This article is far more like brainstorming than most of the other content on this blog. Some things may not be cited or un-edited. This could be inciteful but also a rough read in some lines. Have fun.
In this part I explain a model for neuron activation priority. Blood flow will prioritize dopamine flow towards neurons that are prioritized based on frequency of use and importance. Events of novelty will boost dopamine above normal levels. Normal levels of dopamine have habituated response and flow patterns based on tolerance and neuronal Long Term Potentiation (LTP). The D1 dopamine receptors are the main priority for dopamine activation involving habitual decisions simply by being the most common receptor type (and thus more likely to be bound by dopamine). In essence this is Pavlovian conditioning. Sensory cues will be processed and familiarized via NMDAr and then NMDAr heteromers with D1 receptors will trigger the corresponding learned response and cause dopamine release that will follow a series of neurons down a path of neurons that eventually manifest as automated responses/decisions to the set of sensory cues that initiated this domino effect. I think that this begins with the co-occurrence of sensory stimuli via NMDAr currents and simultaneous behavior that occurs via D1 receptor currents combined with mu-opioid or kappa-opioid currents would cause learning of motivational reinforcement or aversion. It is thought that operant (Pavlovian) conditioning is mediated by NMDAr and D1 simultaneous stimulation. Mu-opioid activity has been known to be involved in LTP, and to potentiate NMDAr activity, and stimulate D1 activity On the other hand, kappa-opioid activity which mediates aversion has been shown to prevent LTP, inhibit NMDAr and inhibit D1 receptor activity, likely halting the associated behavior and any reinforcement of that behavior in the future. So here we see mu-opioid binding to signal as ‘yes’, ‘do’, or ‘reward’, while on the other hand kappa-opioid signals ‘no’, ‘don’t’, and ‘suffering/dysphoria’.
Non-sensory linked D1 will likely also have NMDArs that highlight the sequence of D1 activity that results in the rewarding behavior. In theory, this would create a somewhat linear path from cue to reward, at least after the behavioral response has been very frequently utilized successfully, and other behavioral choice paths have been significantly neglected.
During an event of novelty, generalized dopamine is released in a higher quantity than normal, causing an increase in the likelihood of rarer D2 and D4 dopamine receptor activation, since these receptors are less common (lower density/affinity than D1). These (D2 and D4) receptors form connections and activate together except with certain genetic variations linked to schizophrenia and ADHD.
Novel stimuli could be defined as stimuli with no tolerance, as tolerance to the stimuli has not yet formed. Novel stimuli would trigger an exploratory state and freedom from the Pavlovian prisons of automated behavior via the mechanism of DRD4 and DRD2. DRD4 may function to enhance the contrast between novelty and familiarity, making it easier to notice novelty and harder to notice familiarity. The exploratory state would lead one to seek reward stimuli processed via mu-opioid receptor activity and aversive stimuli processed via kappa-opioid receptor activity and associate them with behavioral signals encoded by D1 dopamine receptors by forming heteromers and then causing LTP via NMDAr stimulation of heteromeric mu-opioid and NMDAr or LTD via kappa-opioid induced NMDAr hypoactivity. To recap: It is known that mu-opioid forms heteromers with NMDAr, and that D1 dopamine receptors form heteromers with NMDAr, and so it may be that combined activation of NMDAr by heteromeric interactions would enhance NMDAr mediated LTP, so that behavior (D1) and reward (mu-opioid) are learned.
D2sh receptors inhibit dopamine flow. External cues would link to a series of D1-D1-D1-D1 that eventually results in action. These sequences are learned based on Mu-Opioid simultaneously being stimulated which indicates successful action or thought has occurred. This series of D1 forms what I will call a habit sequence. Or learned behavioral sequence. Routine levels of dopamine will maintain these habit sequences and eventually you will reach a state that is nearly entirely automated. A habit machine. When dopamine levels rise above routine levels it becomes more likely to stimulate the more rare D2sh receptor which can shut down habit sequences by inhibiting dopamine release. This abolishes the habit machine state. D2 receptor availability is linked to the flow state. It is likely that this is the mechanism for attention directed towards novel stimuli via captivation. It shuts off a cognition that is oriented towards maintaining habits and routines and allows the dopamine to be directed towards novel stimuli (which are presumably the least or even unused neurons) so that this could eventually be encoded into routine reward acquisition.
Even our vision seems to be a series of habit sequences. Illusions. Object recognition. Our perceptions of familiar objects is assumed and over-simplified by the brain.
D2 and D4 dopamine receptors form heteromers, so it may be that when either of them are bound, both of them have the same resulting effects. It may also be that the effect is different depending on which one is in higher ratio (because they have different downstream effects), and that the density ratio between these two receptors plays a role in different behavioral responses. D2sh receptor activation would cause inhibition of dopamine release, preventing further dopamine activity in the surrounding area, while D4 activation would shut down NMDA receptors of these neurons via heteromeric interactions with D4 receptors which would attenuate awareness of the neuron’s access to NMDA receptor signals, with the neuron(s) and thus also shutting down the corresponding Pavlovian response that is linked to the stimuli.
Presumably the neurons are being activated in order of the most frequently accessed, recent, and prioritized neurons. So for example, if you look at a desk that is familiar, but there is something novel on this desk, your attention for the desk would be filtered by NMDAr inhibition via DRD4 heteromers, and the novel objects would be highlighted now without distracting stimuli. This would allow the majority of attention to be reprioritized on novel stimuli and deprioritized on familiar and already learned stimuli. It is known that DRD4 receptors help with learning high-priority (as defined by higher dopamine activity presumably?) stimuli, and also that D4 receptors inhibit GABA(a) activity, which has been shown to increase learning and memory, likely for the specific purpose of learning novelty more rapidly. This model shows novelty prioritization via deprioritization of the most previously prioritized and reinforced pathways of stimulation an effect of DRD4 which has been shown in the research. The exploratory state induced by novelty may be enhanced fluid intelligence. I’ve explained this more thoroughly in Xenotypy, one of my best posts yet. I would even recommend you read that before this article, they both go together really well.
Familiar stimuli would have decreased sensation as tolerance forms, and also the experience would become automated to some degree, especially the most predictable stimuli. The most extreme form of positive pleasure-based predicted stimuli and their corresponding responses are what we know as addiction, a state in which the strongest reward and their corresponding automated responses take priority over other stimuli and their learned responses.
The most extreme form of negative dysphoria-based predicted stimuli and their corresponding automated reactions are what we know as PTSD, a state in which the strongest aversive stimuli and their automated responses take priority over other behavioral responses associated to lesser prioritized stimuli-response combinations.
Familiarity is the basis for our Pavlovian Prisons. It is likely that the default mode network (DMN) is a system of familiarity and automation. The daydreaming that seems to occur may be due to the freedom that consciousness has to think without considering behavioral decisions, since these have become automated and familiarized. reduce the contrast between novelty and familiarity, making perception more diffuse and wide and allowing for patterns between novel and familiar stimuli to form more easily. Familiarity is likely operating both in behavioral and cognitive forms, and probably is highly similar to the concept of crystallized intelligence. The familiar experience is the already-learned experience.
Psychedelics may produce an experience of extreme novelty, or reverse the tolerance to familiar things. This would involve a state of exploration similar to the response to novelty, but also an awareness of all stimuli, not just novel stimuli. The psychedelic state would then allow you to reprogram familiarity as if it were novel, as well as combining novel and more updated stimuli/memories that can help improve the state of familiarity. It has been shown that psychedelics change how we experience familiar and novel stimuli. The purpose of this state is exploration of stimuli, which requires familiarity to be reduced as a whole because automation prevents and distracts from exploration. In this sense, addiction and PTSD are both extreme forms of automation that highlight what occurs on a smaller scale constantly as we learn and familiarize our environment. Psychedelics may induce this effect via the set of heteromeric interactions involving the 5HT2a receptor, which may be the control valve or center of these interactions. 5HT2a receptors form heteromers with D2 dopamine receptors, and it may be that abnormally high levels of dopamine and serotonin trigger the cascading effects that lead to exploration and deprioritization of familiarity via the mechanism of D4 and D2 dopamine receptors. 5HT2a receptors also form heteromers with mGlu2 receptors that are inhibited when 5HT2a receptors are stimulated. When mGlu2 receptors are inhibited, glutamate release is disinhibited, which should cause an effect that is opposite to glutamate receptor blockers. NMDA receptor blockers decrease sensation and cause anesthesia and decreased consciousness, so it follows that increasing NMDA receptor activity would increase sensation and consciousness.
Psychedelia may decrease behavioral automation without shutting off , as to allow further exploration of stimuli that you are frequently exposed to, as if to allow re-analysis and alternate possible behavioral choices rather than the automated one. This is likely most useful for high amounts of novel stimuli, namely childhood in which forming assumptions and conclusions too quickly could lead to worse judgment that is too lasting. 5HT2a is known to have NMDAr partial agonist effects, which may override the D2 and D4 receptor effect of NMDAr inhibition, and activate only under the circumstance of serotonin stimulation and may reduce the contrast between novelty and familiarity, making perception more diffuse and wide and allowing for patterns between novel and familiar stimuli to form more easily. This would explain the study showing that psychedelia increases sensitivity to previously familiarized stimuli while decreasing the intensity of novel stimuli, likely only because familiarity and novelty are becoming diffuse rather than focused into novelty. In essence, this state frees you from the confines of your behavioral prisons.
Novelty experience that is primarily a result of dopamine excess may only mildly have 5HT2a involvement while serotonin excess would start to have a combined effect that begins to reduce the contrast between novelty and familiarity, allowing for exploration of both, without the distracting urges of automation. In some sense, the familiar may be temporarily novel under this condition, and the decreased response to novelty may only be due to competing novel stimuli. It is likely that in the lower levels of psychedelia, there is still an intact sense of familiarity that is merely a reduced level of tolerance for the stimuli, rather than an abolished level of tolerance and as the level of psychedelia increases, the tolerance becomes abolished which would lead to a diffuse awareness where all stimuli is temporarily novel. This would be an unraveling of what we assume we know.
It is known that serotonin increases with access to environmental resources like food (cite) and also when an individual becomes the alpha. It may be that exploration of the familiar is excessive and a luxury that should only spend out energy when we have secure resources. This may even be able to explain a difference in wild animals and humans, where humans may almost always have more secure resources than wild animals due to the nature of human society. Social dominance and being alpha may increase serotonin based on gaining the security of social support and may function to allow the alpha to do most of the exploring while subordinates may mostly function as creatures of habit. It may not be the social support, but perhaps the sense of freedom of one’s own choices and behavior, as the alpha is respected while subordinates have limited freedom and are expected to obey the limitations or else consequences will occur.
It is also known that serotonin is increased in childhood and slowly decreases with age, likely it is that the 5HT2a receptor mediates the exploratory behavior in childhood as to allow for an improved formation of understanding about the world around us by reinterpreting it and relearning it to find the best perspectives. The child may have high serotonin levels based on a perceived unlimited resources given by the parent, and this may be a factor in determining differences in outcome based on early life environmental factors such as poverty and decreased family resources. I also wonder if having a child may increase serotonin levels for a similar reason that being alpha would. It may help monitor and manage the child, whereas the alpha manages the herd. This may explain some of the psychological changes that occur after giving birth, such as postpartum depression and postpartum psychosis.
During sickness, serotonin may increase (cite about immune serotonin) in order to help find the source that is causing sickness, such as bad water supply, poisoned food, toxins or other sickness agents that may not necessarily be novel and thus ignored habitually as they are assumed to be safe due to prior survival and success. If these sources weren’t novel, the creature would continue to habitually consume a water supply and have a tolerance to sensations that may be critical to becoming aware of the source of sickness, such as odd tasting water or food. In this way, the effect may cause hypersensitivity to already familiarized sensations in order to detect nuances that may be causing sickness.
Depression may occur when tolerance has formed to the stimuli preventing the subjective experience of reward. Under normal conditions, this promotes exploratory behavior of novel stimuli by dis-incentivizing repetitious lifestyles that exploit the same rewards over and over. Those who experience depression may require novel experiences that have no tolerance and thus maximum sensation and consequently maximum reward. Life circumstance and environmental factors likely restrict the individuals from accessing novel experiences, for example working at a stable job and living a stable and consistent lifestyle without sufficient sources of novelty would lead to a lower degree of reward because of the tolerance developed from frequent exposure to the events of daily life. It is worth noting again that seeking sufficient levels of novelty is not a luxury that everyone can have, more especially those with lower socioeconomic status (and in some sense social dominance). As excess of familiarity and a deficiency of novelty may be a core problem for many with depression.
For those with depression, psychedelics may abolish behavioral maladaptions, assumptions and predictions that cause learned helplessness, and a decreased tolerance of familiarity that may restore the excess of tolerance towards daily life. The exploratory state may allow one to re-evaluate their daily life so that a novel evaluation is made, thus making daily life more novel under a different perspective of the same familiar stimuli. This would mean less tolerance has developed for the new evaluation of one’s life, leading to heightened sense of reward.
There is also a point where exploration is dangerous and so depression may inhibit exploration as a safety precaution. Once the new behaviors have been habitualized, even when the conditions are better, the habits may remain. Much like how a person’s poverty behaviors may linger even after they become rich, such as living a life of scarcity. Psychedelics could shut down habits and allow re-analysis of life.
Addiction and PTSD
Addiction and PTSD are essentially the highest forms of familiarity. Under conditions of low resources and low social status these states are useful for efficient decision making and automation of behavior as to reduce energy use while maintaining a level of security. There are clear maladaptive problems with addiction and PTSD such as reduced control of behavior and the making of decisions that are highly prioritized on something that may not be valuable for progress. These states would truly classify as Pavlovian Prisons. Exploration would allow for increased variety of choices and freedom from these behavioral prisons. During times of higher resource, increased levels of energy could be sent to exploratory behavior as to relearn and form new habits that are superior to the ones you currently make: addiction and PTSD behaviors.
Consider Pavlov’s dogs who associated the sound of a bell with food, in which they had an automated response of salivating at the sound of the bell. The pure novelty seeking effect of the dopaminergic side would lead to a lowered awareness of the bell and food during an event of novelty. The NMDAr inhibition would be bell/food/familiarity inhibition. Psychedelics would restore the awareness of the bell and the food, but the inhibition of dopamine via D2sh receptors would remove the associated behavioral responses, thus the salivation should be attenuated. This allows relearning of associations and thus attenuation of addiction and PTSD.
A study found that Mu-opioid receptors interact with 5HT2a receptors in terms of behavior. This is significant as Mu receptors are known to be implicated in addiction of various substances, even beyond opioid drugs. Cocaine addiction is partly mediated by dynorphin which is the body’s natural kappa-opioid agonist and also dysphoria-inducing agent. Withdrawals of drugs causes dysphoric experiences while the high causes euphoric experiences mediated by Mu receptors.
I believe that psychedelia often represents mania very well, both from my personal experience with bipolar mania, and due to the pharmacological similarity that seems to exist. It is likely that those with bipolar disorder have an increased perception of social dominance and resource status. This is something I’ve explored in my DMT hypothesis of bipolar disorder, which may really just be a serotonin and dopamine hypothesis in reality. Those with bipolar disorder are known to be highly exploratory and have traits that seem alpha, such as grandiosity, which may be perceived by others as a sense of alpha-ness that is incorrect. This is a complicated topic due to the fact that bipolar types may have increased abilities to some degree, which I have explored in this post here. It may be that the increased ability would increase sense of social dominance, or it may be that the freedom of the psychedelia/exploratory states would give rise to the increased ability. Due to the involvement of reduced GABA(a) subunit alpha5 receptors and the known cognitive benefits that reducing these receptors has on cognitive function, it may be an actual increased ability. Another possibility is that it is a combined effect of the increased ability, increased serotonin levels caused by decreased MAO A, and maybe even actual social dominance that may further enhance mania.
Those with ADHD have higher amounts of D4 dopamine receptors often. It seems that they have enhanced learning of novelty, but problems like depression or a dysfunction of maintaining useful habits or inhibiting novelty seeking behaviors which may distract them from daily tasks may occur. Those without ADHD may be more numerous and thus society may be structured in favor of less novelty affinity, which would result in negative consequences for those with higher novelty affinity, because it means they aren’t going to follow the structural basis of society. This could mean creativity for some, but it may mean depression, stigma, and failures for others.
Recall this line from earlier in the article:
“When an action has lead to sufferable outcomes, the process goes beyond mere neglect, and is actively turned down by NMDAr inhibition.”
Consider that schizophrenics undergo excess pruning, which may be due to a mix of neglect but also sufferable (trauma in this case) induced NMDAr inhibition by dynorphin mechanisms. I’ve explained how schizophrenia could really be the result of trauma and social mechanisms in the past. The inhibition of dopamine activity by dynorphin could upregulate dopamine activity. High dopamine activity is known to upregulate dynorphin, and so it is easy to see a feedback loop here. On one hand, there would be an effect of familiarity neglect, and then hypersensitivity to reacting as if stimuli were novel. Part of this may mean excessive DRD4 activity. I’ve presented a case for why DRD4 would enhance learning, especially of novelty here.
Psychosis may be a little more tricky to understand. There seems to be a feedback loop that occurs. It could be that high amounts of the dopaminergic mechanisms of novelty processing are heightened but to a degree that causes too frequent dissociation from familiarity, and eventually familiarity itself may cease to exist, because of the infrequency of familiar memory usage. This seems to make sense with the fact that those in psychosis have hypoactivity of NMDA receptors. It could be that novelty is so frequently engaged that a near constant dissociation of the familiar allows for a sort of tolerance break to the familiar, which then leads to hypersensitivity of both novelty and familiarity, making it difficult to distinguish between stimuli and also causing dissociative symptoms. High amounts of dopamine may cause more extreme experiences of novelty and each novel stimuli may shut the rest of the world out for total focus on the novelty, and causing one to think far too deeply about the novel stimuli, in essence assuming it is far more significant than it is.
The D2 receptor count is increased in those with schizophrenia. The excessive stimulation of D2 receptors may continually attenuate previous associations and interpretations of the stimuli in daily life, and cause one to continuously update their perspective with novel data rather than rely on habitually activated data. This may be useful in the beginning of learning about new experiences but the eventual result might be so many re-interpretations that you end up going deeper into a rabbit hole that is built by your deeper and excessive analyses of what the experiences in your life mean. Conspiracy, paranoia, and complex assumptions that those with schizophrenia seem to be evidence of this.
Another issue may be that the default mode network is in some sense a ‘Pavlovain Prison’ as well. The constant exploratory state might result in an excessive detachment from the default mode network, and may result in the dissociative symptoms that are common to the disorder. In some sense, much of the problems may stem from social conflicts between those who heavily use the DMN and the schizophrenic. There would be communication disorders between these two groups of people because their experience in daily life would not relate. Then those with more constant DMN are the majority of people and they will take dominance over what is ‘correct’.
It also seems that schizophrenics will tend to be novelty-seekers due to the overlap with ADHD genes at the DRD4 7R polymorphism. It could be that novelty-seekers eventually confront traumatic situations that result in psychotic symptoms, which may really be synonymous with PTSD. Those who have schizophrenic symptoms after psychedelic use may have been traumatized during and after the experience. Imagine that you act out in an aggressive or shameful way on the psychedelic or express personal things that you’ve been hiding due to fear of rejection and the psychedelic disinhibited this and made you trust others enough. Then your identity may be forever altered and even destroyed by either of these two actions. The psychedelic may reduce all the pavlovian coping strategies and leave you very vulnerable, enhancing the likelihood you would be traumatized. This lowering of prior pavlovian conditioning could last after the drug wears off, and as your identity changes to ‘crazy person’ you become traumatized. It can mean losing all of your trust and closeness with the people around you, and losing the life you lived prior to acting out. Also we must consider that hiding the personal information may have been due to fear of judgment and may have been a sound judgment, and then now one of this individual’s greatest fears may have been publicized.
For example, imagine a homosexual Christian who has uncontrollable desires and interests in the same sex but simultaneously have deep fears and aversions towards. The aversion neurotransmitter, dynorphin, is known to induce psychotic type effects such as dissociation. So it may be that the Christian homosexual would dissociate from the inner thoughts associated to their homosexual urges, resisting from identifying the self with these urges. Eventually the traumaticness of this reality may be compounded by external experiences with his/her peers as they express hate towards the identity of homosexuality. Eventually the dissociation may grow enough that the thoughts are experienced as a separate voice.
It is known some individuals with schizophrenia have positive interactions with their voices, and it may be more complicated than disagreeing with the voice or fearing it. It could be dissociative effects that do not initially stem from the fear directly or even non-fear related mechanisms that we generalize as schizophrenia with the rest of the people who experience hallucinations. Many hallucinations could be caused by other mechanisms that result in dissociation as well, perhaps sleep deprivation is causing NMDAr hypoactivity by some mechanism.
We have seen how social factors can be involved in psychoses in even medical settings with the Rosenhan experiments. A team of researched feigned mental illness and then once admitted to mental hospitals they began to act normally and told the doctors they no longer experienced any hallucinations. They were forced to take medications and were trapped for nearly a month before escaping. They described the treatment by medical staff as dehumanizing, objectifying, and sometimes even abusive. The staff would talk to each other in front of the pseudopatients as if they weren’t there or as if they were a dog. Read the Wikipedia post to get an overview, it is pretty disturbing.
Consider how these biases and perceptions would manifest from non-professional, untrained friends and family. Imagine if your family diagnoses you as ‘crazy’ after your behaviors during or after using psychedelics and how much worse it could be compared to professional doctors and nurses trained in mental health treatment. Imagine how much deeper the judgments will impact you coming from those who you were closest to. Imagine having no friends or family left to turn to as a way of coping because they have all deemed you as broken and emotionally invalid. Imagine being extra sensitive to all of this due to the psychedelic drug and how your reaction could be more extreme just anticipating these events unfolding. It becomes more clear now how psychedelics might bring upon psychotic episodes. We must remember how many absurd diagnoses existed in the past and consider how our own confirmation biases may be generating psychology, even when it is in the realm of ‘science’ and ‘professionalism’. Consider the Dancing Plague, in which many died from contagious dancing behaviors. After all of these considerations, it no longer seems that criticism of the psychotic diagnoses is unreasonable. This isn’t a denial of hallucinations or ‘delusions’ but more so revealing that much of the accompanying symptoms may be the result of hysteria and fear of being labeled as psychologically and emotionally invalid. Hallucinations seem more common than people admit, almost everyone I’ve met has experienced them at one point, but the fear of diagnoses causes people to hide these experiences and those who are honest are punished with the label of ‘invalid thinker’. There must be an insanity when trying to reject one’s own divergent thoughts that appear rational to the individual and rejecting rationality altogether in order to assume that the popular opinion is always correct (which is a known fallacy), which is the case with being labeled delusional. There is delusion on both sides, where psychiatrists, peers, and family who label an individual as psychotic are delusional as well as the individual themselves. None of us even have a close rendition of true reality, and to shame and target deviating ideas will only generate narcistic responses much like actual narcissists who constantly seek validation, which only results in others being much less likely to validate due to the desperate and offensive nature of their validation seeking. Grandiosity as if to advertise how certain one is of an idea or judgement and also defensiveness for example.
It may be that individuals with autism do not experience as much of the childhood psychedelic state, causing them to more rapidly form judgments, and experience the effects of Pavlovian conditioning. Their stimming behavior may represent addiction, while their loss of contact with social realities and mutism may be due to PTSD-like effects. There is some evidence of this, as those with autism tend to have hyper-developed prefrontal cortex and one mechanism of the subjective effects of psychedelic drugs is to shut down activity in this region. This study suggests that those with autism have less available serotonin for binding and thus reduced 5HT2 binding.
Random notes below: Im not done but I have anhedonia on this post sorry. It is also too important so I will keep it public.
Differential effects on heteromers. Or perhaps extreme disconnect from default mode causes dissociative issues in general and thus psychotic symptoms.
Research ratios of D4 and D2 receptors in psychopathology.
D2 and novelty
Fear and addiction
Psychedelics cause Pavlovian fear extinction.