamine release, which may function to explain cognitive reductions as NMDAr and dopamine are critical in learning and memory.

The picture gets a little more interesting when we consider major dynorphin-implicated conditions. One such condition is PTSD. Stress and depression have also been linked to dynorphin.

So what does this mean for intelligence here? Well, PTSD has been linked to lower IQ scores. The research linked here has noted that premorbid IQ being lower also made PTSD worse, but this may be due to early life stress or prior trauma is limiting IQ and even promoting more severe stress reactions in adulthood. It was found that exposure to domestic violence suppressed IQ. Prior trauma is a risk factor for experiencing further trauma after a second event. So it seems likely that prior trauma may be at play here with premorbid IQ scores. This post on Psychology Today explores a study that showed a 10-15 IQ point drop correlated with stress. Unfortunately I was unable to find the original study. The post mentions amygdala activity suppressing prefrontal cortex activity as part of the explanation for intelligence differences and dynorphin is key to amygdala activity.

A study on cops found that their openness to experience was reduced after experiencing a traumatic event, which is significant because openness to experience is the only Big 5 trait linked to intelligence. I’ve explained before that negative experiences seem to reduce openness in a way that becomes obvious in context. Imagine that you experience an abusive relationship. You will become more aversive towards potential abusive relationships, which fall under the umbrella of “relationships”. You may become less willing to expose your vulnerable side in relationships and essentially this is one of the many issues with PTSD, an unwillingness to be vulnerable, to take risks. It’s really worth reading the full post on this concept. The relevance here is that openness may be a promoter for engagement with novel (and potentially risky/unknown) experiences. Novel experiences promote learning because these are the very situations needing to be learned (you don’t learn the already learned stuff).

Traumatic experiences may reduce the range of experiences a person is willing to engage with when the expectation is that these experiences would be potentially negative or risky. Prior to the trauma, experiences would have been good-good-good and there isn’t a clear reason to be cautious if bad things don’t seem to happen. This unwillingness to engage in unpredictable and novel situations might lead to a decline in cognition simply due to cognitive neglect. It also seems to be the case that the more negative someone is feeling, the more they would desire a reward that is highly predictable because they care more about ending the suffering than they would about exploring new things. Suffering adds a dimension of motivating one towards seeking distraction, in which we must quell the pain and boredom is of less priority than security. So not only would dynorphin promote specific aversions in the case of PTSD, but it would also invoke general malaise that becomes a high priority issue, detracting from one’s curiosity and reprioritizing our behavioral biases towards security. In this case, people may favor their comfort foods, as opposed to trying a new food that is potentially dislikable. The disappointment of disliked novel food would only stack with the prior stressors and make things worse so it is good to ensure successful reward acquisition rather than take a risk. For those who’s lives are generally good, they will build a tolerance towards repetitious rewards and begin to desire something more fulfilling: novel rewards for which we have no tolerance built towards.

This is likely the role dynorphin plays in addiction. The benefits of the drug become the most predictable reward that is capable of attenuating suffering. Alongside that, dynorphin is generally upregulated by most or even all rewarding drugs. Eventually your willingness to seek rewards other than the drug shrink down as suffering becomes more ubiquitous.

I’ve explored how addiction, dynorphin, and schizophrenia may relate to each other in the past. Relevant here, it is known that schizophrenic severity is negatively correlated with IQ. From here we can explore the connection dynorphin seems to have to schizophrenia.

Schizophrenia

The dopamine hypothesis of schizophrenia has become popularly known among the psychological community. It is the idea that lots of dopamine and high D2 receptor density lead to psychotic states. Another common hypothesis is that people in psychosis have hypoactive NMDArs. Dynorphin may bind both the dopaminergic and glutamatergic hypothesis as well as explaining the link between schizophrenia and childhood trauma.

KORs colocalize with D2 receptors and were found to sensitize D2 receptors. Chronically elevated dopamine levels have been shown to upregulate dynorphin and neutralize learning benefits of dopamine. Dynorphin inhibits dopamine release. Dopamine receptor blockers that prevent dopamine activity from occurring upregulate the receptors. So when dynorphin reduces dopamine activity, this likely upregulates dopamine receptors in response, and once dopamine is releasing again it may upregulate dynorphin levels again, suppressing the hyperactivity of dopamine. This is a feedback loop and provides a mechanism for psychosis. This would explain why stimulant-induced psychosis takes a while to manifest, as dynorphin will upregulate in response to increased dopamine receptor activity after a period.

Psychosis seems to be a response to prolonged periods of suffering. PTSD is very similar but may be context-dependent and much more specific in what is causing the suffering. Another difference I suspect exists between PTSD and schizophrenia is that schizophrenia is more about ongoing pain and trauma which causes an accumulation of dissociative symptoms induced by dynorphin activity, whereas PTSD is the skeleton of that experience where your mind is still conditioned to fear the pain despite a lack of real threat. In essence, schizophrenia may deal with suffering in the here and now, while PTSD is the afterglow of bad experiences. Psychosis may pose a different set of problems that don’t exist in PTSD as well. With psychosis it may be a much more generalized state of suffering and likely the person’s ongoing problems only get compounded with increasing symptoms. A feedback loop occurs in which symptoms increase as a response to suffering and suffering increases in response to the symptoms.

When suffering is significant, one’s mentality may orient itself towards threat detection in order to prevent further increasing problems. This is similar to the process that the addict is undergoing, where rather than focusing on finding new sources of pleasure and happiness, one becomes preoccupied with avoiding suffering. The risk of experimenting is too high, and more eminent issues get prioritized. The schizophrenic seems to turn numb to the ongoing sources and associations to suffering due to constant exposure, while avoidance of potentially dangerous novel situations like meeting new people increases.

Openness to experience has been linked to the DRD4 long variant polymorphisms. These long variants have been labeled a risk factor for schizophrenia, PTSD, and addiction. I’ve written an in depth exploration of my hypothesis that the DRD4 longer variants enhance learning, in which addiction and PTSD are both extreme forms of pleasure and pain learning.

What’s interesting is that schizophrenics actually have decreased openness to experience. I believe that schizophrenics begin in life with high openness and that this actually makes them more prone to trauma. This is because high openness would lead to a wider range of both positive and negative experiences. Openness will mean that you try things that less open people will be unwilling to try. This openness could mean drugs or any number of things. It will mean once consequences emerge from engaging with trial and error, you will be identified by others as the person who makes mistakes. This will cause less open people to distance themselves increasingly. So not only are you more likely to engage in risky, potentially traumatic experiences, you will also face social problems along the way. You will become the black sheep. If you are lucky, you may end up only as a schizotypal creative. If you are unlucky, perhaps a schizophrenic freak. Openness may also lead to breaking rules earlier in life, and thus being punished for these misbehaviors. Non-psychotic deviant behavior has been linked to developing schizophrenia later on which supports this concept. Explore this dynamic of openness in depth in my post, Nexus. This is essentially the social defeat hypothesis of schizophrenia. Dynorphin mediates social-defeat stress so this makes sense. Dynorphin has been linked to psychosis before.

I believe that dynorphin is suffering, is “bad”.

I believe that experiencing pain is likely not negative if you block dynorphin activity, but only a neutral sensation. I have noticed this on naltrexone, a kappa, mu, and delta opioid antagonist. I had an increased sensitivity to physical pain but I had no aversion to this pain. It felt like a tingly neutral experience. I also experienced a sort of hyper-vigilance reminiscent of trauma except that I had no negative feelings. I actually quite liked this effect. This experience was not always consistent and likely depends on how much antagonism is occurring. Read my naltrexone report here.

Racism

In recent years the debate on race and IQ, or as the euphemistic like to say “race realism”, has surfaced likely as a defense or justification for racist ideology. This is the case for people like Richard Spencer. This debate gets into the observed IQ mean difference that is seen with each race. Typically black Americans are low, whites in the middle, and then on the top there is Asian and Jewish people. The debate has even caused controversy among people like Sam Harris because he attempts to stay rational and unbiased towards explanations that we desire. Sadly this leads many to think of simple explanations because the observation of IQ seems simple enough.

So I present an anti-racist position, that dynorphin may play a role in racism and the difference seen in IQ scores. Trauma by racism is a major factor of living as a black American. There even exists far more trauma by the living conditions in poverty such as domestic violence, something which has already been shown to suppress IQ. There is also high rates of black on black crime and violence. Black people also go to jail more than other races in America. Schizophrenia has also become a black disease. The case may be that racism is increasing dynorphin which is having these effects. The reality could be that people like Richard Spencer are part of the movement to make more black people suffer. Of course this is much more widespread and systemic than one person.

A Big Think video featuring Andrew Yang explores research that suggest scarcity of various forms may reduce IQ.

https://youtu.be/ewPEzuXO61Y

This section below is theoretical and I still must add sources.

It seems that dynorphin may signal scarcity, suffering, and low reward conditions of life and thus reduce the mind and body in order to save energy. A depression-like mechanism or maybe even something like hibernation. Serotonin receptor 5HT2a is found to attenuate the KOR system and also forms heteromers with MOR. KOR relies on SERT activation through MAPK mechanisms in order to induce its aversion effects. This means extracellular serotonin must be reduced for dynorphin to exhibit its effects properly. It is likely to be that reducing extracellular serotonin would reduce activity of the KOR-activity attenuating 5HT2a receptor. This may reveal mechanisms of social hierarchy involving the serotonergic system and also explain the link of social defeat stress and dynorphin, where serotonin signals for abundance and dynorphin signals for scarcity. Since serotonin downregulates SERT, it would automatically maintain regular serotonin activity that is higher, while KOR agonists like salvia have been shown to upregulate SERT, likely because serotonin is lowered temporarily which enhances KOR which further causes SERT to lower serotonin and eventually serotonin is low enough that SERT can upregulate because there is no extracellular serotonin to cause downregulation of SERT. MOR activity may stimulate 5HT2a via crosstalk and cause KOR attenuation that may lead to increased extracellular serotonin which downregulates SERT. Since MOR is commonly involved in reward processing it may be that rewards can cause downstream effects on SERT levels via this mechanism and lead to social hierarchies based on who has more rewards and less aversions (essentially losses). This provides two forms of feedback loops (serotonin and dynorphin) that maintain a stasis of high or low status that could form social hierarchy tendencies and explain social defeat.